Dani JA


Full name : Dani John A

First name : John A

Mail : Department of Neuroscience, Perelman School of Medicine, University of Pennsylvania, 211 Clincal Research Building, 415 Curie Blvd, Philadelphia, PA 19104

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Country : USA

Email : johndani@pennmedicine.upenn.edu

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Website : \/\/www.med.upenn.edu\/apps\/faculty\/index.php\/g309\/c1604\/p8661661

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References (85)

Title : The medial habenula and interpeduncular nucleus circuitry is critical in addiction, anxiety, and mood regulation - McLaughlin_2017_J.Neurochem_142 Suppl 2_130
Author(s) : McLaughlin I , Dani JA , De Biasi M
Ref : Journal of Neurochemistry , 142 Suppl 2 :130 , 2017
Abstract : Abstinence from chronic use of addictive drugs triggers an aversive withdrawal syndrome that compels relapse and deters abstinence. Many features of this syndrome are common across multiple drugs, involving both affective and physical symptoms. Some of the network signaling underlying withdrawal symptoms overlaps with activity that is associated with aversive mood states, including anxiety and depression. Given these shared features, it is not surprising that a particular circuit, the dorsal diencephalic conduction system, and the medial habenula (MHb) and interpeduncular nucleus (IPN), in particular, have been identified as critical to the emergence of aversive states that arise both as a result and, independently, of drug addiction. As the features of this circuit continue to be characterized, the MHb-IPN axis is emerging as a viable target for therapeutics to aid in the treatment of addiction to multiple drugs of abuse as well as mood-associated disorders. This is an article for the special issue XVth International Symposium on Cholinergic Mechanisms.
ESTHER : McLaughlin_2017_J.Neurochem_142 Suppl 2_130
PubMedSearch : McLaughlin_2017_J.Neurochem_142 Suppl 2_130
PubMedID: 28791703

Title : Dopamine and norepinephrine receptors participate in methylphenidate enhancement of in vivo hippocampal synaptic plasticity - Jenson_2015_Neuropharmacol_90_23
Author(s) : Jenson D , Yang K , Acevedo-Rodriguez A , Levine A , Broussard JI , Tang J , Dani JA
Ref : Neuropharmacology , 90 :23 , 2015
Abstract : Attention-deficit hyperactive disorder (ADHD) is the most commonly studied and diagnosed psychiatric disorder in children. Methylphenidate (MPH, e.g., Ritalin) has been used to treat ADHD for over 50 years. It is the most commonly prescribed treatment for ADHD, and in the past decade it was the drug most commonly prescribed to teenagers. In addition, MPH has become one of the most widely abused drugs on college campuses. In this study, we examined the effects of MPH on hippocampal synaptic plasticity, which serves as a measurable quantification of memory mechanisms. Field potentials were recorded with permanently implanted electrodes in freely-moving mice to quantify MPH modulation of perforant path synaptic transmission onto granule cells of the dentate gyrus. Our hypothesis was that MPH affects hippocampal synaptic plasticity underlying learning because MPH boosts catecholamine signaling by blocking the dopamine and norepinephrine transporters (DAT and NET respectively). In vitro hippocampal slice experiments indicated MPH enhances perforant path plasticity, and this MPH enhancement arose from action via D1-type dopamine receptors and beta-type adrenergic receptors. Similarly, MPH boosted in vivo initiation of long-term potentiation (LTP). While there was an effect via both dopamine and adrenergic receptors in vivo, LTP induction was more dependent on the MPH-induced action via D1-type dopamine receptors. Under biologically reasonable experimental conditions, MPH enhances hippocampal synaptic plasticity via catecholamine receptors.
ESTHER : Jenson_2015_Neuropharmacol_90_23
PubMedSearch : Jenson_2015_Neuropharmacol_90_23
PubMedID: 25445492

Title : Cigarettes and alcohol: The influence of nicotine on operant alcohol self-administration and the mesolimbic dopamine system - Ostroumov_2015_Biochem.Pharmacol_97(4)_550
Author(s) : Ostroumov A , Thomas AM , Dani JA , Doyon WM
Ref : Biochemical Pharmacology , 97 :550 , 2015
Abstract : Studies in human populations consistently demonstrate an interaction between nicotine and ethanol use, each drug influencing the use of the other. Here we present data and review evidence from animal studies that nicotine influences operant self-administration of ethanol. The operant reinforcement paradigm has proven to be a behaviorally relevant and quantitative model for studying ethanol-seeking behavior. Exposure to nicotine can modify the reinforcing properties of ethanol during different phases of ethanol self-administration, including acquisition, maintenance, and reinstatement. Our data suggest that non-daily intermittent nicotine exposure can trigger a long-lasting increase in ethanol self-administration. The biological basis for interactions between nicotine and ethanol is not well understood but may involve the stress hormone systems and adaptations in the mesolimbic dopamine system. Future studies that combine operant self-administration with techniques for monitoring or manipulating in vivo neurophysiology may provide new insights into the neuronal mechanisms that link nicotine and alcohol use.
ESTHER : Ostroumov_2015_Biochem.Pharmacol_97(4)_550
PubMedSearch : Ostroumov_2015_Biochem.Pharmacol_97(4)_550
PubMedID: 26253689

Title : Poster: Nicotine pretreatment alters the responses to ethanol and diazepam via GABAA receptor signaling -
Author(s) : Ostroumov A , Doyon W , Dani JA
Ref : Biochemical Pharmacology , 97 :624 , 2015

Title : Nicotinic acetylcholine receptors as therapeutic targets: Emerging frontiers in basic research and clinical science--Editorial Comments -
Author(s) : Dani JA , Donnelly-Roberts D , Bertrand D
Ref : Biochemical Pharmacology , 97 :351 , 2015
PubMedID: 26074266

Title : Dopamine D1 and D5 receptors modulate spike timing-dependent plasticity at medial perforant path to dentate granule cell synapses - Yang_2014_J.Neurosci_34_15888
Author(s) : Yang K , Dani JA
Ref : Journal of Neuroscience , 34 :15888 , 2014
Abstract : Although evidence suggests that DA modulates hippocampal function, the mechanisms underlying that dopaminergic modulation are largely unknown. Using perforated-patch electrophysiological techniques to maintain the intracellular milieu, we investigated how the activation of D1-type DA receptors regulates spike timing-dependent plasticity (STDP) of the medial perforant path (mPP) synapse onto dentate granule cells. When D1-type receptors were inhibited, a relatively mild STDP protocol induced LTP only within a very narrow timing window between presynaptic stimulation and postsynaptic response. The stimulus protocol produced timing-dependent LTP (tLTP) only when the presynaptic stimulation was followed 30 ms later by depolarization-induced postsynaptic action potentials. That is, the time between presynaptic stimulation and postsynaptic response was 30 ms (Deltat = +30 ms). When D1-type receptors were activated, however, the same mild STDP protocol induced tLTP over a much broader timing window: tLTP was induced when -30 ms </= Deltat </= +30 ms. The result indicated that D1-type receptor activation enabled synaptic potentiation even when postsynaptic activity preceded presynaptic stimulation within this Deltat range. Results with null mice lacking the Kv4.2 potassium channel and with the potassium channel inhibitor, 4-aminopyridine, suggested that D1-type receptors enhanced tLTP induction by suppressing the transient IA-type K(+) current. Results obtained with antagonists and DA receptor knock-out mice indicated that endogenous activity of both D1 and D5 receptors modulated plasticity in the mPP. The DA D5 receptors appeared particularly important in regulating plasticity of the mPP onto the dentate granule cells.
ESTHER : Yang_2014_J.Neurosci_34_15888
PubMedSearch : Yang_2014_J.Neurosci_34_15888
PubMedID: 25429131

Title : Alpha oscillations in response to affective and cigarette-related stimuli in smokers - Cui_2013_Nicotine.Tob.Res_15_917
Author(s) : Cui Y , Versace F , Engelmann JM , Minnix JA , Robinson JD , Lam CY , Karam-Hage M , Brown VL , Wetter DW , Dani JA , Kosten TR , Cinciripini PM
Ref : Nicotine Tob Res , 15 :917 , 2013
Abstract : INTRODUCTION: The presence of cigarette-related cues has been associated with smoking relapse. These cues are believed to activate brain mechanisms underlying emotion, attention, and memory. Electroencephalography (EEG) alpha desynchronization (i.e., reduction in alpha power) has been suggested to index the engagement of these mechanisms. Analyzing EEG alpha desynchronization in response to affective and smoking cues might improve our understanding of how smokers process these cues, and the potential impact of this processing on relapse.
METHODS: Before the start of a medication-assisted cessation attempt, we recorded EEG from 179 smokers during the presentation of neutral, pleasant, unpleasant, and cigarette-related pictures. Wavelet analysis was used to extract EEG alpha oscillations (8-12 Hz) in response to these pictures. Alpha oscillations were analyzed as a function of picture valence and arousal dimensions.
RESULTS: Emotional and cigarette-related stimuli induced a higher level of alpha desynchronization (i.e., less power in the alpha frequency band) than neutral stimuli. In addition, the level of alpha desynchronization induced by cigarette-related stimuli was similar to that induced by highly arousing stimuli (i.e., erotica and mutilations).
CONCLUSIONS: These results suggest that, for smokers, cigarette-related cues are motivationally significant stimuli that may engage emotional, attentional, and memory-related neural mechanisms at a level comparable to that seen in response to highly arousing stimuli. This finding suggests that activation of emotional, attentional, and memory-related brain mechanisms may be an important contributor to cue-induced smoking relapse.
ESTHER : Cui_2013_Nicotine.Tob.Res_15_917
PubMedSearch : Cui_2013_Nicotine.Tob.Res_15_917
PubMedID: 23060019

Title : Mesolimbic dopamine and habenulo-interpeduncular pathways in nicotine withdrawal - Dani_2013_Cold.Spring.Harb.Perspect.Med_3_
Author(s) : Dani JA , De Biasi M
Ref : Cold Spring Harb Perspect Med , 3 : , 2013
Abstract : The majority of people who attempt to quit smoking without some assistance relapse within the first couple of weeks, indicating the increased vulnerability during the early withdrawal period. The habenula, which projects via the fasciculus retroflexus to the interpeduncular nucleus, plays an important role in the withdrawal syndrome. Particularly the alpha2, alpha5, and beta4 subunits of the nicotinic acetylcholine receptor have critical roles in mediating the somatic manifestations of withdrawal. Furthermore, withdrawal from nicotine induces a hypodopaminergic state, but there is a relative increase in the sensitivity to phasic dopamine release that is caused by nicotine. Therefore, acute nicotine re-exposure causes a phasic DA response that more potently reinforces relapse to smoking during the withdrawal period.
ESTHER : Dani_2013_Cold.Spring.Harb.Perspect.Med_3_
PubMedSearch : Dani_2013_Cold.Spring.Harb.Perspect.Med_3_
PubMedID: 23732854

Title : Poster: Nicotine decreases ethanol-induced dopamine signaling and increases ethanol self-administration via stress hormones -
Author(s) : Thomas AM , Doyon WM , Dong Y , Ostroumov A , Zhang TA , Dani JA
Ref : Biochemical Pharmacology , 86 :1235 , 2013

Title : Nicotine decreases ethanol-induced dopamine signaling and increases self-administration via stress hormones - Doyon_2013_Neuron_79_530
Author(s) : Doyon WM , Dong Y , Ostroumov A , Thomas AM , Zhang TA , Dani JA
Ref : Neuron , 79 :530 , 2013
Abstract : Tobacco smoking is a well-known risk factor for subsequent alcohol abuse, but the neural events underlying this risk remain largely unknown. Alcohol and nicotine reinforcement involve common neural circuitry, including the mesolimbic dopamine system. We demonstrate in rodents that pre-exposure to nicotine increases alcohol self-administration and decreases alcohol-induced dopamine responses. The blunted dopamine response was due to increased inhibitory synaptic transmission onto dopamine neurons. Blocking stress hormone receptors prior to nicotine exposure prevented all interactions with alcohol that we measured, including the increased inhibition onto dopamine neurons, the decreased dopamine responses, and the increased alcohol self-administration. These results indicate that nicotine recruits neuroendocrine systems to influence neurotransmission and behavior associated with alcohol reinforcement.
ESTHER : Doyon_2013_Neuron_79_530
PubMedSearch : Doyon_2013_Neuron_79_530
PubMedID: 23871233

Title : Nicotinic acetylcholine receptors as therapeutic targets: emerging frontiers in basic research and clinical science--editorial comments -
Author(s) : Dani JA , Donnelly-Roberts D , Bertrand D
Ref : Biochemical Pharmacology , 86 :1041 , 2013
PubMedID: 23684691

Title : Choline transporter hemizygosity results in diminished basal extracellular dopamine levels in nucleus accumbens and blunts dopamine elevations following cocaine or nicotine - Dong_2013_Biochem.Pharmacol_86(8)_1084
Author(s) : Dong Y , Dani JA , Blakely RD
Ref : Biochemical Pharmacology , 86 :1084 , 2013
Abstract : Dopamine (DA) signaling in the central nervous system mediates the addictive capacities of multiple commonly abused substances, including cocaine, amphetamine, heroin and nicotine. The firing of DA neurons residing in the ventral tegmental area (VTA), and the release of DA by the projections of these neurons in the nucleus accumbens (NAc), is under tight control by cholinergic signaling mediated by nicotinic acetylcholine (ACh) receptors (nAChRs). The capacity for cholinergic signaling is dictated by the availability and activity of the presynaptic, high-affinity, choline transporter (CHT, SLC5A7) that acquires choline in an activity-dependent matter to sustain ACh synthesis. Here, we present evidence that a constitutive loss of CHT expression, mediated by genetic elimination of one copy of the Slc5a7 gene in mice (CHT+/-), leads to a significant reduction in basal extracellular DA levels in the NAc, as measured by in vivo microdialysis. Moreover, CHT heterozygosity results in blunted DA elevations following systemic nicotine or cocaine administration. These findings reinforce a critical role of ACh signaling capacity in both tonic and drug-modulated DA signaling and argue that genetically imposed reductions in CHT that lead to diminished DA signaling may lead to poor responses to reinforcing stimuli, possibly contributing to disorders linked to perturbed cholinergic signaling including depression and attention-deficit hyperactivity disorder (ADHD).
ESTHER : Dong_2013_Biochem.Pharmacol_86(8)_1084
PubMedSearch : Dong_2013_Biochem.Pharmacol_86(8)_1084
PubMedID: 23939187

