Bordia T

References (23)

Title : Alpha7 nicotinic receptors as therapeutic targets for Parkinson's disease - Quik_2015_Biochem.Pharmacol_97(4)_399
Author(s) : Quik M , Zhang D , McGregor M , Bordia T
Ref : Biochemical Pharmacology , 97 :399 , 2015
Abstract : Accumulating evidence suggests that CNS alpha7 nicotinic acetylcholine receptors (nAChRs) are important targets for the development of therapeutic approaches for Parkinson's disease. This progressive neurodegenerative disorder is characterized by debilitating motor deficits, as well as autonomic problems, cognitive declines, changes in affect and sleep disturbances. Currently l-dopa is the gold standard treatment for Parkinson's disease motor problems, particularly in the early disease stages. However, it does not improve the other symptoms, nor does it reduce the inevitable disease progression. Novel therapeutic strategies for Parkinson's disease are therefore critical. Extensive pre-clinical work using a wide variety of experimental models shows that nicotine and nAChR agonists protect against damage to nigrostriatal and other neuronal cells. This observation suggests that nicotine and/or nAChR agonists may be useful as disease modifying agents. Additionally, studies in several parkinsonian animal models including nonhuman primates show that nicotine reduces l-dopa-induced dyskinesias, a side effect of l-dopa therapy that may be as incapacitating as Parkinson's disease itself. Work with subtype selective nAChR agonists indicate that alpha7 nAChRs are involved in mediating both the neuroprotective and antidyskinetic effects, thus offering a targeted strategy with optimal beneficial effects and minimal adverse responses. Here, we review studies demonstrating a role for alpha7 nAChRs in protection against neurodegenerative effects and for the reduction of l-dopa-induced dyskinesias. Altogether, this work suggests that alpha7 nAChRs may be useful targets for reducing Parkinson's disease progression and for the management of the dyskinesias that arise with l-dopa therapy.
ESTHER : Quik_2015_Biochem.Pharmacol_97(4)_399
PubMedSearch : Quik_2015_Biochem.Pharmacol_97(4)_399
PubMedID: 26093062

Title : Poster: Striatal cholinergic interneurons regulate L-dopa-induced dyskinesias -
Author(s) : Bordia T , Xiomara Perez XA , Zhang D , Quik M
Ref : Biochemical Pharmacology , 97 :630 , 2015
PubMedID:

Title : Evidence for a role for alpha6( *) nAChRs in l-dopa-induced dyskinesias using Parkinsonian alpha6( *) nAChR gain-of-function mice - Bordia_2015_Neurosci_295_187
Author(s) : Bordia T , McGregor M , McIntosh JM , Drenan RM , Quik M
Ref : Neuroscience , 295 :187 , 2015
Abstract : l-Dopa-induced dyskinesias (LIDs) are a serious side effect of dopamine replacement therapy for Parkinson's disease. The mechanisms that underlie LIDs are currently unclear. However, preclinical studies indicate that nicotinic acetylcholine receptors (nAChRs) play a role, suggesting that drugs targeting these receptors may be of therapeutic benefit. To further understand the involvement of alpha6beta2( *) nAChRs in LIDs, we used gain-of-function alpha6( *) nAChR (alpha6L9S) mice that exhibit a 20-fold enhanced sensitivity to nAChR agonists. Wildtype (WT) and alpha6L9S mice were lesioned by unilateral injection of 6-hydroxydopamine (6-OHDA, 3mug/ml) into the medial forebrain bundle. Three to 4wk later, they were administered l-dopa (3mg/kg) plus benserazide (15mg/kg) until stably dyskinetic. l-dopa-induced abnormal involuntary movements (AIMs) were similar in alpha6L9S and WT mice. WT mice were then given nicotine in the drinking water in gradually increasing doses to a final 300mug/ml, which resulted in a 40% decline AIMs. By contrast, there was no decrease in AIMs in alpha6L9S mice at a maximally tolerated nicotine dose of 20mug/ml. However, the nAChR antagonist mecamylamine (1mg/kg ip 30min before l-dopa) reduced l-dopa-induced AIMs in both alpha6L9S and WT mice. Thus, both a nAChR agonist and antagonist decreased AIMs in WT mice, but only the antagonist was effective in alpha6L9S mice. Since nicotine appears to reduce LIDs via desensitization, hypersensitive alpha6beta2( *) nAChRs may desensitize less readily. The present data show that alpha6beta2( *) nAChRs are key regulators of LIDs, and may be useful therapeutic targets for their management in Parkinson's disease.
ESTHER : Bordia_2015_Neurosci_295_187
PubMedSearch : Bordia_2015_Neurosci_295_187
PubMedID: 25813704

