Lotfipour S

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Full name : Lotfipour Shahrdad

First name : Shahrdad

Mail : Department of Psychiatry and Biobehavioral Sciences, Hatos Center for Neuropharmacology, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, California 90024 lotfipour@gmail.com

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Country : USA

Email : shahrdad@ucla.edu

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References (12)

Title : alpha2-Null mutant mice have altered levels of neuronal activity in restricted midbrain and limbic brain regions during nicotine withdrawal as demonstrated by cfos expression - Upton_2015_Biochem.Pharmacol_97(4)_558
Author(s) : Upton M , Lotfipour S
Ref : Biochemical Pharmacology , 97 :558 , 2015
Abstract : Neuronal nicotinic acetylcholine receptors (nAChRs) are the primary binding sites for nicotine within the brain. Using alpha(alpha)2 nAChR subunit-null mutant mice, the current study evaluates whether the absence of this gene product during mecamylamine-precipitated nicotine withdrawal eliminates neuronal activity within selective midbrain and limbic brain regions, as determined by the expression of the immediate early gene, cfos. Our results demonstrate that nicotine withdrawal enhances neuronal activity within the interpeduncular nucleus and dorsal hippocampus, which is absent in mice null for alpha2-containing nAChRs. In contrast, we observe that alpha2-null mutant mice exhibit a suppression of neuronal activity in the dentate gyrus in mice undergoing nicotine withdrawal. Interestingly, alpha2-null mutant mice display potentiated neuronal activity specifically within the stratum lacunosum moleculare layer of the hippocampus, independent of nicotine withdrawal. Overall, our findings demonstrate that alpha2-null mutant mice have altered cfos expression in distinct populations of neurons within selective midbrain and limbic brain structures that mediate baseline and nicotine withdrawal-induced neuronal activity.
ESTHER : Upton_2015_Biochem.Pharmacol_97(4)_558
PubMedSearch : Upton_2015_Biochem.Pharmacol_97(4)_558
PubMedID: 26111579

Title : Maternal cigarette smoking during pregnancy predicts drug use via externalizing behavior in two community-based samples of adolescents - Lotfipour_2014_Addiction_109_1718
Author(s) : Lotfipour S , Ferguson E , Leonard G , Miettunen J , Perron M , Pike GB , Richer L , Seguin JR , Veillette S , Jarvelin MR , Moilanen I , Maki P , Nordstrom T , Pausova Z , Veijola J , Paus T
Ref : Addiction , 109 :1718 , 2014
Abstract : BACKGROUND AND AIMS: Prenatal exposure to maternal cigarette smoking (PEMCS) is associated with a higher probability of substance use in adolescence. We explore if externalizing behavior mediates this relationship, while controlling for a number of potential covariates of this mediation process.
METHODS: We used data obtained in two geographically distinct community samples of adolescents. The first (cross-sectional) sample consisted of 996 adolescents (12-18 years of age) recruited from the Saguenay Youth Study (SYS) in Canada (47% with PEMCS). The second (longitudinal) sample consisted of 1141 adolescents (49% with PEMCS) from the Northern Finland Birth Cohort (NFBC1986). In both samples, externalizing behavior and substance use were assessed during adolescence. In the NFBC1986 cohort, externalizing behavior was also assessed in childhood.
RESULTS: In both populations, PEMCS is associated with a higher likelihood of adolescent drug experimentation. In the NFBC1986 cohort, exposed (versus non-exposed) adolescents experiment with an extra 1.27 [B = 0.24, 95% confidence intervals (CI) = 0.15, 0.33 P < 0.001] drugs. In the SYS cohort, a clear protective effect of not being exposed is shown: non-exposed (versus exposed) adolescents are 1.5 times [B = -0.42, 95% CI = -0.75, -0.09, P = 0.013] less likely to take drugs. These associations between PEMCS and drug experimentation remain in the multivariate and mediational analyses.
CONCLUSIONS: Prenatal exposure to maternal cigarette smoking appears to be associated with a higher probability of experimenting with drugs during adolescence, both directly and indirectly via externalizing behavior and the number of peers reported as using drugs.
ESTHER : Lotfipour_2014_Addiction_109_1718
PubMedSearch : Lotfipour_2014_Addiction_109_1718
PubMedID: 24942256