Title : Potential substrates for nicotine and alcohol interactions: a focus on the mesocorticolimbic dopamine system - Doyon_2013_Biochem.Pharmacol_86(8)_1181
Author(s) : Doyon WM , Thomas AM , Ostroumov A , Dong Y , Dani JA
Ref : Biochemical Pharmacology , 86 :1181 , 2013
Abstract : Epidemiological studies consistently find correlations between nicotine and alcohol use, yet the neural mechanisms underlying their interaction remain largely unknown. Nicotine and alcohol (i.e., ethanol) share many common molecular and cellular targets that provide potential substrates for nicotine-alcohol interactions. These targets for interaction often converge upon the mesocorticolimbic dopamine system, where the link to drug self-administration and reinforcement is well documented. Both nicotine and alcohol activate the mesocorticolimbic dopamine system, producing downstream dopamine signals that promote the drug reinforcement process. While nicotine primarily acts via nicotinic acetylcholine receptors, alcohol acts upon a wider range of receptors and molecular substrates. The complex pharmacological profile of these two drugs generates overlapping responses that ultimately intersect within the mesocorticolimbic dopamine system to promote drug use. Here we will examine overlapping targets between nicotine and alcohol and provide evidence for their interaction. Based on the existing literature, we will also propose some potential targets that have yet to be directly tested. Mechanistic studies that examine nicotine-alcohol interactions would ultimately improve our understanding of the factors that contribute to the associations between nicotine and alcohol use.
ESTHER : Doyon_2013_Biochem.Pharmacol_86(8)_1181
PubMedSearch : Doyon_2013_Biochem.Pharmacol_86(8)_1181
PubMedID: 23876345

Title : Differential cigarette-related startle cue reactivity among light, moderate, and heavy smokers - Cui_2012_Addict.Behav_37_885
Author(s) : Cui Y , Robinson JD , Versace F , Lam CY , Minnix JA , Karam-Hage M , Dani JA , Kosten TR , Wetter DW , Brown VL , Cinciripini PM
Ref : Addict Behav , 37 :885 , 2012
Abstract : In this study, we examined the relationship between the level of daily cigarette consumption and the startle response to affective and cigarette-related cues among treatment-seeking smokers. Before receiving any behavioral or pharmacological treatment, 136 smokers attended a baseline laboratory session, during which we recorded their reflexive eyeblink responses to acoustic startle probes while they were viewing pleasant, unpleasant, neutral, and cigarette-related pictures. We found that 1) cigarette-related and pleasant pictures similarly reduced the startle magnitude compared to neutral pictures; 2) the magnitude of startle modulation rendered by pleasant or unpleasant pictures did not differ among light, moderate, and heavy smokers; and 3) startle attenuation by cigarette-related pictures was greater in heavy smokers than in light smokers. These results suggest that similar to pleasant stimuli, cigarette-related cues are motivationally salient for smokers, and that this salience increases with nicotine dependence.
ESTHER : Cui_2012_Addict.Behav_37_885
PubMedSearch : Cui_2012_Addict.Behav_37_885
PubMedID: 22571920

Title : Withdrawal from chronic nicotine exposure alters dopamine signaling dynamics in the nucleus accumbens - Zhang_2012_Biol.Psychiatry_71_184
Author(s) : Zhang L , Dong Y , Doyon WM , Dani JA
Ref : Biological Psychiatry , 71 :184 , 2012
Abstract : BACKGROUND: Unaided attempts to quit smoking commonly fail during the first 2 weeks of the nicotine withdrawal syndrome. Alterations in dopamine (DA) signaling correlate with withdrawal from chronic nicotine exposure, but those changes have not been well-characterized.
METHODS: Mice were administered nicotine in their drinking water for 4 or 12 weeks. Then nicotine was withheld for 1 to 10 days while DA signaling was characterized with in vivo microdialysis or fast-scan cyclic voltammetry.
RESULTS: Upon withdrawal of nicotine, the basal DA concentration in the nucleus accumbens decreased as measured by microdialysis. The length of time that the low basal DA state lasted depended on the length of the chronic nicotine treatment. Microdialysis indicated that acute re-exposure to nicotine during withdrawal temporarily reversed this hypodopaminergic state. Voltammetry measurements supported the microdialysis results by showing that nicotine withdrawal decreased tonic and phasic DA release. The basal DA concentration and tonic DA signals, however, were disproportionately lower than the phasic DA signals. Therefore, the phasic/tonic DA signaling ratio was increased during the withdrawal period.
CONCLUSIONS: The relative increase in the sensitivity of DA release to phasic stimulation suggests an increase in the signal-to-noise relationship of DA signaling during the withdrawal period. Therefore, the DA signal produced by acute nicotine re-exposure produces a DA response that might reinforce relapse to drug use (i.e., smoking). Because the basal DA concentration is low during withdrawal, therapies aimed at elevating the background DA signal represent a reasonable treatment strategy for nicotine-dependent individuals attempting to quit.
ESTHER : Zhang_2012_Biol.Psychiatry_71_184
PubMedSearch : Zhang_2012_Biol.Psychiatry_71_184
PubMedID: 21872847

Title : Historical and current perspective on tobacco use and nicotine addiction - Dani_2011_Trends.Neurosci_34_383
Author(s) : Dani JA , Balfour DJ
Ref : Trends in Neurosciences , 34 :383 , 2011
Abstract : Although the addictive influence of tobacco was recognized very early, the modern concepts of nicotine addiction have relied on knowledge of cholinergic neurotransmission and nicotinic acetylcholine receptors (nAChRs). The discovery of the 'receptive substance' by Langley, that would turn out to be nAChRs, and 'Vagusstoff' (acetylcholine) by Loewi, coincided with an exciting time when the concept of chemical synaptic transmission was being formulated. More recently, the application of more powerful techniques and the study of animal models that replicate key features of nicotine dependence have led to important advancements in our understanding of molecular, cellular and systems mechanisms of nicotine addiction. In this review, we present a historical perspective and overview of the research that has led to our present understanding of nicotine addiction.
ESTHER : Dani_2011_Trends.Neurosci_34_383
PubMedSearch : Dani_2011_Trends.Neurosci_34_383
PubMedID: 21696833

Title : Neurophysiology of Nicotine Addiction - Dani_2011_J.Addict.Res.Ther_S1_
Author(s) : Dani JA , Jenson D , Broussard JI , De Biasi M
Ref : J Addict Res Ther , S1 : , 2011
Abstract : Tobacco use is a major health problem, and nicotine is the main addictive component. Nicotine binds to nicotinic acetylcholine receptors (nAChR) to produce its initial effects. The nAChRs subtypes are composed of five subunits that can form in numerous combinations with varied functional and pharmacological characteristics. Diverse psychopharmacological effects contribute to the overall process of nicotine addiction, but two general neural systems are emerging as critical for the initiation and maintenance of tobacco use. Mesocorticolimbic circuitry that includes the dopaminergic pathway originating in the ventral tegmental area and projecting to the nucleus accumbens is recognized as vital for reinforcing behaviors during the initiation of nicotine addiction. In this neural system beta2, alpha4, and alpha6 are the most important nAChR subunits underlying the rewarding aspects of nicotine and nicotine self-administration. On the other hand, the epithalamic habenular complex and the interpeduncular nucleus, which are connected via the fasciculus retroflexus, are critical contributors regulating nicotine dosing and withdrawal symptoms. In this case, the alpha5 and beta4 nAChR subunits have critical roles in combination with other subunits. In both of these neural systems, particular nAChR subtypes have roles that contribute to the overall nicotine addiction process.
ESTHER : Dani_2011_J.Addict.Res.Ther_S1_
PubMedSearch : Dani_2011_J.Addict.Res.Ther_S1_
PubMedID: 22454789

Title : Reward, addiction, withdrawal to nicotine - De Biasi_2011_Annu.Rev.Neurosci_34_105
Author(s) : De Biasi M , Dani JA
Ref : Annual Review of Neuroscience , 34 :105 , 2011
Abstract : Nicotine is the principal addictive component that drives continued tobacco use despite users' knowledge of the harmful consequences. The initiation of addiction involves the mesocorticolimbic dopamine system, which contributes to the processing of rewarding sensory stimuli during the overall shaping of successful behaviors. Acting mainly through nicotinic receptors containing the alpha4 and beta2 subunits, often in combination with the alpha6 subunit, nicotine increases the firing rate and the phasic bursts by midbrain dopamine neurons. Neuroadaptations arise during chronic exposure to nicotine, producing an altered brain condition that requires the continued presence of nicotine to be maintained. When nicotine is removed, a withdrawal syndrome develops. The expression of somatic withdrawal symptoms depends mainly on the alpha5, alpha2, and beta4 (and likely alpha3) nicotinic subunits involving the epithalamic habenular complex and its targets. Thus, nicotine taps into diverse neural systems and an array of nicotinic acetylcholine receptor (nAChR) subtypes to influence reward, addiction, and withdrawal.
ESTHER : De Biasi_2011_Annu.Rev.Neurosci_34_105
PubMedSearch : De Biasi_2011_Annu.Rev.Neurosci_34_105
PubMedID: 21438686

Title : Acute in vivo nicotine administration enhances synchrony among dopamine neurons - Li_2011_Biochem.Pharmacol_82(8)_977
Author(s) : Li W , Doyon WM , Dani JA
Ref : Biochemical Pharmacology , 82 :977 , 2011
Abstract : Altered functional interactions among midbrain dopamine (DA) neurons contribute to the reinforcing properties of environmental stimuli and addictive drugs. To examine correlations among DA neurons, acute nicotine was administrated to rats via an intraperitoneal catheter and unit activity was measured using multi-tetrode in vivo recordings. Nicotine administration enhanced the correlated activity of simultaneously recorded DA neurons from the ventral tegmental area (VTA). The strength of the correlations between DA neuron pairs, as measured by cross covariance among two spike trains, showed dynamic changes over time. Nicotine produced a gradual rise in firing rate and burst activity that reached a stable plateau approximately 20 min after the intraperitoneal nicotine infusion. Shortly after that time the cross correlations measured using 5-ms bins increased significantly above baseline. In addition, nicotine increased the firing rates of DA neurons in the posterior VTA more than in the anterior VTA. Unlike nicotine, eticlopride administration also boosted DA neuron firing activity but did not enhance synchronization, indicating that the cross correlations induced by nicotine were not due to a non-specific increase in firing rate. The overall results show that nicotine induces nearly synchronous firing by a subset of DA neurons, and those changes in correlative firing will enhance the DA signal that contributes to nicotine-induced behavioral reinforcement.
ESTHER : Li_2011_Biochem.Pharmacol_82(8)_977
PubMedSearch : Li_2011_Biochem.Pharmacol_82(8)_977
PubMedID: 21684263

Title : Route of nicotine administration influences in vivo dopamine neuron activity: habituation, needle injection, and cannula infusion - Dong_2010_J.Mol.Neurosci_40_164
Author(s) : Dong Y , Zhang T , Li W , Doyon WM , Dani JA
Ref : Journal of Molecular Neuroscience , 40 :164 , 2010
Abstract : Mesolimbic dopamine (DA) systems play a critical role in tobacco addiction driven by nicotine. Nicotine activates midbrain DA neurons and, consequently, elevates DA concentrations in targets, especially in the nucleus accumbens (NAc) of the ventral striatum. The route of drug administration influences the impact of addictive drugs. Here, we examine whether the nature of the administration alters DA neuron activity and DA concentrations in the NAc. Using unhabituated naive freely moving rats, microdialysis measurements showed that nicotine administered via needle injection caused greater DA release in the NAc than the same dose administered via an implanted chronic cannula. After habituation to the needle injections, however, there was no significant difference in DA signaling between the needle and cannula routes of administration. Consistent with these microdialysis results after habituation, our in vivo tetrode unit recordings showed no significant difference in midbrain DA neuron activity in response to nicotine delivered by needle or cannula as long as predictive cues were avoided
ESTHER : Dong_2010_J.Mol.Neurosci_40_164
PubMedSearch : Dong_2010_J.Mol.Neurosci_40_164
PubMedID: 19714495

Title : Addictive nicotine alters local circuit inhibition during the induction of in vivo hippocampal synaptic potentiation - Zhang_2010_J.Neurosci_30_6443
Author(s) : Zhang TA , Tang J , Pidoplichko VI , Dani JA
Ref : Journal of Neuroscience , 30 :6443 , 2010
Abstract : The drug addiction process shares many commonalities with normal learning and memory. Addictive drugs subvert normal synaptic plasticity mechanisms, and the consequent synaptic changes underlie long-lasting modifications in behavior that accrue during the progression from drug use to addiction. Supporting this hypothesis, it was recently shown that nicotine administered to freely moving mice induces long-term synaptic potentiation of the perforant path connection to granule cells of the dentate gyrus. The perforant path carries place and spatial information that links the environment to drug taking. An example of that association is the nicotine-induced synaptic potentiation of the perforant path that was found to underlie nicotine-conditioned place preference. The present study examines the influence of nicotine over local GABAergic inhibition within the dentate gyrus during the drug-induced synaptic potentiation. In vivo recordings from freely moving mice suggested that both feedforward and feedback inhibition onto granules cells were diminished by nicotine during the induction of synaptic potentiation. In vitro brain slice studies indicated that nicotine altered local circuit inhibition within the dentate gyrus leading to disinhibition of granule cells. These changes in local inhibition contributed to nicotine-induced in vivo synaptic potentiation, thus, likely contributed to drug-associated memories. Through this learning process, environmental features become cues that motivate conditioned drug-seeking and drug-taking behaviors.
ESTHER : Zhang_2010_J.Neurosci_30_6443
PubMedSearch : Zhang_2010_J.Neurosci_30_6443
PubMedID: 20445070

Title : Age dependent nicotinic influences over dopamine neuron synaptic plasticity - Placzek_2009_Biochem.Pharmacol_78(7)_686
Author(s) : Placzek AN , Zhang TA , Dani JA
Ref : Biochemical Pharmacology , 78 :686 , 2009
Abstract : The dopamine (DA) system of the ventral midbrain plays a critical role as mammals learn adaptive behaviors driven by environmental salience and reward. Addictive drugs, including nicotine, exert powerful influences over the mesolimbic DA system by activating and desensitizing nicotinic acetylcholine receptors (nAChRs) in a subtype-dependent manner. Nicotine induces synaptic plasticity at excitatory synapses onto DA neurons, thereby sending elevated DA signals that participate during the reinforcement of addictive behaviors. While humans and animals of any developmental age are potentially vulnerable to these drug-induced effects, evidence from clinical and epidemiological studies indicates that adolescents have an increased risk of addiction. Although this risk arises from a complex set of variables including societal and psychosocial influences, a contributing factor involves age dependent sensitivity to addictive drugs. One aspect of that sensitivity is drug-induced synaptic plasticity at excitatory synapses onto the dopamine neurons in the ventral midbrain. A single, acute exposure to addictive drugs, including nicotine, produces long-term potentiation (LTP) that can be quantified by measuring the shift in the subtypes of ionotropic glutamate receptors mediating evoked synaptic transmission. This change in glutamatergic transmission is expressed as an increased ratio of AMPA receptors to NMDA receptors at glutamatergic synapses. Age-related differences in the excitability and the nicotine sensitivity within the midbrain dopamine system may contribute to the greater risk of nicotine addiction in adolescent animals and humans.
ESTHER : Placzek_2009_Biochem.Pharmacol_78(7)_686
PubMedSearch : Placzek_2009_Biochem.Pharmacol_78(7)_686
PubMedID: 19464268

Title : Poster: Nicotine activates a dopamine signal that enables in vivo synaptic plasticity of the kind that underlies associative memory -
Author(s) : Tang J , Dani JA
Ref : Biochemical Pharmacology , 78 :909 , 2009