Title : The alpha7 nicotinic receptor agonist ABT-107 protects against nigrostriatal damage in rats with unilateral 6-hydroxydopamine lesions - Bordia_2015_Exp.Neurol_263_277
Author(s) : Bordia T , McGregor M , Papke RL , Decker MW , McIntosh JM , Quik M
Ref : Experimental Neurology , 263 :277 , 2015
Abstract : The finding that smoking is inversely correlated with Parkinson's disease and that nicotine attenuates nigrostriatal damage in Parkinsonian animals supports the idea that nicotine may be neuroprotective. Nicotine is thought to exert this effect by acting at nicotinic receptors (nAChRs), including the alpha7 subtype. The objective of this study was twofold: first, to test the protective potential of ABT-107, an agonist with high selectivity for alpha7 nAChRs; and second, to investigate its cellular mechanism of action. Rats were implanted with minipumps containing ABT-107 (0.25mg/kg/d). In addition, we tested the effect of nicotine (1mg/kg/d) as a positive control, and also DMXB (2mg/kg/d) which acts primarily with alpha7 but also alpha4beta2* nAChRs. Two weeks after minipump placement, the rats were lesioned by unilateral administration of 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle. Lesioning alone decreased contralateral forelimb use and adjusted stepping, two measures of Parkinsonism. ABT-107 and nicotine treatment significantly improved these behaviors at all weeks tested, with variable improvement with DMXB. We next investigated the cellular mechanism involved. The striatal dopamine transporter (DAT), a marker of dopaminergic integrity, was reduced ~70% with lesioning. ABT-107 or nicotine treatment significantly increased DAT levels in lesioned striatum; these drugs did not alter DAT levels in intact striatum. ABT-107 and nicotine also significantly improved basal dopamine release from lesioned striatum, as well as nicotine-stimulated dopamine release mediated via alpha4beta2* and alpha6beta2* nAChRs. These data suggest that alpha7 nAChR agonists may improve motor behaviors associated with nigrostriatal damage by enhancing striatal dopaminergic function.
ESTHER : Bordia_2015_Exp.Neurol_263_277
PubMedSearch : Bordia_2015_Exp.Neurol_263_277
PubMedID: 25261754