Title : Targeted deletion of the mouse alpha2 nicotinic acetylcholine receptor subunit gene (Chrna2) potentiates nicotine-modulated behaviors - Lotfipour_2013_J.Neurosci_33_7728
Author(s) : Lotfipour S , Byun JS , Leach P , Fowler CD , Murphy NP , Kenny PJ , Gould TJ , Boulter J
Ref : Journal of Neuroscience , 33 :7728 , 2013
Abstract : Baseline and nicotine-modulated behaviors were assessed in mice harboring a null mutant allele of the nicotinic acetylcholine receptor (nAChR) subunit gene alpha2 (Chrna2). Homozygous Chrna2(-/-) mice are viable, show expected sex and Mendelian genotype ratios, and exhibit no gross neuroanatomical abnormalities. A broad range of behavioral tests designed to assess genotype-dependent effects on anxiety (elevated plus maze and light/dark box), motor coordination (narrow bean traverse and gait), and locomotor activity revealed no significant differences between mutant mice and age-matched wild-type littermates. Furthermore, a panel of tests measuring traits, such as body position, spontaneous activity, respiration, tremors, body tone, and startle response, revealed normal responses for Chrna2-null mutant mice. However, Chrna2(-/-) mice do exhibit a mild motor or coordination phenotype (a decreased latency to fall during the accelerating rotarod test) and possess an increased sensitivity to nicotine-induced analgesia in the hotplate assay. Relative to wild-type, Chrna2(-/-) mice show potentiated nicotine self-administration and withdrawal behaviors and exhibit a sex-dependent enhancement of nicotine-facilitated cued, but not trace or contextual, fear conditioning. Overall, our results suggest that loss of the mouse nAChR alpha2 subunit has very limited effects on baseline behavior but does lead to the potentiation of several nicotine-modulated behaviors.
ESTHER : Lotfipour_2013_J.Neurosci_33_7728
PubMedSearch : Lotfipour_2013_J.Neurosci_33_7728
PubMedID: 23637165

Title : A single administration of low-dose varenicline saturates alpha4beta2* nicotinic acetylcholine receptors in the human brain - Lotfipour_2012_Neuropsychopharmacology_37_1738
Author(s) : Lotfipour S , Mandelkern M , Alvarez-Estrada M , Brody AL
Ref : Neuropsychopharmacology , 37 :1738 , 2012
Abstract : The primary objective of this project was to determine the alpha4beta2(*) nicotinic acetylcholine receptor (nAChR) occupancy in human brain of a single low dose of varenicline (0.5 mg), and to explore the relationship between receptor occupancy by varenicline and tobacco withdrawal symptoms ((*)denoting other putative nAChR subunits). Otherwise healthy smokers (n=9) underwent two positron emission tomography (PET) sessions with the selective alpha4beta2(*) radioligand 2-FA. For the PET sessions, participants received either a low dose of varenicline (0.5 mg) or matching placebo pill (double-blind, random order) before imaging. For both sessions, participants received bolus plus continuous infusions of 2-FA, were scanned for 1 h after allowing the radiotracer to reach a steady state, smoked to satiety, and were scanned for 2 more hours. We estimated the fractional receptor occupancy by a single dose of varenicline (0.5 mg) and the corresponding varenicline dissociation constant (K(V)), along with the effect of low-dose varenicline, pill placebo, and smoking-to-satiety on withdrawal rating scales. The data are compatible with 100% occupancy of alpha4beta2(*) nAChRs by a single dose of varenicline, with a 90% lower confidence limit of 89% occupancy for the thalamus and brainstem. The corresponding 90% upper limit on effective K(V) with respect to plasma varenicline was 0.49 nM. Smoking to satiety, but not low-dose varenicline, significantly reduced withdrawal symptoms. Our findings demonstrate that low-dose varenicline results in saturation of alpha4beta2(*) nAChRs in the thalamus and brainstem without reducing withdrawal symptoms.
ESTHER : Lotfipour_2012_Neuropsychopharmacology_37_1738
PubMedSearch : Lotfipour_2012_Neuropsychopharmacology_37_1738
PubMedID: 22395733