Title : Dopamine enables in vivo synaptic plasticity associated with the addictive drug nicotine - Tang_2009_Neuron_63_673
Author(s) : Tang J , Dani JA
Ref : Neuron , 63 :673 , 2009
Abstract : Addictive drugs induce a dopamine signal that contributes to the initiation of addiction, and the dopamine signal influences drug-associated memories that perpetuate drug use. The addiction process shares many commonalities with the synaptic plasticity mechanisms normally attributed to learning and memory. Environmental stimuli repeatedly linked to addictive drugs become learned associations, and those stimuli come to elicit memories or sensations that motivate continued drug use. Applying in vivo recording techniques to freely moving mice, we show that physiologically relevant concentrations of the addictive drug nicotine directly cause in vivo hippocampal synaptic potentiation of the kind that underlies learning and memory. The drug-induced long-term synaptic plasticity required a local hippocampal dopamine signal. Disrupting general dopamine signaling prevented the nicotine-induced synaptic plasticity and conditioned place preference. These results suggest that dopaminergic signaling serves as a functional label of salient events by enabling and scaling synaptic plasticity that underlies drug-induced associative memory.
ESTHER : Tang_2009_Neuron_63_673
PubMedSearch : Tang_2009_Neuron_63_673
PubMedID: 19755109

Title : Synaptic plasticity within midbrain dopamine centers contributes to nicotine addiction -
Author(s) : Placzek AN , Dani JA
Ref : Nebr Symp Motiv , 55 :5 , 2009
PubMedID: 19013936

Title : Nicotinic mechanisms influencing synaptic plasticity in the hippocampus - Placzek_2009_Acta.Pharmacol.Sin_30_752
Author(s) : Placzek AN , Zhang TA , Dani JA
Ref : Acta Pharmacol Sin , 30 :752 , 2009
Abstract : Nicotinic acetylcholine receptors (nAChRs) are expressed throughout the hippocampus, and nicotinic signaling plays an important role in neuronal function. In the context of learning and memory related behaviors associated with hippocampal function, a potentially significant feature of nAChR activity is the impact it has on synaptic plasticity. Synaptic plasticity in hippocampal neurons has long been considered a contributing cellular mechanism of learning and memory. These same kinds of cellular mechanisms are a factor in the development of nicotine addiction. Nicotinic signaling has been demonstrated by in vitro studies to affect synaptic plasticity in hippocampal neurons via multiple steps, and the signaling has also been shown to evoke synaptic plasticity in vivo. This review focuses on the nAChRs subtypes that contribute to hippocampal synaptic plasticity at the cellular and circuit level. It also considers nicotinic influences over long-term changes in the hippocampus that may contribute to addiction.
ESTHER : Placzek_2009_Acta.Pharmacol.Sin_30_752
PubMedSearch : Placzek_2009_Acta.Pharmacol.Sin_30_752
PubMedID: 19434057

Title : UBXD4, a UBX-containing protein, regulates the cell surface number and stability of alpha3-containing nicotinic acetylcholine receptors - Rezvani_2009_J.Neurosci_29_6883
Author(s) : Rezvani K , Teng Y , Pan Y , Dani JA , Lindstrom JM , Garcia Gras EA , McIntosh JM , De Biasi M
Ref : Journal of Neuroscience , 29 :6883 , 2009
Abstract : Adaptor proteins are likely to modulate spatially and temporally the trafficking of a number of membrane proteins, including neuronal nicotinic acetylcholine receptors (nAChRs). A yeast two-hybrid screen identified a novel UBX-containing protein, UBXD4, as one of the cytosolic proteins that interact directly with the alpha3 and alpha4 nAChR subunits. The function of UBX-containing proteins is largely unknown. Immunoprecipitation and confocal microscopy confirmed the interaction of UBXD4 with alpha3-containing nAChRs (alpha3* nAChRs) expressed in HEK293 cells, PC12 cells, and rat cortical neurons. Overexpression of UBXD4 in differentiated PC12 cells (dPC12) increased nAChR cell surface expression, especially that of the alpha3beta2 subtype. These findings were corroborated by electrophysiology, immunofluorescent staining, and biotinylation of surface receptors. Silencing of UBXD4 led to a significant reduction of alpha3* nAChRs in rat cortical neurons and dPC12 cells. Biochemical and immunofluorescence studies of endogenous UBXD4 showed that the protein is located in both the ER and cis-Golgi compartments. Our investigations also showed that the alpha3 subunit is ubiquitinated and that UBXD4 can interfere with its ubiquitination and consequent degradation by the proteasome. Our data suggest that UBXD4 modulates the distribution of alpha3* nAChRs between specialized intracellular compartments and the plasma membrane. This effect is achieved by controlling the stability of the alpha3 subunit and, consequently, the number of receptors at the cell surface.
ESTHER : Rezvani_2009_J.Neurosci_29_6883
PubMedSearch : Rezvani_2009_J.Neurosci_29_6883
PubMedID: 19474315

Title : Regulation of synaptic transmission and plasticity by neuronal nicotinic acetylcholine receptors - McKay_2007_Biochem.Pharmacol_74(8)_1120
Author(s) : McKay BE , Placzek AN , Dani JA
Ref : Biochemical Pharmacology , 74 :1120 , 2007
Abstract : Nicotinic acetylcholine receptors (nAChRs) are widely expressed throughout the central nervous system and participate in a variety of physiological functions. Recent advances have revealed roles of nAChRs in the regulation of synaptic transmission and synaptic plasticity, particularly in the hippocampus and midbrain dopamine centers. In general, activation of nAChRs causes membrane depolarization and directly and indirectly increases the intracellular calcium concentration. Thus, when nAChRs are expressed on presynaptic membranes their activation generally increases the probability of neurotransmitter release. When expressed on postsynaptic membranes, nAChR-initiated calcium signals and depolarization activate intracellular signaling mechanisms and gene transcription. Together, the presynaptic and postsynaptic effects of nAChRs generate and facilitate the induction of long-term changes in synaptic transmission. The direction of hippocampal nAChR-mediated synaptic plasticity - either potentiation or depression - depends on the timing of nAChR activation relative to coincident presynaptic and postsynaptic electrical activity, and also depends on the location of cholinergic stimulation within the local network. Therapeutic activation of nAChRs may prove efficacious in the treatment of neuropathologies where synaptic transmission is compromised, as in Alzheimer's or Parkinson's disease.
ESTHER : McKay_2007_Biochem.Pharmacol_74(8)_1120
PubMedSearch : McKay_2007_Biochem.Pharmacol_74(8)_1120
PubMedID: 17689497

Title : Functional polymorphisms in the human beta4 subunit of nicotinic acetylcholine receptors - Liang_2005_Neurogenetics_6_37
Author(s) : Liang Y , Salas R , Marubio L , Bercovich D , De Biasi M , Beaudet AL , Dani JA
Ref : Neurogenetics , 6 :37 , 2005
Abstract : Human nicotinic acetylcholine receptor (nAChR) polymorphisms occur in different ethnic populations and may result in differences in nAChR ion channel properties. We have identified four nAChR beta 4 subunit (beta4) nucleotide variants: 392C-->T, 526C-->T, 538A-->G, and 1519A-->G. Their corresponding amino acid substitutions are: Thr to Ile at codon 91 (T91I), Arg to Trp at codon 136 (R136W), Ser to Gly at codon 140 (S140G), and Met to Val at codon 467 (M467V), respectively. The nAChR ion channel properties of these variants were studied and compared with the more-common (wild-type) allele as wild-types. The nAChRs (alpha4beta4 channels) were expressed heterologously in Xenopus oocytes and studied using the two-electrode voltage clamp technique to reveal functional differences between the wild-type and the variants. The receptors containing the R136W and M467V mutations (or variants) had a higher sensitivity to acetylcholine and lower EC50 than the wild-type. The T91I mutation had lower sensitivity to acetylcholine and the EC50 was larger than in wild-type nAChRs. The S140G mutation had a dose-response relationship that was similar to the wild-type. The T91I, R136W, and M467V mutations (or variants) also showed a slightly greater degree of steady-state desensitization than the wild-type in response to a 30-min exposure to one tenth of their EC50. The present results demonstrate that human beta4 nAChR DNA polymorphisms result in functional changes, and suggest that certain individuals with those variants may be more or less sensitive to cholinergic drugs or to dysfunctions associated with nicotinic cholinergic systems.
ESTHER : Liang_2005_Neurogenetics_6_37
PubMedSearch : Liang_2005_Neurogenetics_6_37
PubMedID: 15742216

Title : Marine alkaloids (-)-pictamine and (-)-lepadin B block neuronal nicotinic acetylcholine receptors - Tsuneki_2005_Biol.Pharm.Bull_28_611
Author(s) : Tsuneki H , You Y , Toyooka N , Sasaoka T , Nemoto H , Dani JA , Kimura I
Ref : Biol Pharm Bull , 28 :611 , 2005
Abstract : Ascidians (sea squirts) contain a wealth of alkaloids, but their influence over neuronal nicotinic acetylcholine receptors (nAChRs) has not been evaluated. In this study, we examined the effects of two synthetic compounds, (-)-pictamine, a quinolizidine alkaloid from Clavelina picta, and (-)-lepadin B, a decahydroquinoline alkaloid from Clavelina lepadiformis, on major types of neuronal nicotinic receptors (alpha4beta2 and alpha7) expressed in Xenopus oocytes. We found that these alkaloids are potent blockers at these receptors: acetylcholine-elicited currents through alpha4beta2 and alpha7 receptors were blocked by (-)-pictamine with IC(50) values of 1.5 microM and 1.3 microM, respectively, and by (-)-lepadin B with IC(50) values of 0.9 microM and 0.7 microM, respectively. Interestingly, no recovery was observed after the removal of (-)-pictamine in oocytes expressing alpha4beta2 receptors, whereas the inhibited alpha7 currents quickly recovered after the removal of (-)-pictamine. Since there are few compounds that elicit irreversible blocks of alpha4beta2 receptors, (-)-pictamine will be a novel, valuable tool to remove the alpha4beta2-nAChR action from neuronal activities mediated by these two major types of nAChRs.
ESTHER : Tsuneki_2005_Biol.Pharm.Bull_28_611
PubMedSearch : Tsuneki_2005_Biol.Pharm.Bull_28_611
PubMedID: 15802796

Title : Nicotinic acetylcholine receptors at glutamate synapses facilitate long-term depression or potentiation - Ge_2005_J.Neurosci_25_6084
Author(s) : Ge S , Dani JA
Ref : Journal of Neuroscience , 25 :6084 , 2005
Abstract : The hippocampus is a center for learning and memory that receives abundant cholinergic innervation and richly expresses nicotinic acetylcholine receptors (nAChRs). Nicotinic mechanisms acting on the hippocampus influence attention, learning, and memory. During Alzheimer's dementia, nAChRs and cholinergic innervation decline in the hippocampus. Using mouse hippocampal slices, we examined the potential diversity of nAChR influences at the Schaffer collateral synapse onto CA1 pyramidal neurons. When nAChR currents were elicited locally at those excitatory synapses, various outcomes were possible depending on the relationship between the nAChR-mediated excitation and mild electrical stimulation. When mild presynaptic stimulation coincided with or preceded nAChR-induced action potentials by 1-5 s, then long-term potentiation was induced. However, if the nAChR-induced action potentials fell within 1 s before the electrical stimulation, then long-term depression resulted. Outside of these time frames, the mismatch of nAChR activity and stimulation led to short-term potentiation. The results indicate that nAChRs may have various influences over excitatory events in the hippocampus. Ongoing nAChR activity likely modulates the impact of glutamate transmission and alters the probabilities for various forms of synaptic plasticity. The fine network of cholinergic fibers running through the hippocampus forms synaptic contacts onto pyramidal cells, granule cells, and interneurons, ensuring continual modulatory influence by nicotinic mechanisms throughout the hippocampal complex. Disruption of events such as those described here may contribute to the deficits associated with the decline of nicotinic cholinergic functions during degenerative diseases such as Alzheimer's dementia.
ESTHER : Ge_2005_J.Neurosci_25_6084
PubMedSearch : Ge_2005_J.Neurosci_25_6084
PubMedID: 15987938

Title : Cholinergic drugs for Alzheimer's disease enhance in vitro dopamine release - Zhang_2004_Mol.Pharmacol_66_538
Author(s) : Zhang L , Zhou FM , Dani JA
Ref : Molecular Pharmacology , 66 :538 , 2004
Abstract : Alzheimer's disease is a neurodegenerative disorder associated with a decline in cognitive abilities. Patients also frequently have noncognitive symptoms, such as anxiety, depression, apathy, and psychosis, that impair daily living. The most commonly prescribed treatments for Alzheimer's disease are acetylcholinesterase inhibitors, such as donepezil and galantamine. Enhanced cholinergic functions caused by these compounds are believed to underlie improvements in learning, memory, and attention. The noncognitive aspects of dementia, however, are usually linked to serotonin and dopamine rather than acetylcholine because those neurotransmitter systems most directly influence mood, emotional balance, and psychosis. Fast-scan cyclic voltammetry applied to mouse striatal brain slices was used to measure the real-time release of dopamine arising from spontaneous activity or from single electrical stimulations. At concentrations that include their prescribed dosage ranges, donepezil (1-1000 nM) and galantamine (50-1000 nM) increase action potential-dependent dopamine release. Consistent with previous literature, the data support slightly different modes of action for donepezil and galantamine. The ability of these commonly prescribed drugs to alter catecholamine release may underlie their influence over noncognitive symptoms of dementia. Furthermore, these results suggest that acting via nicotinic receptors, these drugs may serve presently untapped therapeutic roles by altering dopamine release in other disorders involving dopaminergic systems.
ESTHER : Zhang_2004_Mol.Pharmacol_66_538
PubMedSearch : Zhang_2004_Mol.Pharmacol_66_538
PubMedID: 15322245

Title : Potential applications of nicotinic ligands in the laboratory and clinic - Dani_2004_Bioorg.Med.Chem.Lett_14_1837
Author(s) : Dani JA , De Biasi M , Liang Y , Peterson J , Zhang L , Zhang T , Zhou FM
Ref : Bioorganic & Medicinal Chemistry Lett , 14 :1837 , 2004
Abstract : The nicotinic acetylcholine receptor (nAChR) is a receptor, ion channel complex composed of five polypeptide subunits. There are many different nAChR subtypes constructed from a variety of different subunit combinations. This structural diversity contributes to the varied roles of nAChRs in the peripheral and central nervous system, and this diversity offers an excellent opportunity for chemists who are producing ligands. Subunit specific ligands could have wide and varied effects in the laboratory as experimental tools and in the clinic as therapeutic agents. Because presynaptic nAChRs have been shown to enhance the release of many neurotransmitters, new nicotinic ligands that potentiate nAChR activity would be very useful. Such ligands could enhance the release of various neurotransmitters during degenerative diseases that cause neurotransmitter systems to decrease their output. For example, boosting the release from cholinergic neurons would help patients with Alzheimer's disease, and boosting the release from dopaminergic neurons would help patients with Parkinson's disease.
ESTHER : Dani_2004_Bioorg.Med.Chem.Lett_14_1837
PubMedSearch : Dani_2004_Bioorg.Med.Chem.Lett_14_1837
PubMedID: 15050611