Title : ABT-089 and ABT-894 reduce levodopa-induced dyskinesias in a monkey model of Parkinson's disease - Zhang_2014_Mov.Disord_29_508
Author(s) : Zhang D , Bordia T , McGregor M , McIntosh JM , Decker MW , Quik M
Ref : Movement Disorders , 29 :508 , 2014
Abstract : Levodopa-induced dyskinesias (LIDs) are a serious complication of levodopa therapy for Parkinson's disease for which there is little treatment. Accumulating evidence shows that nicotinic acetylcholine receptor (nAChR) drugs decrease LIDs in parkinsonian animals. Here, we examined the effect of two beta2 nAChR agonists, ABT-089 and ABT-894, that previously were approved for phase 2 clinical trials for other indications. Two sets of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned monkeys were administered levodopa/carbidopa (10 mg/kg and 2.5 mg/kg, respectively) twice daily 5 days a week until they were stably dyskinetic. Each set had a vehicle-treated group, an nAChR agonist-treated group, and a nicotine-treated group as a positive control. Set A monkeys had previously received other nAChR drugs (nAChR drug-primed), whereas Set B monkeys were initially nAChR drug-naive. Both sets were administered the partial agonist ABT-089 (range, 0.01-1.0 mg/kg) orally 5 days a week twice daily 30 minutes before levodopa with each dose given for 1 to 5 weeks. ABT-089 decreased LIDs by 30% to 50% compared with vehicle-treated monkeys. Nicotine reduced LIDs by 70% in a parallel group. After 4 weeks of washout, the effect of the full agonist ABT-894 (range, 0.0001-0.10 mg/kg) was assessed on LIDs in Set A and Set B. ABT-894 reduced LIDs by 70%, similar to nicotine. Both drugs acted equally well at alpha4beta2* and alpha6beta2* nAChRs; however, ABT-089 was 30 to 60 times less potent than ABT-894. Tolerance did not develop for the time periods tested (range, 3-4 months). The nAChR drugs did not worsen parkinsonism or cognitive ability. Emesis, a common problem with nAChR drugs, was not observed. ABT-894 and ABT-089 appear to be good candidate nAChR drugs for the management of LIDs in Parkinson's disease.
ESTHER : Zhang_2014_Mov.Disord_29_508
PubMedSearch : Zhang_2014_Mov.Disord_29_508
PubMedID: 24515328

Title : Role for the nicotinic cholinergic system in movement disorders\; therapeutic implications - Quik_2014_Pharmacol.Ther_144_50
Author(s) : Quik M , Zhang D , Perez XA , Bordia T
Ref : Pharmacol Ther , 144 :50 , 2014
Abstract : A large body of evidence using experimental animal models shows that the nicotinic cholinergic system is involved in the control of movement under physiological conditions. This work raised the question whether dysregulation of this system may contribute to motor dysfunction and whether drugs targeting nicotinic acetylcholine receptors (nAChRs) may be of therapeutic benefit in movement disorders. Accumulating preclinical studies now show that drugs acting at nAChRs improve drug-induced dyskinesias. The general nAChR agonist nicotine, as well as several nAChR agonists (varenicline, ABT-089 and ABT-894), reduces l-dopa-induced abnormal involuntary movements or dyskinesias up to 60% in parkinsonian nonhuman primates and rodents. These dyskinesias are potentially debilitating abnormal involuntary movements that arise as a complication of l-dopa therapy for Parkinson's disease. In addition, nicotine and varenicline decrease antipsychotic-induced abnormal involuntary movements in rodent models of tardive dyskinesia. Antipsychotic-induced dyskinesias frequently arise as a side effect of chronic drug treatment for schizophrenia, psychosis and other psychiatric disorders. Preclinical and clinical studies also show that the nAChR agonist varenicline improves balance and coordination in various ataxias. Lastly, nicotine has been reported to attenuate the dyskinetic symptoms of Tourette's disorder. Several nAChR subtypes appear to be involved in these beneficial effects of nicotine and nAChR drugs including alpha4beta2*, alpha6beta2* and alpha7 nAChRs (the asterisk indicates the possible presence of other subunits in the receptor). Overall, the above findings, coupled with nicotine's neuroprotective effects, suggest that nAChR drugs have potential for future drug development for movement disorders.
ESTHER : Quik_2014_Pharmacol.Ther_144_50
PubMedSearch : Quik_2014_Pharmacol.Ther_144_50
PubMedID: 24836728