Title : The monoamine oxidase (MAO) inhibitor tranylcypromine enhances nicotine self-administration in rats through a mechanism independent of MAO inhibition - Lotfipour_2011_Neuropharmacol_61_95
Author(s) : Lotfipour S , Arnold MM , Hogenkamp DJ , Gee KW , Belluzzi JD , Leslie FM
Ref : Neuropharmacology , 61 :95 , 2011
Abstract : Our current study aims to evaluate the mechanisms of tranylcypromine (TCP)-mediated enhancement of nicotine self-administration. We replicated our previous findings which demonstrate that 1 h pretreatment with TCP (3 mg/kg, i.p.) enhances nicotine self-administration (7.5 mug/kg/inj, i.v.) when compared with vehicle-treated rodents. We tested whether TCP-mediated enhancement of nicotine self-administration was due to MAO inhibition or off-target effects by (i) extending the TCP pretreatment time from 1 to 20 h, and (ii) evaluating the role of the individual TCP stereoisomers in nicotine self-administration studies. While 20 h and (-)TCP pretreatment induced significant inhibition of MAO (60-90%), animals found nicotine only weakly reinforcing. Furthermore, while both (+) and (+/-)TCP treatment induced nearly 100% MAO inhibition, (+)TCP pretreated animals took longer to acquire nicotine self-administration compared to (+/-)TCP pretreated animals. Stable nicotine self-administration in (+)TCP pretreated animals was influenced by nicotinic receptor activation but not nicotine-paired cues. The opposite was found in (+/-)TCP pretreated animals. Treatment with (-) or (+/-)TCP increased dopamine and serotonin overflow, while the (+) and (+/-)TCP treatment enhanced monoamine overflow subsequent to nicotine. Together, our data suggests TCP enhancement of nicotine self-administration are mediated through mechanisms independent of MAO inhibition, including nicotine-paired cues and monoamine uptake inhibition.
ESTHER : Lotfipour_2011_Neuropharmacol_61_95
PubMedSearch : Lotfipour_2011_Neuropharmacol_61_95
PubMedID: 21419142

Title : Quantitative Molecular Imaging of Neuronal Nicotinic Acetylcholine Receptors in the Human Brain with A-85380 Radiotracers - Lotfipour_2011_Curr.Med.Imaging.Rev_7_107
Author(s) : Lotfipour S , Mandelkern M , Brody AL
Ref : Curr Med Imaging Rev , 7 :107 , 2011
Abstract : Neuronal nicotinic acetylcholine receptors (nAChRs) have been implicated in a spectrum of cognitive functions as well as psychiatric and neurodegenerative disorders, including tobacco addiction and Alzheimer's Disease. The examination of neuronal nAChRs in living humans is a relatively new field. Researchers have developed brain-imaging radiotracers for nAChRs, with radiolabeled A-85380 compounds having the most widespread use. We provide a brief background on nAChRs, followed by a discussion of the development and application of A-85380 radiotracers in human imaging studies. We describe potential future studies using nicotinic receptor radioligands for the study of tobacco addiction, including the mechanism of action of the smoking-cessation therapy varenicline. Throughout this review, we focus on the significant potential that resides in the identification and quantification of nAChRs in the living human brain.
ESTHER : Lotfipour_2011_Curr.Med.Imaging.Rev_7_107
PubMedSearch : Lotfipour_2011_Curr.Med.Imaging.Rev_7_107
PubMedID: 22773924

Title : Prenatal exposure to maternal cigarette smoking interacts with a polymorphism in the alpha6 nicotinic acetylcholine receptor gene to influence drug use and striatum volume in adolescence -
Author(s) : Lotfipour S , Leonard G , Perron M , Pike B , Richer L , Seguin JR , Toro R , Veillette S , Pausova Z , Paus T
Ref : Mol Psychiatry , 15 :6 , 2010
PubMedID: 20029407

Title : Orbitofrontal cortex and drug use during adolescence: role of prenatal exposure to maternal smoking and BDNF genotype - Lotfipour_2009_Arch.Gen.Psychiatry_66_1244
Author(s) : Lotfipour S , Ferguson E , Leonard G , Perron M , Pike B , Richer L , Seguin JR , Toro R , Veillette S , Pausova Z , Paus T
Ref : Arch Gen Psychiatry , 66 :1244 , 2009
Abstract : CONTEXT: Prenatal exposure to maternal cigarette smoking (PEMCS) may affect brain development and behavior in adolescent offspring. OBJECTIVE: To evaluate the involvement of the orbitofrontal cortex (OFC) in mediating the relationship between PEMCS and substance use. DESIGN: Cross-sectional analyses from the Saguenay Youth Study aimed at evaluating the effects of PEMCS on brain development and behavior among adolescents. Nonexposed adolescents were matched with adolescents exposed prenatally to cigarette smoking by maternal educational level. PARTICIPANTS AND SETTING: A French Canadian founder population of the Saguenay-Lac-Saint-Jean region of Quebec, Canada. The behavioral data set included 597 adolescents (275 sibships; 12-18 years of age), half of whom were exposed in utero to maternal cigarette smoking. Analysis of cortical thickness and genotyping were performed using available data from 314 adolescents. MAIN OUTCOME MEASURES: The likelihood of substance use was assessed with the Diagnostic Interview Schedule for Children Predictive Scales. The number of different drugs tried by each adolescent was assessed using another questionnaire. Thickness of the OFC was estimated from T1-weighted magnetic resonance images using FreeSurfer software.
RESULTS: Prenatal exposure to maternal cigarette smoking is associated with an increased likelihood of substance use. Among exposed adolescents, the likelihood of drug experimentation correlates with the degree of OFC thinning. In nonexposed adolescents, the thickness of the OFC increases as a function of the number of drugs tried. The latter effect is moderated by a brain-derived neurotrophic factor (BDNF) genotype (Val66Met).
CONCLUSIONS: We speculate that PEMCS interferes with the development of the OFC and, in turn, increases the likelihood of drug use among adolescents. In contrast, we suggest that, among nonexposed adolescents, drug experimentation influences the OFC thickness via processes akin to experience-induced plasticity.
ESTHER : Lotfipour_2009_Arch.Gen.Psychiatry_66_1244
PubMedSearch : Lotfipour_2009_Arch.Gen.Psychiatry_66_1244
PubMedID: 19884612