Title : Nicotinic cholinergic synaptic mechanisms in the ventral tegmental area contribute to nicotine addiction - Pidoplichko_2004_Learn.Mem_11_60
Author(s) : Pidoplichko VI , Noguchi J , Areola OO , Liang Y , Peterson J , Zhang T , Dani JA
Ref : Learn Mem , 11 :60 , 2004
Abstract : Tobacco use is a major health problem that is estimated to cause 4 million deaths a year worldwide. Nicotine is the main addictive component of tobacco. It acts as an agonist to activate and desensitize nicotinic acetylcholine receptors (nAChRs). A component of nicotine's addictive power is attributable to actions on the mesolimbic dopaminergic system, which serves a fundamental role in the acquisition of behaviors that are inappropriately reinforced by addictive drugs. Here we show that nicotine, in the same concentration and time ranges as obtained from tobacco, has three main actions that regulate the activity of midbrain dopamine (DA) neurons. Nicotine first activates and then desensitizes nAChRs on the DA neurons. This process directly excites the DA neurons for a short period of time before the nAChRs desensitize. Nicotine also enhances glutamatergic excitation and decreases GABAergic inhibition onto DA neurons. These events increase the probability for synaptic plasticity, such as long-term potentiation. The short-lived direct excitation of the DA neurons coupled with the enhanced glutamatergic afferent activity provides the presynaptic and postsynaptic coincidence necessary to initiate synaptic potentiation. In total, these synaptic events lead to a relatively long-lasting heightened activity of midbrain DA neurons. Consistent with other summarized studies, this work indicates that the synaptic changes normally associated with learning and memory can be influenced and commandeered during the nicotine addiction process.
ESTHER : Pidoplichko_2004_Learn.Mem_11_60
PubMedSearch : Pidoplichko_2004_Learn.Mem_11_60
PubMedID: 14747518

Title : Alkaloids indolizidine 235B', quinolizidine 1-epi-207I, and the tricyclic 205B are potent and selective noncompetitive inhibitors of nicotinic acetylcholine receptors - Tsuneki_2004_Mol.Pharmacol_66_1061
Author(s) : Tsuneki H , You Y , Toyooka N , Kagawa S , Kobayashi S , Sasaoka T , Nemoto H , Kimura I , Dani JA
Ref : Molecular Pharmacology , 66 :1061 , 2004
Abstract : Nicotinic acetylcholine receptors are key molecules in cholinergic transmission in the nervous system. Because of their structural complexity, only a limited number of subtype-specific agonists and antagonists are available to study nicotinic receptor functions. To overcome this limitation, we used voltageclamp recordings to examine the effects of several frog skin alkaloids on acetylcholine-elicited currents in Xenopus laevis oocytes expressing major types of neuronal nicotinic receptors (alpha4beta2, alpha7, alpha3beta2, alpha3beta4, and alpha4beta4). We found that the 5,8-disubstituted indolizidine (-)-235B' acted as a potent noncompetitive blocker of alpha4beta2 nicotinic receptors (IC50 = 74 nM). This effect was highly selective for alpha4beta2 receptors compared with alpha3beta2, alpha3beta4, and alpha4beta4 receptors. The inhibition of alpha4beta2 currents by (-)-235B' was more pronounced as the acetylcholine concentration increased (from 10 nM to 100 microM). Moreover, the blockade of alpha4beta2 currents by (-)-235B' was voltage-dependent (more pronounced at hyperpolarized potentials) and use-dependent, indicating that (-)-235B' behaves as an open-channel blocker of this receptor. Several other 5,8-disubstituted indolizidines (5-n-propyl-8-n-butylindolizidines), two 5,6,8-trisubstituted indolizidines ((-)-223A and (+)-6-epi-223A), and a 1,4-disubstituted quinolizidine ((+)-207I) were less potent than (-)-235B', and none showed selectivity for alpha4beta2 receptors. The quinolizidine (-)-1-epi-207I and the tricyclic (+)-205B had 8.7- and 5.4-fold higher sensitivity, respectively, for inhibition of the alpha7 nicotinic receptor than for inhibition of the alpha4beta2 receptor. These results show that frog alkaloids alter the function of nicotinic receptors in a subtype-selective manner, suggesting that an analysis of these alkaloids may aid in the development of selective drugs to alter nicotinic cholinergic functions.
ESTHER : Tsuneki_2004_Mol.Pharmacol_66_1061
PubMedSearch : Tsuneki_2004_Mol.Pharmacol_66_1061
PubMedID: 15258256

Title : Altered anxiety-related responses in mutant mice lacking the beta4 subunit of the nicotinic receptor - Salas_2003_J.Neurosci_23_6255
Author(s) : Salas R , Pieri F , Fung B , Dani JA , De Biasi M
Ref : Journal of Neuroscience , 23 :6255 , 2003
Abstract : Nicotine, acting at nicotinic acetylcholine receptors (nAChRs), is the primary addictive component of tobacco. Smokers often report an anxiolytic effect of cigarettes. This relief of anxiety, attributed to nicotine, is an important contributor to relapse when smokers try to quit. Hence, the study of the anxiolytic effects of nicotine is important for understanding the mechanisms underlying nicotine addiction. Mammalian nAChRs are pentameric ion channels usually composed of alpha andbeta subunits. Taking advantage of beta4-homozygous-null mice (beta4-/-), we examined the role of the nAChR beta4 subunit in anxiety-related behaviors. The beta4-/- mice behaved as though they were less anxious than wild-type littermates on the elevated-plus and staircase mazes, tests that measure anxiety-related behaviors. To obtain an independent, physiological indication of the stress produced by several tests, we measured changes in heart rate using telemetry. Consistently with the behavioral phenotype, beta4-/- mice had a smaller heart rate increase in the elevated-plus maze than did wild-type littermates. In contrast, during social isolation, a separate test for anxiety,beta4-/- mice exhibited a greater increase in heart rate than did wild-type littermates. Finally, beta4-/- mice were indistinguishable from their wild-type littermates in the open field, the light/dark box, and the mirrored chamber. The overall results demonstrate that beta4-containing (beta4*) nAChRs influence behavioral responses during anxiety-related tests, and that this effect depends on the type of anxiety-provoking experience. Through their influence on anxiety-related behavior, beta4* nAChRs might influence both tobacco consumption and smoking relapse.
ESTHER : Salas_2003_J.Neurosci_23_6255
PubMedSearch : Salas_2003_J.Neurosci_23_6255
PubMedID: 12867510

Title : Roles of dopamine signaling in nicotine addiction -
Author(s) : Dani JA
Ref : Mol Psychiatry , 8 :255 , 2003
PubMedID: 12660795

Title : Differential desensitization and distribution of nicotinic acetylcholine receptor subtypes in midbrain dopamine areas - Wooltorton_2003_J.Neurosci_23_3176
Author(s) : Wooltorton JR , Pidoplichko VI , Broide RS , Dani JA
Ref : Journal of Neuroscience , 23 :3176 , 2003
Abstract : Although many psychopharmacological factors contribute to nicotine addiction, midbrain dopaminergic systems have received much attention because of their roles in reinforcement and associative learning. It is generally thought that the mesocorticolimbic dopaminergic system is important for the acquisition of behaviors that are reinforced by the salient drives of the environment or by the inappropriate stimuli of addictive drugs. Nicotine, as obtained from tobacco, can activate nicotinic acetylcholine receptors (nAChRs) and excite midbrain neurons of the mesocorticolimbic system. Using midbrain slices from rats, wild-type mice, and genetically engineered mice, we have found differences in the nAChR currents from the ventral tegmental area (VTA) and the substantia nigra compacta (SNc). Nicotinic AChRs containing the alpha7 subunit (alpha7* nAChRs) have a low expression density. Electrophysiological analysis of nAChR currents, autoradiography of [125I]-alpha-bungarotoxin binding, and in situ hybridization revealed that alpha7* nAChRs are more highly expressed in the VTA than the SNc. In contrast, beta2* nAChRs are move evenly distributed at a higher density in both the VTA and SNc. At the concentration of nicotine obtained by tobacco smokers, the slow components of current (mainly mediated by beta2* nAChRs) become essentially desensitized. However, the minority alpha7* component of the current in the VTA/SNc is not significantly desensitized by nicotine in the range < or =100 nm. These results suggest that nicotine, as obtained from tobacco, can have multiple effects on the midbrain areas by differentially influencing dopamine neurons of the VTA and SNc and differentially desensitizing alpha7* and non-alpha7 nAChRs.
ESTHER : Wooltorton_2003_J.Neurosci_23_3176
PubMedSearch : Wooltorton_2003_J.Neurosci_23_3176
PubMedID: 12716925

Title : Mouse muscle denervation increases expression of an alpha7 nicotinic receptor with unusual pharmacology - Tsuneki_2003_J.Physiol_547_169
Author(s) : Tsuneki H , Salas R , Dani JA
Ref : Journal of Physiology , 547 :169 , 2003
Abstract : Neuronal nicotinic alpha7 subunits have been found in chick and rat skeletal muscle during development and denervation. In the present study, reverse transcriptase-polymerase chain reaction was used to detect alpha7 subunit mRNA in denervated mouse muscle. To determine whether the alpha7 subunit forms functional nicotinic acetylcholine receptors (nAChRs) in muscle, choline was used to induce a membrane depolarization because choline has been considered a specific agonist of alpha7-containing (alpha7*) nAChRs. We found, however, that choline (3-10 mM) also weakly activates muscle nAChRs. After inhibiting muscle nAChRs with a specific muscle nAChR inhibitor, alpha-conotoxin GI (alphaCTxGI), choline was used to activate the alpha7* nAChRs on muscle selectively. Four weeks after denervation, rapid application of choline (10 mM) elicited a substantial depolarization in the presence of alphaCTxGI (0.1 microM). This component of the depolarization was never present in denervated muscles obtained from mutant mice lacking the alpha7 subunit (i.e. alpha7-null mice). The depolarization component that is resistant to alphaCTxGI was antagonized by pancuronium (3-10 microM) and by a 4-oxystilbene derivative (F3, 0.1-0.5 microM) at concentrations considered highly specific for alpha7* nAChRs. Another selective alpha7 antagonist, methyllycaconitine (0.05-5 microM), did not strongly inhibit this choline-induced depolarization. Furthermore, the choline-sensitive nAChRs showed little desensitization over 10 s of application with choline (10-30 mM). These results indicate that functional alpha7* nAChRs are significantly present on denervated muscle, and that these receptors display unusual functional and pharmacological characteristics.
ESTHER : Tsuneki_2003_J.Physiol_547_169
PubMedSearch : Tsuneki_2003_J.Physiol_547_169
PubMedID: 12562921

Title : Muscarinic and nicotinic cholinergic mechanisms in the mesostriatal dopamine systems - Zhou_2003_Neuroscientist_9_23
Author(s) : Zhou FM , Wilson C , Dani JA
Ref : Neuroscientist , 9 :23 , 2003
Abstract : The striatum and its dense dopaminergic innervation originating in the midbrain, primarily from the substantia nigra pars compacta and the ventral tegmental area, compose the mesostriatal dopamine (DA) systems. The nigrostriatal system is involved mainly in motor coordination and in disorders such as Tourette's syndrome, Huntington's disease, and Parkinson's disease. The dopaminergic projections from the ventral tegmental area to the striatum participate more in the processes that shape behaviors leading to reward, and addictive drugs act upon this mesolimbic system. The midbrain DA areas receive cholinergic innervation from the pedunculopontine tegmentum and the laterodorsal pontine tegmentum, whereas the striatum receives dense cholinergic innervation from local interneurons. The various neurons of the mesostriatal systems express multiple types of muscarinic and nicotinic acetylcholine receptors as well as DA receptors. Especially in the striatum, the dense mingling of dopaminergic and cholinergic constituents enables potent interactions. Evidence indicates that cholinergic and dopaminergic systems work together to produce the coordinated functioning of the striatum. Loss of that cooperative activity contributes to the dysfunction underlying Parkinson's disease.
ESTHER : Zhou_2003_Neuroscientist_9_23
PubMedSearch : Zhou_2003_Neuroscientist_9_23
PubMedID: 12580337

Title : Increased sensitivity to nicotine-induced seizures in mice expressing the L250T alpha 7 nicotinic acetylcholine receptor mutation - Broide_2002_Mol.Pharmacol_61_695
Author(s) : Broide RS , Salas R , Ji D , Paylor R , Patrick JW , Dani JA , De Biasi M
Ref : Molecular Pharmacology , 61 :695 , 2002
Abstract : High doses of nicotine, the addictive component of tobacco, induce clonic-tonic seizures in animals. Pharmacological and biochemical data have suggested that alpha 7-containing neuronal nicotinic receptors (nAChRs) contribute to these seizures. To study potential alpha 7 contributions, we examined alpha 7 subunits with a Leu250-to-Thr substitution in the channel domain, which creates a gain-of-function mutation. Previous studies have shown that mice homozygous for the alpha 7 L250T mutation (T/T) die shortly after birth, but animals heterozygous for the mutation (+/T) are viable and grow to adulthood. Hippocampal neurons from the +/T mice exhibited altered alpha 7-type currents with increased amplitudes and slower desensitization kinetics, confirming a partial gain of function for the alpha 7 nAChR. We found that +/T mice were more sensitive to the convulsant effects of nicotine compared with their wild-type (+/+) littermates. Furthermore, although their behavior was normal in basal conditions, +/T mice showed a unique nicotine-induced phenotype, consisting of head-bobbing and paw-tapping movements. Increased sensitivity to nicotine-induced seizures occurred despite a 60% decline in brain alpha 7 nAChR protein levels. There were no changes in the levels of alpha 4, alpha 5, alpha 6, alpha 7, beta 2, and beta 4 mRNA, or in [(125)I]epibatidine and [(3)H]nicotine binding between +/T and +/+ mice. Recent data from our laboratory show that alpha 7-null mice maintain normal sensitivity to nicotine-induced seizures. Hence, these present findings suggest that alterations in the properties rather than absence of alpha 7 nAChRs might affect the mechanisms underlying the convulsive properties of nicotine.
ESTHER : Broide_2002_Mol.Pharmacol_61_695
PubMedSearch : Broide_2002_Mol.Pharmacol_61_695
PubMedID: 11854451

Title : Cholinergic interneuron characteristics and nicotinic properties in the striatum - Zhou_2002_J.Neurobiol_53_590
Author(s) : Zhou FM , Wilson CJ , Dani JA
Ref : Journal of Neurobiology , 53 :590 , 2002
Abstract : The neostriatum (dorsal striatum) is composed of the caudate and putamen. The ventral striatum is the ventral conjunction of the caudate and putamen that merges into and includes the nucleus accumbens and striatal portions of the olfactory tubercle. About 2% of the striatal neurons are cholinergic. Most cholinergic neurons in the central nervous system make diffuse projections that sparsely innervate relatively broad areas. In the striatum, however, the cholinergic neurons are interneurons that provide very dense local innervation. The cholinergic interneurons provide an ongoing acetylcholine (ACh) signal by firing action potentials tonically at about 5 Hz. A high concentration of acetylcholinesterase in the striatum rapidly terminates the ACh signal, and thereby minimizes desensitization of nicotinic acetylcholine receptors. Among the many muscarinic and nicotinic striatal mechanisms, the ongoing nicotinic activity potently enhances dopamine release. This process is among those in the striatum that link the two extensive and dense local arbors of the cholinergic interneurons and dopaminergic afferent fibers. During a conditioned motor task, cholinergic interneurons respond with a pause in their tonic firing. It is reasonable to hypothesize that this pause in the cholinergic activity alters action potential dependent dopamine release. The correlated response of these two broad and dense neurotransmitter systems helps to coordinate the output of the striatum, and is likely to be an important process in sensorimotor planning and learning.
ESTHER : Zhou_2002_J.Neurobiol_53_590
PubMedSearch : Zhou_2002_J.Neurobiol_53_590
PubMedID: 12436423

Title : Nicotinic receptor activity alters synaptic plasticity -
Author(s) : Dani JA
Ref : ScientificWorldJournal , 1 :393 , 2001
PubMedID: 12806076

Title : Overview of nicotinic receptors and their roles in the central nervous system - Dani_2001_Biol.Psychiatry_49_166
Author(s) : Dani JA
Ref : Biological Psychiatry , 49 :166 , 2001
Abstract : Alzheimer's disease is a complex disorder affecting multiple neurotransmitters. In particular, the degenerative progression is associated with loss within the cholinergic systems. It should be anticipated that both muscarinic and nicotinic mechanisms are affected as cholinergic neurons are lost. This review focuses on the basic roles of neuronal nicotinic receptors, some subtypes of which decrease during Alzheimer's disease. Nicotinic acetylcholine receptors belong to a superfamily of ligand-gated ion channels that play key roles in synaptic transmission throughout the central nervous system. Neuronal nicotinic receptors, however, are not a single entity, but rather there are many different subtypes constructed from a variety of nicotinic subunit combinations. This structural diversity and the presynaptic, axonal, and postsynaptic locations of nicotinic receptors contribute to the varied roles these receptors play in the central nervous system. Presynaptic and preterminal nicotinic receptors enhance neurotransmitter release, and postsynaptic nicotinic receptors mediate a small minority of fast excitatory transmission. In addition, some nicotinic receptor subtypes have roles in synaptic plasticity and development. Nicotinic receptors are distributed to influence many neurotransmitter systems at more than one location, and the broad, but sparse, cholinergic innervation throughout the brain ensures that nicotinic acetylcholine receptors are important modulators of neuronal excitability.
ESTHER : Dani_2001_Biol.Psychiatry_49_166
PubMedSearch : Dani_2001_Biol.Psychiatry_49_166
PubMedID: 11230867

Title : Cellular mechanisms of nicotine addiction - Dani_2001_Pharmacol.Biochem.Behav_70_439
Author(s) : Dani JA , De Biasi M
Ref : Pharmacol Biochem Behav , 70 :439 , 2001
Abstract : In developed countries, tobacco use is estimated to be the largest single cause of premature death [Lancet 339 (1992) 1268]. Nicotine is the main addictive component of tobacco that motivates continued use despite the harmful effects. Nicotinic acetylcholine receptors (nAChRs) are widely distributed throughout the mammalian central nervous system (CNS), where they normally respond to acetylcholine (ACh) and modulate neuronal excitability and synaptic communication. Nicotinic receptors are structurally diverse and have varied roles. Presynaptic and preterminal nAChRs enhance neurotransmitter release. Postsynaptic and somal nAChRs mediate a small proportion of fast excitatory transmission and modulate cytoplasmic second messenger systems. Although the impact of nicotine obtained from tobacco is not completely understood, a portion of nicotine's addictive power is attributable to actions upon the dopaminergic systems, which normally help to reinforce rewarding behaviors. As obtained from tobacco, nicotine activates and desensitizes nAChRs, and both processes contribute to the cellular events that underlie nicotine addiction.
ESTHER : Dani_2001_Pharmacol.Biochem.Behav_70_439
PubMedSearch : Dani_2001_Pharmacol.Biochem.Behav_70_439
PubMedID: 11796143

Title : Synaptic plasticity and nicotine addiction - Dani_2001_Neuron_31_349
Author(s) : Dani JA , Ji D , Zhou FM
Ref : Neuron , 31 :349 , 2001
Abstract : Nicotine, the main addictive component of tobacco, activates and desensitizes nicotinic acetylcholine receptors (nAChRs). In that way, nicotine alters normal nicotinic cholinergic functions. Among the myriad of psychopharmacological effects that underlie the addiction process, nicotine influences nAChR participation in synaptic plasticity. This influence has particular importance in the mesocorticolimbic dopamine system, which serves during the reinforcement of rewarding behaviors.
ESTHER : Dani_2001_Neuron_31_349
PubMedSearch : Dani_2001_Neuron_31_349
PubMedID: 11516393

Title : Endogenous nicotinic cholinergic activity regulates dopamine release in the striatum - Zhou_2001_Nat.Neurosci_4_1224
Author(s) : Zhou FM , Liang Y , Dani JA
Ref : Nat Neurosci , 4 :1224 , 2001
Abstract : Dopamine is vital for coordinated motion and for association learning linked to behavioral reinforcement. Here we show that the precise overlap of striatal dopaminergic and cholinergic fibers underlies potent control of dopamine release by ongoing nicotinic receptor activity. In mouse striatal slices, nicotinic antagonists or depletion of endogenous acetylcholine decreased evoked dopamine release by 90%. Nicotine at the concentration experienced by smokers also regulated dopamine release. In mutant mice lacking the beta2 nicotinic subunit, evoked dopamine release was dramatically suppressed, and those mice did not show cholinergic regulation of dopamine release. The results offer new perspectives when considering nicotine addiction and the high prevalence of smoking in schizophrenics.
ESTHER : Zhou_2001_Nat.Neurosci_4_1224
PubMedSearch : Zhou_2001_Nat.Neurosci_4_1224
PubMedID: 11713470

Title : Timing and location of nicotinic activity enhances or depresses hippocampal synaptic plasticity - Ji_2001_Neuron_31_131
Author(s) : Ji D , Lape R , Dani JA
Ref : Neuron , 31 :131 , 2001
Abstract : This study reveals mechanisms in the mouse hippocampus that may underlie nicotinic influences on attention, memory, and cognition. Induction of synaptic plasticity, arising via generally accepted mechanisms, is modulated by nicotinic acetylcholine receptors. Properly timed nicotinic activity at pyramidal neurons boosted the induction of long-term potentiation via presynaptic and postsynaptic pathways. On the other hand, nicotinic activity on interneurons inhibited nearby pyramidal neurons and thereby prevented or diminished the induction of synaptic potentiation. The synaptic modulation was dependent on the location and timing of the nicotinic activity. Loss of these synaptic mechanisms may contribute to the cognitive deficits experienced during Alzheimer's diseases, which is associated with a loss of cholinergic projections and with a decrease in the number of nicotinic receptors.
ESTHER : Ji_2001_Neuron_31_131
PubMedSearch : Ji_2001_Neuron_31_131
PubMedID: 11498056

Title : Properties underlying the influence of nicotinic receptors on neuronal excitability and epilepsy - Dani_2000_Epilepsia_41_1063
Author(s) : Dani JA
Ref : Epilepsia , 41 :1063 , 2000
Abstract : The great diversity of neuronal nAChRs equips them for many roles. The broad, diffuse projections of the cholinergic system and their influence on multiple neurotransmitter systems enable nAChRs to have a wide modulatory influence on excitability on multiple time scales. Both excitatory and inhibitory synapses are directly modulated by nAChR activity. Although fast nicotinic transmission is not a major excitatory drive, it may alter the excitability of many synapses at one time. Depending on the neural area and stage of development, nAChRs of multiple subtypes will have varying degrees of importance in regulating neuronal excitability.
ESTHER : Dani_2000_Epilepsia_41_1063
PubMedSearch : Dani_2000_Epilepsia_41_1063
PubMedID: 10961642

Title : Variations in desensitization of nicotinic acetylcholine receptors from hippocampus and midbrain dopamine areas - Dani_2000_Eur.J.Pharmacol_393_31
Author(s) : Dani JA , Radcliffe KA , Pidoplichko VI
Ref : European Journal of Pharmacology , 393 :31 , 2000
Abstract : This study addresses two issues arising from the desensitization of nicotinic acetylcholine receptors from the hippocampus, ventral tegmental area, and substantia nigra. First, biophysical studies can find potent and complete desensitization of nicotinic receptors; but in vivo studies often find that desensitization affecting a behavior is less than complete, or that desensitization is important over a different nicotine concentration range. Our results show that there can be significant differences in desensitization when comparing nearby neurons from the same area of the brain. Thus, nicotinic receptors on a minority of neurons may remain active and maintain a behavior under conditions that can produce significant desensitization. Second, agonist applications that are intended to active nicotinic receptors also cause desensitization. The prevailing conditions and the rate of agonist application and removal will control the degree of activation vs. desensitization. These and other factors regulate the efficacy of nicotinic agonists experimentally and physiologically.
ESTHER : Dani_2000_Eur.J.Pharmacol_393_31
PubMedSearch : Dani_2000_Eur.J.Pharmacol_393_31
PubMedID: 10770995

Title : Mice homozygous for the L250T mutation in the alpha7 nicotinic acetylcholine receptor show increased neuronal apoptosis and die within 1 day of birth - Orr-Urtreger_2000_J.Neurochem_74_2154
Author(s) : Orr-Urtreger A , Broide RS , Kasten MR , Dang H , Dani JA , Beaudet AL , Patrick JW
Ref : Journal of Neurochemistry , 74 :2154 , 2000
Abstract : The alpha7 nicotinic acetylcholine receptor (nAChR) has been implicated in modulating neurotransmitter release and may play a role in the regulation of neuronal growth and differentiation. A threonine for leucine 247 substitution in the channel domain of the chick alpha7 nAChR increases agonist affinity and decreases the rate of desensitization, creating a "gain of function" model for this receptor. We have generated mice that express the analogous mutation (L250T) in the alpha7 nAChR using the techniques of homologous recombination and here report their characteristics. Mice heterozygous (+/T) for the L250T mutation are viable, fertile, and anatomically normal compared with wild-type littermates. In contrast, homozygous (T/T) L250T mice die within 2-24 h of birth. Brains of T/T mouse pups exhibit a marked reduction in alpha7 nAChR protein levels and show extensive apoptotic cell death throughout the somatosensory cortex. Furthermore, alpha7 L250T nAChRs are functionally expressed on neurons within the brains of T/T neonatal mice and have properties that are consistent with those observed for the rat alpha7 L250T and the chick alpha7 L247T mutant nAChRs expressed in oocytes. These findings indicate that neurons in the developing brain expressing only alpha7 L250T mutant nAChRs are susceptible to abnormal apoptosis, possibly due to increased Ca2+ influx.
ESTHER : Orr-Urtreger_2000_J.Neurochem_74_2154
PubMedSearch : Orr-Urtreger_2000_J.Neurochem_74_2154
PubMedID: 10800961

Title : Regulation of the sensitivity of acetylcholine receptors to nicotine in rat habenula neurons - Hicks_2000_J.Physiol_529 Pt 3_579
Author(s) : Hicks JH , Dani JA , Lester RA
Ref : Journal of Physiology , 529 Pt 3 :579 , 2000
Abstract : Time-dependent changes in nicotinic acetylcholine receptor (nAChR) function were studied in acutely isolated medial habenula neurons during whole-cell perfusion. The peak amplitude of inward currents induced by 1 s pulses of nicotinic agonists, applied at 30 s intervals, gradually increased over the first several minutes of whole-cell recording. The ratio of response amplitudes at 1 and 15 min (t15/t1) was 1.9. Run-up of responses occurred independently of channel activation and was specific to nAChRs. The channel blocker chlorisondamine (30 microM), co-applied with nicotine, was used to irreversibly block the majority (91 %) of the nAChRs that opened in the first 2 min of recording. Run-up in the remaining 9 % unblocked channels assessed at 15 min (t15/t2 = 3.4) was similar to that in control cells not exposed to nicotine and chlorisondamine simultaneously, implying that run-up is not due to the incorporation of new receptors. A marked alteration in the sensitivity of nAChRs to extracellular Ca2+ was also observed during whole-cell perfusion. The ratio of current amplitudes obtained in 0.2 and 4.0 mM Ca2+ changed from 0.54 (t = 5 min) to 0.82 (t = 30 min). Inward rectification of nicotine-induced responses was reduced during internal dialysis. Voltages for half-maximal conductance were -23.0 and -13.8 mV at 2 and 15 min, respectively. Inclusion of either free Mg2+ ( approximately 2 mM) or spermine (100 microM) in the internal solution counteracted the change in rectification, but did not prevent run-up. The period of run-up was followed by a use-dependent run-down phase. Little run-down in peak current amplitude was induced provided that agonist was applied infrequently (5 min intervals), whereas applications at 30 s intervals produced a loss of channel function after approximately 15 min whole-cell perfusion. The time at which run-down began ( approximately 5-30 min) was correlated with the initial rate of nAChR desensitization ( approximately 200-4000 ms); slowly desensitizing nicotinic currents demonstrated delayed run-down. We suggest that run-up of nAChR-mediated responses does not require receptor activation and may result from a change in channel open probability. We also hypothesize that channel run-down reflects accumulation of nAChRs in long-lived desensitized/inactivated states.
ESTHER : Hicks_2000_J.Physiol_529 Pt 3_579
PubMedSearch : Hicks_2000_J.Physiol_529 Pt 3_579
PubMedID: 11118491

Title : Nicotinic receptors on hippocampal cultures can increase synaptic glutamate currents while decreasing the NMDA-receptor component - Fisher_2000_Neuropharmacol_39_2756
Author(s) : Fisher JL , Dani JA
Ref : Neuropharmacology , 39 :2756 , 2000
Abstract : Activation of presynaptic nicotinic acetylcholine receptors (nAChRs) can enhance the release of glutamate from synapses in hippocampal slices and cultures. In hippocampal cultures making autaptic connections, rapid application of a high concentration of nicotine activated presynaptic, postsynaptic, and somatic nAChRs, which consequently enhanced the amplitude of evoked excitatory postsynaptic currents (eEPSCs) mediated by glutamate receptors. The increased eEPSC amplitudes arose from enhanced glutamate release caused by presynaptic nAChRs (Radcliffe and Dani, 1998, Journal of Neuroscience 18, 7075). The same whole-cell nicotine applications that enhanced non-NMDA eEPSCs often decreased the NMDA-receptor component of the eEPSCs. Furthermore, whole-cell activation of nAChRs by nicotine selectively reduced the amplitude of the whole-cell NMDA-receptor currents without affecting the non-NMDA receptor currents. The inhibition by nicotine was prevented by the alpha7-specific antagonist, methyllycaconitine, and required the presence of extracellular Ca(2+). The calmodulin antagonist fluphenazine prevented inhibition of the NMDA-receptor current by nAChR activity, suggesting that a Ca(2+)-calmodulin-dependent process mediated the effect of nicotine. Our results indicate that activation of nAChRs can modulate glutamatergic synapses in several ways. Presynaptic nAChR activity enhances synaptic transmission by increasing transmitter release. Additionally, somatic or postsynaptic nAChRs can initiate a Ca(2+) signal that can act via calmodulin to reduce the responsiveness of NMDA receptors.
ESTHER : Fisher_2000_Neuropharmacol_39_2756
PubMedSearch : Fisher_2000_Neuropharmacol_39_2756
PubMedID: 11044745