Title : Adolescent maturation of cocaine-sensitive neural mechanisms - Cao_2007_Neuropsychopharmacology_32_2279
Author(s) : Cao J , Lotfipour S , Loughlin SE , Leslie FM
Ref : Neuropsychopharmacology , 32 :2279 , 2007
Abstract : Both clinical and animal studies have shown that adolescents undergo a late maturation of the central nervous system, which may underlie adolescent typical behaviors. In particular, decreased behavioral response to cocaine has been found in adolescents as compared to adults. In the present study, cocaine was used as a tool to explore adolescent brain maturation. Juvenile (postnatal day (P) 27), adolescent (P37), and adult (P90) male Sprague-Dawley rats were treated acutely with cocaine (750 microg/kg/injection x 2, i.v.), and c-fos mRNA expression, a marker of neuronal activation, was evaluated by in situ hybridization. Cocaine-induced c-fos mRNA was similar across ages in the dorsal caudate putamen (CPu), nucleus accumbens, and lateral bed nucleus of the stria terminalis. In contrast, there was a diminished response in juvenile/adolescent ventral CPu and in juvenile central nucleus of the amygdala, and an increased response in juvenile/adolescent cortex. Further studies evaluated the mechanism of the late maturation of cocaine response in ventral CPu. No significant age differences were observed in regional dopamine (DA) transporter binding. Although striatal DA content was significantly reduced at P27 as compared to adult, there was no difference between dorsal and ventral subregions. In contrast, basal- and cocaine-induced extracellular DA overflow, as measured by in vivo microdialysis, was lower in juvenile ventral CPu than in the adults. This age difference was not observed in dorsal CPu. These findings suggest that impulse activity in DA afferents to ventral CPu is immature in adolescents. In conclusion, the present study showed that cocaine-sensitive neuronal circuits continue to mature during adolescence.
ESTHER : Cao_2007_Neuropsychopharmacology_32_2279
PubMedSearch : Cao_2007_Neuropsychopharmacology_32_2279
PubMedID: 17299504

Title : Involvement of alpha1-adrenergic receptors in tranylcypromine enhancement of nicotine self-administration in rat - Villegier_2007_Psychopharmacology.(Berl)_193_457
Author(s) : Villegier AS , Lotfipour S , Belluzzi JD , Leslie FM
Ref : Psychopharmacology (Berl) , 193 :457 , 2007
Abstract : RATIONALE: The mechanisms mediating tobacco addiction remain elusive. Nicotine, the psychoactive component in tobacco, is generally believed to be the main cause of reward and addiction. However, tobacco smoke contains thousands of constituents, some of which may interact with nicotine to enhance reward. It has previously been shown that monoamine oxidase (MAO) inhibition, known to result from smoking, can enhance nicotine self-administration. The aim of the present study was to evaluate the role of noradrenergic systems in mediating this enhancement of nicotine reward. OBJECTIVE: The objective of this study was to test the hypothesis that MAO inhibitor pretreatment enhances nicotine self-administration by activation of noradrenergic pathways that regulate dopamine release in the nucleus accumbens (NAc).
METHODS: The effect of prazosin (0.0625-0.5 mg/kg, i.p.), a specific alpha1-adrenergic receptor antagonist, was examined on male rats pretreated with tranylcypromine (3 mg/kg), an irreversible inhibitor of MAO A and B. Acquisition of nicotine (10 mug kg(-1) inj(-1), i.v.) self-administration behavior was examined over a 5-day period. Nicotine (60 mug kg(-1) inj(-1), i.v.)-induced increase in NAc extracellular dopamine levels was examined by in vivo microdialysis in non-self-administering animals.
RESULTS: We have shown that (1) tranylcypromine enhances nicotine self-administration, (2) prazosin pretreatment blocks both the acquisition and the expression of nicotine self-administration, and (3) prazosin pretreatment diminishes nicotine-induced dopamine release in the NAc. CONCLUSION: These data indicate that the stimulation of alpha1-adrenergic receptors is critical for tranylcypromine enhancement of nicotine reward and suggest a critical interplay between the noradrenergic and dopaminergic systems in tobacco addiction.
ESTHER : Villegier_2007_Psychopharmacology.(Berl)_193_457
PubMedSearch : Villegier_2007_Psychopharmacology.(Berl)_193_457
PubMedID: 17486319