Title : Inhibition and disinhibition of pyramidal neurons by activation of nicotinic receptors on hippocampal interneurons - Ji_2000_J.Neurophysiol_83_2682
Author(s) : Ji D , Dani JA
Ref : Journal of Neurophysiology , 83 :2682 , 2000
Abstract : Nicotinic acetylcholine receptors (nAChRs) are expressed in the hippocampus, and their functional roles are beginning to be delineated. The effect of nAChR activation on the activity of both interneurons and pyramidal neurons in the CA1 region was studied in rat hippocampal slices. In CA1 stratum radiatum with muscarinic receptors inhibited, local pressure application of acetylcholine (ACh) elicited a nicotinic current in 82% of the neurons. The majority of the ACh-induced currents were sensitive to methyllycaconitine, which is a specific inhibitor of alpha7-containing nAChRs. Methyllycaconitine-insensitive nicotinic currents also were present as detected by a nonspecific nAChR inhibitor. The ACh-sensitive neurons in the s. radiatum were identified as GABAergic interneurons by their electrophysiological properties. Pressure application of ACh induced firing of action potentials in approximately 70% of the interneurons. The ACh-induced excitation of interneurons could induce either inhibition or disinhibition of pyramidal neurons. The inhibition was recorded from the pyramidal neuron as a burst of GABAergic synaptic activity. That synaptic activity was sensitive to bicuculline, indicating that GABA(A) receptors mediated the ACh-induced synaptic currents. The disinhibition was recorded from the pyramidal neuron as a reduction of spontaneous GABAergic synaptic activity when ACh was delivered onto an interneuron. Both the inhibition and disinhibition were sensitive to either methyllycaconitine or mecamylamine, indicating that activation of nicotinic receptors on interneurons was necessary for the effects. These results show that nAChRs are capable of regulating hippocampal circuits by exciting interneurons and, subsequently, inhibiting or disinhibiting pyramidal neurons.
ESTHER : Ji_2000_J.Neurophysiol_83_2682
PubMedSearch : Ji_2000_J.Neurophysiol_83_2682
PubMedID: 10805668

Title : International Union of Pharmacology. XX. Current status of the nomenclature for nicotinic acetylcholine receptors and their subunits -
Author(s) : Lukas RJ , Changeux JP , Le Novere N , Albuquerque EX , Balfour DJ , Berg DK , Bertrand D , Chiappinelli VA , Clarke PB , Collins AC , Dani JA , Grady SR , Kellar KJ , Lindstrom JM , Marks MJ , Quik M , Taylor P , Wonnacott S
Ref : Pharmacol Rev , 51 :397 , 1999
PubMedID: 10353988

Title : Distributions of nicotinic acetylcholine receptor alpha7 and beta2 subunits on cultured hippocampal neurons - Zarei_1999_Neurosci_88_755
Author(s) : Zarei MM , Radcliffe KA , Chen D , Patrick JW , Dani JA
Ref : Neuroscience , 88 :755 , 1999
Abstract : The hippocampus receives cholinergic afferents and expresses neuronal nicotinic acetylcholine receptors. In particular, the alpha7 and beta2 nicotinic subunits are highly expressed in the hippocampus. There has been controversy about the location, distribution and roles of neuronal nicotinic acetylcholine receptors [Role L. W. and Berg D. K. (1996) Neuron 16, 1077-1085; Wonnacott S. (1997) Trends Neurosci. 20, 92-98]. Using immunocytochemistry and patch-clamp techniques, we examined the density and distribution of nicotinic receptors on rat hippocampal neurons in primary tissue culture. The density and distribution of alpha7 subunits change with days in culture. Before 10 days in culture, alpha7 expression, monitored immunocytochemically, is low and nicotinic currents are small or absent. In older cultures, about two-thirds of the neurons express nicotinic currents, and alpha7 appears in small patches on the soma and out along the neuronal processes. These patches of alpha7 subunits on the surface of the neuronal processes often co-localize with the presynaptic marker, synaptotagmin. The other most common nicotinic subunit, beta2, stays confined mainly to the soma and proximal processes, and beta2 is distributed more uniformly and is not specifically localized at presynaptic areas. The two subunits, alpha7 and beta2, have different expression patterns on the surface of the cultured hippocampal neurons. Taken together with previous physiological studies, the results indicate that alpha7 subunits can be found at presynaptic terminals, and at these locations, these calcium-permeable channels may influence transmitter release.
ESTHER : Zarei_1999_Neurosci_88_755
PubMedSearch : Zarei_1999_Neurosci_88_755
PubMedID: 10363815

Title : Nicotinic modulation of glutamate and GABA synaptic transmission of hippocampal neurons - Radcliffe_1999_Ann.N.Y.Acad.Sci_868_591
Author(s) : Radcliffe KA , Fisher JL , Gray R , Dani JA
Ref : Annals of the New York Academy of Sciences , 868 :591 , 1999
Abstract : Although the hippocampus expresses nicotinic acetylcholine receptors (nAChRs) and receives cholinergic innervation, the functional roles of these receptors are not completely understood. Our results indicated that presynaptic nAChRs mediated a calcium influx that enhanced the release of both glutamate and GABA. Fura-2 detection of calcium in single mossy fiber presynaptic terminals indicated that nAChRs directly mediated a calcium influx. In hippocampal neurons in primary culture, both spontaneous vesicular release and evoked release of glutamate and GABA were enhanced by nicotine. The nicotinic current displayed rapid desensitization kinetics, and the response to nicotine was inhibited by alpha-bungarotoxin and methyllcaconitine, suggesting that nAChRs containing the alpha 7 subunit mediated the effect. Modulation of synaptic activity by presynaptic calcium influx may represent a physiological role of acetylcholine in the brain, as well as a mechanism of action of nicotine.
ESTHER : Radcliffe_1999_Ann.N.Y.Acad.Sci_868_591
PubMedSearch : Radcliffe_1999_Ann.N.Y.Acad.Sci_868_591
PubMedID: 10414340

Title : Nicotinic stimulation produces multiple forms of increased glutamatergic synaptic transmission - Radcliffe_1998_J.Neurosci_18_7075
Author(s) : Radcliffe KA , Dani JA
Ref : Journal of Neuroscience , 18 :7075 , 1998
Abstract : Synaptic modulation and long-term synaptic changes are thought to be the cellular correlates for learning and memory (Madison et al., 1991; Aiba et al., 1994, Goda and Stevens, 1996). The hippocampus is a center for learning and memory that receives abundant cholinergic innervation and has a high density of nicotinic acetylcholine receptors (nAChRs) (Wada et al., 1989; Woolf, 1991). We report that stro ng, brief stimulation of nAChRs enhanced hippocampal glutamatergic synaptic transmission on two independent time scales and altered the relationship between consecutively evoked synaptic currents. The nicotinic synaptic enhancement required extracellular calcium and was produced by the activation of presynaptic alpha7-containing nAChRs. Although one form of glutamatergic enhancement lasted only for seconds, another form lasted for minutes after the nicotinic stimulation had ceased and the nicotinic agonist had been washed away. The synaptic enhancement lasting minutes suggests that nAChR activity can initiate calcium-dependent mechanisms that are known to induce glutamatergic synaptic plasticity. The results with evoked synaptic currents showed that nAChR activity can alter the relationship between the incoming presynaptic activity and outgoing postsynaptic signaling along glutamatergic fibers. Thus, the same information arriving along the same glutamatergic afferents will be processed differently when properly timed nicotinic activity converges onto the glutamatergic presynaptic terminals. Influencing information processing at glutamatergic synapses may be one way in which nicotinic cholinergic activity influences cognitive processes. Disruption of these nicotinic cholinergic mechanisms may contribute to the deficits associated with the degeneration of cholinergic functions during Alzheimer's disease.
ESTHER : Radcliffe_1998_J.Neurosci_18_7075
PubMedSearch : Radcliffe_1998_J.Neurosci_18_7075
PubMedID: 9736631

Title : Nicotine modifies the activity of ventral tegmental area dopaminergic neurons and hippocampal GABAergic neurons - Fisher_1998_J.Physiol.Paris_92_209
Author(s) : Fisher JL , Pidoplichko VI , Dani JA
Ref : Journal de Physiologie (Paris) , 92 :209 , 1998
Abstract : While trying to mimic the dose and time course of nicotine as it is obtained by a smoker, we found the following results. The initial arrival of even a low concentration of nicotine increased the firing rate of dopaminergic neurons from the ventral tegmental area (VTA) and increased the spontaneous vesicular release of GABA from hippocampal neurons. Longer exposure to nicotine caused variable, but dramatic, desensitization of nicotinic receptors and diminished the effects of nicotine. The addictive properties of nicotine as well as its diverse effects on cognitive function could be mediated through differences in activation and desensitization of nicotinic receptors in various areas of the brain.
ESTHER : Fisher_1998_J.Physiol.Paris_92_209
PubMedSearch : Fisher_1998_J.Physiol.Paris_92_209
PubMedID: 9789810

Title : Calcium flux through predominantly independent purinergic ATP and nicotinic acetylcholine receptors - Rogers_1997_J.Neurophysiol_77_1407
Author(s) : Rogers M , Colquhoun LM , Patrick JW , Dani JA
Ref : Journal of Neurophysiology , 77 :1407 , 1997
Abstract : Ligand-gated nicotinic acetylcholine receptors (nAChRs) and purinergic ATP receptors are often expressed in the same peripheral and central neurons, and ATP and acetylcholine (ACh) are stored together in some synaptic vesicles. Evidence has suggested that nAChRs and ATP receptors are not independent and that some agonists strongly cross-activate and desensitize both receptor types. Rat sympathetic neurons and nAChRs expressed in Xenopus oocytes were studied to determine the significance of the interactions caused by the two agonist types. Current amplitudes included with separate or combined applications of ATP and nicotine are > 90% additive and independent. Half of all neurons tested responded to either ATP or nicotine but not to both, indicating differences in the expression of the two receptors. In neurons that expressed both receptors types, the nAChRs were inhibited by the activity-dependent open-channel blocker chlorisondamine. If the purinergic and nicotinic receptors were significantly dependent and coactivated, then blocking the ion channels opened by a nicotinic agonist should diminish the current activated by a purinergic agonist. That result was not seen; rather, complete open-channel block of nAChRS with chlorisondamine did not significantly alter the amplitude or kinetics of ATP-induced currents in the same neurons. Finally, when cloned nAChR subunits were expressed in oocytes, ATP activated only very small currents compared with the current activated by Ach. For the 13 different nAChR subunit combinations that were studied, ATP (50-500 microM) activated a current that ranged from 0 to 4% of the size of the current activated by 100 microM ACh. In summary, we find that there is little cross reactivity, and nAChRs and purinergic ATP receptors are predominantly independent, acting with separable physiological characteristics. Therefore the quantitative Ca2+ flux could be separately determined for nAChRs and ATP receptors. The fraction of total current that is carried by Ca2+ was quantitatively determined by simultaneously measuring the whole cell current and the associated change in intracellular Ca2+ with fura-2. For sympathetic neurons bathed in 2.5 mM Ca2+ at a holding potential of -50 mV, Ca2+ carries 4.8 +/- 0.3% (mean +/- SE) of the inward current through neuronal nAChRs and 6.5 +/- 0.1% of the current through purinergic ATP receptors. In conclusion, activity-dependent Ca2+ influx through predominately independent populations of nAChRS and ATP neurons can produce different intracellular signals at purinergic and cholinergic synapses.
ESTHER : Rogers_1997_J.Neurophysiol_77_1407
PubMedSearch : Rogers_1997_J.Neurophysiol_77_1407
PubMedID: 9084606

Title : Nicotine activates and desensitizes midbrain dopamine neurons - Pidoplichko_1997_Nature_390_401
Author(s) : Pidoplichko VI , De Biasi M , Williams JT , Dani JA
Ref : Nature , 390 :401 , 1997
Abstract : Tobacco use in developed countries is estimated to be the single largest cause of premature death. Nicotine is the primary component of tobacco that drives use, and like other addictive drugs, nicotine reinforces self-administration and place preference in animal studies. Midbrain dopamine neurons normally help to shape behaviour by reinforcing biologically rewarding events, but addictive drugs such as cocaine can inappropriately exert a reinforcing influence by acting upon the mesolimbic dopamine system. Here we show that the same concentration of nicotine achieved by smokers activates and desensitizes multiple nicotinic receptors thereby regulating the activity of mesolimbic dopamine neurons. Initial application of nicotine can increase the activity of the dopamine neurons, which could mediate the rewarding aspects of tobacco use. Prolonged exposure to even these low concentrations of nicotine, however, can cause desensitization of the nicotinic receptors, which helps to explain acute tolerance to nicotine's effects. The effects suggest a cellular basis for reports that the first cigarette of the day is the most pleasurable, whereas the effect of subsequent cigarettes may depend on the interplay between activation and desensitization of multiple nicotinic receptors.
ESTHER : Pidoplichko_1997_Nature_390_401
PubMedSearch : Pidoplichko_1997_Nature_390_401
PubMedID: 9389479

Title : Mice deficient in the alpha7 neuronal nicotinic acetylcholine receptor lack alpha-bungarotoxin binding sites and hippocampal fast nicotinic currents - Orr-Urtreger_1997_J.Neurosci_17_9165
Author(s) : Orr-Urtreger A , Goldner FM , Saeki M , Lorenzo I , Goldberg L , De Biasi M , Dani JA , Patrick JW , Beaudet AL
Ref : Journal of Neuroscience , 17 :9165 , 1997
Abstract : The alpha7 subunit of the neuronal nicotinic acetylcholine receptor (nAChR) is abundantly expressed in hippocampus and is implicated in modulating neurotransmitter release and in binding alpha-bungarotoxin (alpha-BGT). A null mutation for the alpha7 subunit was prepared by deleting the last three exons of the gene. Mice homozygous for the null mutation lack detectable mRNA, but the mice are viable and anatomically normal. Neuropathological examination of the brain revealed normal structure and cell layering, including normal cortical barrel fields; histochemical assessment of the hippocampus was also normal. Autoradiography with [3H]nicotine revealed no detectable abnormalities of high-affinity nicotine binding sites, but there was an absence of high-affinity [125I]alpha-BGT sites. Null mice also lack rapidly desensitizing, methyllycaconitine-sensitive, nicotinic currents that are present in hippocampal neurons. The results of this study indicate that the alpha-BGT binding sites are equivalent to the alpha7-containing nAChRs that mediate fast, desensitizing nicotinic currents in the hippocampus. These mice demonstrate that the alpha7 subunit is not essential for normal development or for apparently normal neurological function, but the mice may prove to have subtle phenotypic abnormalities and will be valuable in defining the functional role of this gene product in vivo.
ESTHER : Orr-Urtreger_1997_J.Neurosci_17_9165
PubMedSearch : Orr-Urtreger_1997_J.Neurosci_17_9165
PubMedID: 9364063

Title : Hippocampal synaptic transmission enhanced by low concentrations of nicotine - Gray_1996_Nature_383_713
Author(s) : Gray R , Rajan AS , Radcliffe KA , Yakehiro M , Dani JA
Ref : Nature , 383 :713 , 1996
Abstract : Nicotine obtained from tobacco can improve learning and memory on various tasks and has been linked to arousal, attention, rapid information processing, working memory, and long-term memories that can cause craving years after someone has stopped smoking. One likely target for these effects is the hippocampus, a centre for learning and memory that has rich cholinergic innervation and dense nicotinic acetylcholine receptor (nAChR) expression. During Alzheimer's dementia there are fewer nAChRs and the cholinergic inputs to the hippocampus degenerate. However, there is no evidence for fast synaptic transmission mediated by nAChRs in the hippocampus, and their role is not understood. Nicotine is known to act on presynaptic nAChRs within the habenula of chick to enhance glutamatergic transmission; here we report that a similar mechanism operates in the hippocampus. Measurements of intracellular Ca2+ in single mossy-fibre presynaptic terminals indicate that nAChRs containing the alpha7 subunit can mediate a Ca2+ influx that is sufficient to induce vesicular neurotransmitter release. We propose that nicotine from tobacco influences cognition by enhancing synaptic transmission. Conversely, a decreased efficacy of transmission may account for the deficits associated with the loss of cholinergic innervation during Alzheimer's disease.
ESTHER : Gray_1996_Nature_383_713
PubMedSearch : Gray_1996_Nature_383_713
PubMedID: 8878480

Title : Molecular and cellular aspects of nicotine abuse -
Author(s) : Dani JA , Heinemann S
Ref : Neuron , 16 :905 , 1996
PubMedID: 8630247

Title : Mechanism for modulation of nicotinic acetylcholine receptors that can influence synaptic transmission - Amador_1995_J.Neurosci_15_4525
Author(s) : Amador M , Dani JA
Ref : Journal of Neuroscience , 15 :4525 , 1995
Abstract : Only recently has it been appreciated that neuronal nicotinic ACh receptors (NnAChRs) are highly permeable to Ca2+ and are modulated by Ca2+ in a dose-dependent manner. These findings suggest that Ca2+ could have roles in cholinergic synaptic plasticity. We report a possible mechanism for Ca(2+)-initiated synaptic plasticity that differs from the intracellular Ca2+ cascade associated with plasticity of glutamatergic synapses. Rapid changes in external Ca2+ modulate cholinergic spontaneous synaptic currents in superior cervical ganglionic sympathetic neurons. Inhibition of cholinergic currents by chlorisondamine, which blocks only open channels and becomes trapped in the pore, showed that the modulation is not by a mechanism that activates a previously unresponsive population of NnAChRs. Rather, single-channel recordings with ganglionic NnAChRs from chromaffin cells indicated that Ca2+ directly alters the probability of the channels being open. We hypothesize from the results that activity-dependent decreases in external Ca2+, which occur throughout the nervous system, could directly underlie a rapid negative-feedback mechanism that decreases the responsiveness of NnAChRs at synapses. When external Ca2+ is decreased, presynaptic Ca2+ currents and transmitter release also are diminished. Thus, several mechanisms could combine to potently and rapidly depress synaptic nicotinic receptors until the external Ca2+ concentration recovers.
ESTHER : Amador_1995_J.Neurosci_15_4525
PubMedSearch : Amador_1995_J.Neurosci_15_4525
PubMedID: 7790921

Title : Acetylcholine receptor desensitization induced by nicotine in rat medial habenula neurons - Lester_1995_J.Neurophysiol_74_195
Author(s) : Lester RA , Dani JA
Ref : Journal of Neurophysiology , 74 :195 , 1995
Abstract : 1. The activation and desensitization properties of nicotinic acetylcholine receptor (nAChR) channels were examined in acutely isolated medial habenula (MHb) neurons using whole cell patch-clamp recordings. nAChR-mediated currents were evoked by applying known concentrations of nicotinic agonists using rapid solution exchange techniques. 2. At a membrane potential of -60 mV, nAChR currents were observed above a concentration of approximately 100 mM nicotine. The peak current amplitude at low doses of agonist was proportional to the square of the concentration of nicotine, indicating that at least two molecules of agonist were required for channel opening. The concentration of nicotine required for half-maximal nAChR activation was estimated as 77 microM from a complete concentration-response curve. 3. During the continuous activation (2-5 s) of nAChRs by high concentrations of nicotine (300 microM), the current desensitized rapidly and extensively. The desensitization phase was described by the sum of two exponentials, with time constants of 210 and 1,435 ms. The fast component comprised 74% of the desensitizing phase of the current. Recovery from desensitization induced by 2- s applications of 300 microM nicotine was also fast and could be reasonably well described by a single exponential with a time constant of approximately 800 ms. Both the time courses of desensitization and recovery from desensitization were slightly slower at positive membrane potentials. 4. Incubation of neurons with low concentrations of nicotine (100 nM-10 microM) caused a slowly developing but pronounced desensitization of the nAChRs. In these cases desensitization was assessed from the reduction in the amplitude of the peak nicotinic current induced by repetitively applied pulses of a higher test concentration of agonist. A 5-min continuous exposure to 1 microM nicotine reduced the amplitude of the acetylcholine (30 microM, 1 s) test response to < 30% of its control value. As with higher concentrations of nicotine, the onset of the desensitization induced by 1 microM nicotine was biexponential, with fast and slow time constants of 15 s and 1.74 min, respectively. Recovery from the desensitization induced by these longer applications of nicotine was much slower than that observed with the brief pulses of high concentrations of nicotine. The concentration required for half-maximal desensitization after a 5-min incubation was approximately 300 nM. 5. Peak nAChR currents were approximately 85% smaller at +40 mV compared with -40 mV. The receptors that do not open at positive potentials desensitize almost as well as they would at negative potentials after channel opening.(ABSTRACT TRUNCATED AT 400 WORDS)
ESTHER : Lester_1995_J.Neurophysiol_74_195
PubMedSearch : Lester_1995_J.Neurophysiol_74_195
PubMedID: 7472323

Title : Structure and function of glutamate and nicotinic acetylcholine receptors - Dani_1995_Curr.Opin.Neurobiol_5_310
Author(s) : Dani JA , Mayer ML
Ref : Current Opinion in Neurobiology , 5 :310 , 1995
Abstract : The past year has seen remarkable progress in defining the structure of various ligand-gated ion channels. Images of opened and closed nicotinic acetylcholine receptors at 9 A resolution have now made it easier to identify the conformational changes underlying gating. In addition, recent studies on glutamate receptors have led to a radical revision of their postulated transmembrane topology: models for agonist-binding and allosteric domains now use sites previously thought to lie in cytoplasmic loops. Other areas that are being actively pursued include identification of the amino acids lining the ion channels, accurate measurements of Ca2+ fluxes, and tests of transmembrane topology in kainate receptor subunits.
ESTHER : Dani_1995_Curr.Opin.Neurobiol_5_310
PubMedSearch : Dani_1995_Curr.Opin.Neurobiol_5_310
PubMedID: 7580153

Title : Comparison of quantitative calcium flux through NMDA, ATP, and ACh receptor channels - Rogers_1995_Biophys.J_68_501
Author(s) : Rogers M , Dani JA
Ref : Biophysical Journal , 68 :501 , 1995
Abstract : NMDA receptors, ATP receptors, and nicotinic ACh receptors respond to agonist by undergoing conformational changes that open weakly selective cationic channels that are permeable to calcium. We determined the fraction of the current carried by calcium by simultaneously measuring membrane current using whole-cell patch-clamp techniques and intracellular Ca2+ using the fluorescent indicator Fura-2. The Fura-2 response to free Ca2+ was calibrated individually for each cell. Two different calibration methods are compared: one uses voltage-activated Ca2+ channels, and the other uses the same ligand-gated channels that are being tested but in a pure Ca2+ solution. The two methods give quantitatively different results. The method using pure Ca2+ currents through ligand-gated channels calibrates the Fura-2 signal through the same influx pathway that generates the test response, thus controlling for the distribution of channels and ensuring a similar interaction between the incoming Ca2+ and Fura-2. In a physiologic solution containing 2.5 mM Ca2+ at a holding potential of -50 mV, the percentage of inward current carried by Ca2+ through NMDA receptors in hippocampal neurons is 12.4%. By comparison, in sympathetic neurons the percentage of current carried by Ca2+ through neuronal nAChRs is 4.7%, and through ATP-activated purinergic receptors it is 6.5%. These percentages can be used to estimate the amount of Ca2+ entry through these receptors during synaptic activation, but care must be exercised in considering the many subtypes of each receptor.
ESTHER : Rogers_1995_Biophys.J_68_501
PubMedSearch : Rogers_1995_Biophys.J_68_501
PubMedID: 7696503

Title : Time-dependent changes in central nicotinic acetylcholine channel kinetics in excised patches - Lester_1994_Neuropharmacol_33_27
Author(s) : Lester RA , Dani JA
Ref : Neuropharmacology , 33 :27 , 1994
Abstract : The behavior of nicotinic acetylcholine receptor (nAChR) channels in acutely isolated habenula neurons was examined by rapidly applying nicotinic agonists to outside-out membrane patches. At negative membrane potentials, applications of 100 microM nicotine routinely produced macroscopic currents due to the opening of a large number of channels. During the continuous application of the agonist, the number of open nAChR channels decreased exponentially, i.e. receptor desensitization. A progressive loss in the number of channels contributing to the peak current was observed with time following outside-out patch excision, i.e. receptor rundown. In addition to rundown there was a time-dependent increase in the rate of desensitization and a concomitant slowing in the rate of recovery from desensitization. The extent of rundown and the changes in desensitization were coupled to the time after patch excision and were not dependent on ligand activation of nicotinic channels.
ESTHER : Lester_1994_Neuropharmacol_33_27
PubMedSearch : Lester_1994_Neuropharmacol_33_27
PubMedID: 7514279

Title : Improved technique for studying ion channels expressed in Xenopus oocytes, including fast superfusion - Costa_1994_Biophys.J_67_395
Author(s) : Costa AC , Patrick JW , Dani JA
Ref : Biophysical Journal , 67 :395 , 1994
Abstract : The study of whole-cell currents from ion channels expressed in Xenopus oocytes with conventional two-electrode voltage clamp has two major limitations. First, the large diameter and spherical geometry of oocytes prevent extremely fast solution changes. Second, the internal medium is not controlled, which limits the experimental versatility of the oocyte expression system. For example, because the internal medium is not controlled, endogenous calcium-activated chloride conductances can contaminate currents measured with channels that are permeable to calcium. We describe a new technique that combines vaseline-gap voltage clamp for oocytes with a fast superfusion system. The vaseline-gap procedure is simplified by having the micropipette that monitors voltage serve a dual role as a perfusion micropipette that controls the internal solution. In addition, the technique provides fast external solution changes that are complete in 30-50 ms. We applied the approach to measure the calcium permeability of a muscle and a neuronal nicotinic acetylcholine receptor. Very fast agonist induced currents were measured without contamination by the secondary activation of calcium-dependent chloride channels.
ESTHER : Costa_1994_Biophys.J_67_395
PubMedSearch : Costa_1994_Biophys.J_67_395
PubMedID: 7522597

Title : Quantitative measurement of calcium flux through muscle and neuronal nicotinic acetylcholine receptors - Vernino_1994_J.Neurosci_14_5514
Author(s) : Vernino S , Rogers M , Radcliffe KA , Dani JA
Ref : Journal of Neuroscience , 14 :5514 , 1994
Abstract : A new approach was developed to determine quantitatively the fraction of current carried by Ca2+ through an ion channel under physiological conditions. This approach entails the simultaneous measurement of membrane current and intracellular Ca2+ for single cells. Whole-cell patch-clamp techniques were used to measure current, and intracellular Ca2+ was monitored with the fluorescent indicator fura-2. To obtain a quantitative measure of the fraction of current carried by Ca2+, a cell-by-cell calibration method was devised to account for differences among cells in such factors as cellular volume and Ca2+ buffering. The method was used to evaluate the Ca2+ flux through muscle and neuronal nicotinic ACh receptors (nAChRs). In a solution containing 2.5 mM Ca2+ at a holding potential of -50 mV, Ca2+ carries 2.0% of the inward current through muscle nAChRs from BC3H1 cells and 4.1% of the inward current through neuronal nAChRs from adrenal chromaffin cells. The Ca2+ flux through neuronal nAChRs of adrenal chromaffin cells is insensitive to alpha-bungarotoxin. The influx of Ca2+ is voltage dependent, and because of the Ca2+ concentration difference across the cellular membrane, there is Ca2+ influx into the cell even when there is a large net outward current. At both muscle and neuronal cholinergic synapses, activity-dependent Ca2+ influx through nicotinic receptors produces intracellular signals that may have important roles in synaptic development, maintenance, and plasticity.
ESTHER : Vernino_1994_J.Neurosci_14_5514
PubMedSearch : Vernino_1994_J.Neurosci_14_5514
PubMedID: 8083751

Title : Functional diversity of neuronal nicotinic acetylcholine receptors -
Author(s) : Patrick J , Sequela P , Vernino S , Amador M , Luetje C , Dani JA
Ref : Prog Brain Res , 98 :113 , 1993
PubMedID: 8248498

Title : Molecular cloning, functional properties, and distribution of rat brain alpha 7: a nicotinic cation channel highly permeable to calcium - Seguela_1993_J.Neurosci_13_596
Author(s) : Seguela P , Wadiche J , Dineley-Miller K , Dani JA , Patrick JW
Ref : Journal of Neuroscience , 13 :596 , 1993
Abstract : A full-length clone coding for the rat alpha 7 nicotinic receptor subunit was isolated from an adult brain cDNA library and expressed in Xenopus oocytes. A significant proportion of the current through alpha 7-channels is carried by Ca2+. This Ca2+ influx then activates a Ca(2+)-dependent Cl- conductance, which is blocked by the chloride channel blockers niflumic and fluflenamic acid. Increasing the external NaCl concentration caused the reversal potentials for the alpha 7-channels and the Ca(2+)-dependent Cl- channels to be shifted in opposite directions. Under these conditions, agonist application activates a biphasic current with an initial inward current through alpha 7-channels followed by a niflumic acid- and fluflenamic acid-blockable outward current through Ca(2+)-dependent Cl- channels. A relative measure of the Ca2+ permeability was made by measuring the shift in the reversal potential caused by adding 10 mM Ca2+ to the external solution. Measurements made in the absence of Cl-, to avoid artifactual current through Ca(2+)-activated Cl- channels, indicate that alpha 7-homooligomeric channels have a greater relative Ca2+ permeability than the other nicotinic ACh receptors. Furthermore, alpha 7-channels have an even greater relative Ca2+ permeability than the NMDA subtype of glutamate receptors. High levels of alpha 7-transcripts were localized by in situ hybridization in the olfactory areas, the hippocampus, the hypothalamus, the amygdala, and the cerebral cortex. These results imply that alpha 7-containing receptors may play a role in activating calcium-dependent mechanisms in specific neuronal populations of the adult rat limbic system.
ESTHER : Seguela_1993_J.Neurosci_13_596
PubMedSearch : Seguela_1993_J.Neurosci_13_596
PubMedID: 7678857