Title : Tranylcypromine enhancement of nicotine self-administration - Villegier_2007_Neuropharmacol_52_1415
Author(s) : Villegier AS , Lotfipour S , McQuown SC , Belluzzi JD , Leslie FM
Ref : Neuropharmacology , 52 :1415 , 2007
Abstract : Tobacco use has one of the highest rates of addiction of any abused drug. Paradoxically, in animal models, nicotine appears to be a weak reinforcer. We report here that the inhibition of monoamine oxidase (MAO), a major effect of tobacco smoke, increases the reinforcing effect of nicotine. Rats (aged postnatal day 27 and 90) were tested for self-administration, without prior response training, in five daily 3-h sessions. Whereas control rats did not self-administer nicotine, low doses of nicotine (2.5 to 21 microg/kg/injection) were avidly self-administered following a pretreatment with tranylcypromine (3 mg/kg), an irreversible and non-selective MAO inhibitor. Tranylcypromine-enhanced nicotine (10 microg/kg/injection, i.v.) self-administration was reduced by systemic injection of a D1-dopaminergic receptor antagonist, SCH23390 (0.02 mg/kg). Moreover, an increase in extracellular dopamine in the nucleus accumbens was detected, using microdialysis, following nicotine (60 microg/kg) injection in tranylcypromine pre-treated rats. Depending on the time of tranylcypromine pretreatment (20 or 1 h), MAO activity was decreased by 72% and 99% and nicotine intake at day 5 was increased by 619 and 997%, respectively. Taken together, these results indicate that in a stringent self-administration acquisition test, MAO inhibition increases the rewarding effect of low doses of nicotine, possibly via a dopamine-dependent mechanism.
ESTHER : Villegier_2007_Neuropharmacol_52_1415
PubMedSearch : Villegier_2007_Neuropharmacol_52_1415
PubMedID: 17412372

Title : Adolescent development of forebrain stimulant responsiveness: insights from animal studies - Leslie_2004_Ann.N.Y.Acad.Sci_1021_148
Author(s) : Leslie FM , Loughlin SE , Wang R , Perez L , Lotfipour S , Belluzzia JD
Ref : Annals of the New York Academy of Sciences , 1021 :148 , 2004
Abstract : Although initiation of drug abuse occurs primarily during adolescence, little is known about the central effects of nicotine and other abused drugs during this developmental period. Here evidence, derived from studies in rodents, is presented that suggests that tobacco use initiation during early adolescence results from a higher reward value of nicotine. The developmental profiles of the rewarding effects of other abused drugs, such as cocaine, differ from that of nicotine. Using in situ hybridization to quantify mRNA levels of the immediate early gene, cfos, the neuronal activating effects of nicotine in limbic and sensory cortices at different developmental stages are evaluated. Significant age changes in basal levels of cfos mRNA expression in cortical regions are observed, with a peak of responding of limbic cortices during early adolescence. A changing pattern of nicotine-induced neuronal activation is seen across the developmental spectrum, with unique differences in both limbic and sensory cortex responding during adolescence. An attentional set-shifting task was also used to evaluate whether the observed differences during adolescence reflect early functional immaturity of prefrontal cortices that regulate motivated behavior and psychostimulant responding. The finding of significantly better responding during adolescence suggests apparent functional maturity of prefrontal circuits and greater cognitive flexibility at younger ages. These findings in rodent models suggest that adolescence is a period of altered sensitivity to environmental stimuli, including abused drugs. Further efforts are required to overcome technical challenges in order to evaluate drug effects systematically in this age group.
ESTHER : Leslie_2004_Ann.N.Y.Acad.Sci_1021_148
PubMedSearch : Leslie_2004_Ann.N.Y.Acad.Sci_1021_148
PubMedID: 15251884