Title : Structure, diversity, and ionic permeability of neuronal and muscle acetylcholine receptors - Dani_1993_EXS_66_47
Author(s) : Dani JA
Ref : Exs , 66 :47 , 1993
Abstract : Nicotinic acetylcholine receptors (nAChRs) form a family of ligand-gated, cation-selective channels that are concentrated at cholinergic synapses on vertebrate neurons and muscle cells. At the neuromuscular endplate, muscle nAChRs bind acetylcholine released by the presynaptic motor neuron. The receptors then undergo a conformational change that opens their ion channels. Cations move passively through the water-filled pores down their electrochemical gradients, completing synaptic transmission by depolarizing the postsynaptic muscle. The channel only weakly discriminates among permeant cations, which include all monovalent and divalent cations that are small enough to fit through the narrowest cross section. The membrane-spanning region of the pore is lined by uncharged domains that are bracketed by residues with net negative charge. The pore has large entrance vestibules, especially facing extracellularly. The narrowest cross-section is located near the cytoplasmic end of the membrane-spanning region, and this short narrow region probably provides the main cation binding site that is directly in the permeation pathway. Neuronal nAChRs share many of the properties of muscle nAChRs, but the neuronal receptor subtypes are more heterogenous genetically, pharmacologically, and functionally. There are especially important functional differences between muscle and neuronal nAChRs. For example, neuronal nAChRs are more highly permeable to Ca2+ and physiological levels of Ca2+ very potently modulate neuronal nicotinic currents. This variety of nAChRs suggests that these receptor/channels serve many roles in the excitable tissues of vertebrates.
ESTHER : Dani_1993_EXS_66_47
PubMedSearch : Dani_1993_EXS_66_47
PubMedID: 7505663

Title : Calcium modulation and high calcium permeability of neuronal nicotinic acetylcholine receptors - Vernino_1992_Neuron_8_127
Author(s) : Vernino S , Amador M , Luetje CW , Patrick J , Dani JA
Ref : Neuron , 8 :127 , 1992
Abstract : Two properties were found to distinguish neuronal from muscle nicotinic acetylcholine receptors (nAChRs). First, neuronal nAChRs have a greater Ca2+ permeability. The high Ca2+ flux through neuronal nAChRs activates a Ca(2+)-dependent Cl- conductance, and the Ca2+ to Cs+ permeability ratio (PCa/PCs) is 7 times greater for neuronal than for muscle nAChRs. A second difference between the receptor types is that neuronal nAChRs are potently modulated by physiological levels of external Ca2+. Neuronal nAChR currents are enhanced by external Ca2+ in a dose-dependent manner. The results indicate that changes in extracellular Ca2+ modulate neuronal nAChRs and may modulate cholinergic synapses in the CNS. Also, activation of neuronal nAChRs produces a significant influx of Ca2+ that could be an important intracellular signal.
ESTHER : Vernino_1992_Neuron_8_127
PubMedSearch : Vernino_1992_Neuron_8_127
PubMedID: 1370370

Title : Nicotinic acetylcholine receptors are directly affected by agents used to study protein phosphorylation - Reuhl_1992_J.Neurophysiol_68_407
Author(s) : Reuhl TO , Amador M , Moorman JR , Pinkham J , Dani JA
Ref : Journal of Neurophysiology , 68 :407 , 1992
Abstract : 1. Messenger RNAs for the subunits of the muscle nicotinic acetylcholine receptor (nAChR) were expressed in Xenopus oocytes. A two-electrode voltage clamp was used to measure the acetylcholine (ACh)-induced macroscopic currents. In addition, patch-clamp techniques were used to study nAChR channels in whole cells and in outside-out patches excised from BC3H-1 cells and in patches from oocytes. The single-channel and macroscopic currents were modified by compounds that are usually used to study protein phosphorylation. 2. IBMX (3-isobutyl-1-methylxanthine) is a phosphodiesterase inhibitor. Because it elevates the intracellular concentration of adenosine 3',5'-cyclic monophosphate (cAMP), IBMX is often used to indirectly activate cAMP-dependent protein kinase. H-7 [1-(5-isoquinolinylsulfonyl)-2-methylpiperazine] is mainly used as a rather nonspecific inhibitor of protein kinase activity. Both IBMX and H-7 directly inhibit ACh-induced currents independent of their action on phosphorylation. This direct effect of these compounds is similar to the previously reported inhibition of nAChRs and K+ channels by forskolin, which is commonly used to elevate intracellular cAMP. 3. Macroscopic currents induced in the oocytes by 50 microM ACh had an average peak current of 605 nA, and the currents decayed biexponentially with tau of 15 and 225 s. When 300 microM H-7 was added simultaneously with the ACh, the average peak current was 228 nA and the tau were 1 and 108 s. When 500 microM IBMX was added simultaneously with the ACh, the average peak current was 308 nA and the tau were 9 and 237 s. H-7 and IBMX decreased the peak current induced by ACh, and the compounds increased the decay rate of the current. Under these experimental conditions, the IC50 for reduction of peak amplitude at -30 mV was 160 microM for H-7 and 475 microM for IBMX. 4. H-7 preferentially inhibits the open conformation of the nAChR channel, but there is also some inhibition of the closed channel. The inhibition is voltage dependent: inhibition decreases e-fold per 34 mV depolarization. H-7 does not become trapped within the closed channel and does not significantly alter desensitization under our experimental conditions. 5. H-7 and IBMX interrupt or terminate single-channel openings in membrane patches excised from oocytes or BC3H-1 cells.(ABSTRACT TRUNCATED AT 400 WORDS)
ESTHER : Reuhl_1992_J.Neurophysiol_68_407
PubMedSearch : Reuhl_1992_J.Neurophysiol_68_407
PubMedID: 1382118

Title : MK-801 inhibition of nicotinic acetylcholine receptor channels - Amador_1991_Synapse_7_207
Author(s) : Amador M , Dani JA
Ref : Synapse , 7 :207 , 1991
Abstract : MK-801 is a potent inhibitor of the NMDA subtype of glutamate receptors. Single-channel and macroscopic currents indicate that MK-801 also inhibits nicotinic acetylcholine receptors (nAChRs). MK-801 does not significantly increase desensitization of the nAChRs or compete for the ACh binding site. Although there is a slight inhibition of the closed nAChR, the main action of MK-801 is to enter and block the open channel. The voltage dependence for block is consistent with a single binding site within the channel that is 50% of the way through the membrane field. The IC50 for block is 3 microM at -70 mV for currents induced by 0.5 microM ACh. The data from both single-channel and macroscopic currents can be used to estimate a Kd (0) of 7 microM, which is about 40 times higher than the Kd (0) for MK-801 binding to the NMDA receptor. The relative potency of tricyclic compounds like MK-801 for various neurotransmitter systems points out that the pharmacologic action of these drugs could involve complicated interactions in vivo.
ESTHER : Amador_1991_Synapse_7_207
PubMedSearch : Amador_1991_Synapse_7_207
PubMedID: 1715611

Title : Examination of subconductance levels arising from a single ion channel - Dani_1991_J.Theor.Biol_153_401
Author(s) : Dani JA , Fox JA
Ref : Journal of Theoretical Biology , 153 :401 , 1991
Abstract : Single-channel records often show frequent currents at a main conductance level and occasional currents at subconductance levels. In some instances, the conductances occur at regular levels that are multiples of a minimum conductance. It is well-appreciated that multiple conductance levels may arise either from the co-operative gating of more than one pore or from changes that occur in a single pore. In this paper, we used theoretical models of ion permeation to examine subconductances arising in a single-pore channel. In particular, the work focuses on the following question: how can an ion channel that provides only one aqueous pore through the membrane produce regular subconductances and a main conductance that all have the same selectivity and the same ion binding affinity? The three types of ion permeation models used in this study showed that a single-pore channel can have subconductances because of long-lived conformational states, because of alterations in rapid fluctuations between conformational states, or because of slight alterations in the electrostatic properties in the channel's entrance vestibules. Regular subconductances with the same selectivity and binding affinity can arise in a single pore even if the energy profile changes do not meet the constant peak offset condition. The results show that the appearance of regular subconductance levels in a single-channel recording is not sufficient evidence to conclude that identical pores have co-operative gating, as would arise in a channel that is a multi-pore complex.
ESTHER : Dani_1991_J.Theor.Biol_153_401
PubMedSearch : Dani_1991_J.Theor.Biol_153_401
PubMedID: 1724679

Title : Calcium permeability of the nicotinic acetylcholine receptor: the single-channel calcium influx is significant - Decker_1990_J.Neurosci_10_3413
Author(s) : Decker ER , Dani JA
Ref : Journal of Neuroscience , 10 :3413 , 1990
Abstract : The calcium permeability of the mouse muscle nicotinic ACh receptor (nAChR) was determined using patch-clamp techniques. Single-channel currents were measured in pure external calcium and in mixtures of calcium with cesium or sodium. At low concentrations, calcium decreases the current carried by the monovalent cation. At higher concentrations, calcium displaces the monovalent cation as the main current carrier. In pure external calcium, the conductance of the nAChR is similar to the conductance of the NMDA receptor or the L-type Ca channel. With pure 110-mM calcium as the external cation, the slope conductance of the nAChR channel at negative potentials is 12 pS. An ion-permeation model based on the structure and function of the channel describes the currents. The ion-permeation model predicts that calcium contributes about 2% of the total inward current through a nAChR channel in physiologic solution. The current is about 7% of the calcium current through an L-type Ca channel. Because nAChRs are densely packed at the neuromuscular end plate, the calcium influx at an active synapse is expected to produce a locally high-calcium environment.
ESTHER : Decker_1990_J.Neurosci_10_3413
PubMedSearch : Decker_1990_J.Neurosci_10_3413
PubMedID: 2170596

Title : Site-directed mutagenesis and single-channel currents define the ionic channel of the nicotinic acetylcholine receptor -
Author(s) : Dani JA
Ref : Trends in Neurosciences , 12 :125 , 1989
PubMedID: 2470168

Title : Monovalent and divalent cation permeation in acetylcholine receptor channels. Ion transport related to structure - Dani_1987_J.Gen.Physiol_89_959
Author(s) : Dani JA , Eisenman G
Ref : Journal of General Physiology , 89 :959 , 1987
Abstract : Single channel patch-clamp techniques were used to study nicotinic acetylcholine receptors in cultured rat myotubes. The single channel conductance in pure cesium and sodium levels off at high concentrations, as if a binding site within the channel were saturating. The conductances at very low concentrations, however, are larger than predicted by the simplest one-site transport model fitted to the high-concentration data. At low concentrations, the current-voltage relations are inwardly rectifying, but they become more ohmic if a small amount of divalent cations is added externally. Magnesium and barium are good permeants that have rather high affinities for the channel. Upon adding low millimolar concentrations of these divalent cations externally to a membrane bathed in pure cesium, the inward current carried by cesium is decreased. As more divalent cations are added, the inward-going currents continued to decrease and the divalent cation replaces cesium as the main current carrier. The ion transport data are described by considering the size, shape, and possible net charge of the channel. In that way, even the complex features of transport are explained in a realistic physical framework. The results are consistent with the channel having long, wide, multiply occupied vestibules that serve as transition zones to the short, selective, singly occupied narrow region of the channel. A small amount of net negative charge within the pore could produce concentration-dependent potentials that provide a simple explanation for the more complicated aspects of the permeation properties.
ESTHER : Dani_1987_J.Gen.Physiol_89_959
PubMedSearch : Dani_1987_J.Gen.Physiol_89_959
PubMedID: 2440979

Title : An introduction to molecular architecture and permeability of ion channels -
Author(s) : Eisenman G , Dani JA
Ref : Annu Rev Biophys Biophysical Chemistry , 16 :205 , 1987
PubMedID: 2439095

Title : Slow permeation of organic cations in acetylcholine receptor channels - Sanchez_1986_J.Gen.Physiol_87_985
Author(s) : Sanchez JA , Dani JA , Siemen D , Hille B
Ref : Journal of General Physiology , 87 :985 , 1986
Abstract : Block, permeation, and agonist action of small organic amine compounds were studied in acetylcholine receptor (AChR) channels. Single channel conductances were calculated from fluctuation analysis at the frog neuromuscular junction and measured by patch clamp of cultured rat myotubes. The conductance was depressed by a few millimolar external dimethylammonium, arginine, dimethyldiethanolammonium, and Tris. Except with dimethylammonium, the block was intensified with hyperpolarization. A two-barrier Eyring model describes the slowed permeation and voltage dependence well for the three less permeant test cations. The cations were assumed to pause at a site halfway across the electric field of the channel while passing through it. For the voltage-independent action of highly permeant dimethylammonium, a more appropriate model might be a superficial binding site that did not prevent the flow of other ions, but depressed it. Solutions of several amine compounds were found to have agonist activity at millimolar concentrations, inducing brief openings of AChR channels on rat myotubes in the absence of ACh.
ESTHER : Sanchez_1986_J.Gen.Physiol_87_985
PubMedSearch : Sanchez_1986_J.Gen.Physiol_87_985
PubMedID: 2425045

Title : Ion-channel entrances influence permeation. Net charge, size, shape, and binding considerations - Dani_1986_Biophys.J_49_607
Author(s) : Dani JA
Ref : Biophysical Journal , 49 :607 , 1986
Abstract : Many ion channels have wide entrances that serve as transition zones to the more selective narrow region of the pore. Here some physical features of these vestibules are explored. They are considered to have a defined size, funnel shape, and net-negative charge. Ion size, ionic screening of the negatively charged residues, cation binding, and blockage of current are analyzed to determine how the vestibules influence transport. These properties are coupled to an Eyring rate theory model for the narrow length of the pore. The results include the following: Wide vestibules allow the pore to have a short narrow region. Therefore, ions encounter a shorter length of restricted diffusion, and the channel conductance can be greater. The potential produced by the net-negative charge in the vestibules attracts cations into the pore. Since this potential varies with electrolyte concentration, the conductance measured at low electrolyte concentrations is larger than expected from measurements at high concentrations. Net charge inside the vestibules creates a local potential that confers some cation vs. anion, and divalent vs. monovalent selectivity. Large cations are less effective at screening (diminishing) the net-charge potential because they cannot enter the pore as well as small cations. Therefore, at an equivalent bulk concentration the attractive negative potential is larger, which causes large cations to saturate sites in the pore at lower concentrations. Small amounts of large or divalent cations can lead to misinterpretation of the permeation properties of a small monovalent cation.
ESTHER : Dani_1986_Biophys.J_49_607
PubMedSearch : Dani_1986_Biophys.J_49_607
PubMedID: 2421791

Title : Acetylcholine-activated channel current-voltage relations in symmetrical na solutions -
Author(s) : Dani JA , Eisenman G
Ref : Biophysical Journal , 45 :10 , 1984
PubMedID: 19431525