Title : The nicotine-mediated decline in l-dopa-induced dyskinesias is associated with a decrease in striatal dopamine release - Bordia_2013_J.Neurochem_125_291
Author(s) : Bordia T , McIntosh JM , Quik M
Ref : Journal of Neurochemistry , :291 , 2013
Abstract : l-dopa-induced dyskinesias (LIDs) are a side effect of Parkinson's disease therapy that is thought to arise, at least in part, because of excessive dopaminergic activity. Thus, drugs that regulate dopaminergic tone may provide an approach to manage LIDs. Our previous studies showed that nicotine treatment reduced LIDs in Parkinsonian animal models. This study investigates whether nicotine may exert its beneficial effects by modulating pre-synaptic dopaminergic function. Rats were unilaterally lesioned by injection of 6-hydroxydopamine (6-OHDA) (2 x 3 ug per site) into the medial forebrain bundle to yield moderate Parkinsonism. They were then implanted with minipumps containing vehicle or nicotine (2.0 mg/kg/d) and rendered dyskinetic with l-dopa (8 mg/kg plus 15 mg/kg benserazide). Lesioning alone decreased the striatal dopamine transporter, nicotinic receptor (nAChR) levels, and nAChR-mediated 3 H-dopamine release, consistent with previous results. Nicotine administration reduced l-dopa-induced abnormal involuntary movements throughout the course of the study (4 months). Nicotine treatment led to declines in the striatal dopamine transporter, alpha6beta2* nAChRs and various components of alpha6beta2* and alpha4beta2* nAChR-mediated release. l-dopa treatment had no effect. These data suggest that nicotine may improve LIDs in Parkinsonian animal models by dampening striatal dopaminergic activity.
ESTHER : Bordia_2013_J.Neurochem_125_291
PubMedSearch : Bordia_2013_J.Neurochem_125_291
PubMedID: 23373725

Title : Alpha4beta2 nicotinic receptors play a role in the nAChR-mediated decline in L-dopa-induced dyskinesias in parkinsonian rats - Quik_2013_Neuropharmacol_71_191
Author(s) : Quik M , Campos C , Bordia T , Strachan JP , Zhang J , McIntosh JM , Letchworth SR , Jordan K
Ref : Neuropharmacology , 71 :191 , 2013
Abstract : L-dopa-induced dyskinesias are a serious long-term side effect of dopamine replacement therapy for Parkinson's disease for which there are few treatment options. Our previous studies showed that nicotine decreased l-dopa-induced abnormal involuntary movements (AIMs). Subsequent work with knockout mice demonstrated that alpha6beta2 nicotinic receptors (nAChRs) play a key role. The present experiments were done to determine if alpha4beta2 nAChRs are also involved in l-dopa-induced dyskinesias. To approach this, we took advantage of the finding that alpha6beta2 nAChRs are predominantly present on striatal dopaminergic nerve terminals, while a significant population of alpha4beta2 nAChRs are located on other neurons. Thus, a severe dopaminergic lesion would cause a major loss in alpha6beta2, but not alpha4beta2 nAChRs. Experiments were therefore done in which rats were unilaterally lesioned with 6-hydroxydopamine, at a dose that led to severe nigrostriatal damage. The dopamine transporter, a dopamine nerve terminal marker, was decreased by >99%. This lesion also decreased striatal alpha6beta2 nAChRs by 97%, while alpha4beta2 nAChRs were reduced by only 12% compared to control. A series of beta2 nAChR compounds, including TC-2696, TI-10165, TC-8831, TC-10600 and sazetidine reduced l-dopa-induced AIMs in these rats by 23-32%. TC-2696, TI-10165, TC-8831 were also tested for parkinsonism, with no effect on this behavior. Tolerance did not develop with up to 3 months of treatment. Since alpha4alpha5beta2 nAChRs are also predominantly on striatal dopamine terminals, these data suggest that drugs targeting alpha4beta2 nAChRs may reduce l-dopa-induced dyskinesias in late stage Parkinson's disease.
ESTHER : Quik_2013_Neuropharmacol_71_191
PubMedSearch : Quik_2013_Neuropharmacol_71_191
PubMedID: 23583932

Title : Nicotine-mediated improvement in L-dopa-induced dyskinesias in MPTP-lesioned monkeys is dependent on dopamine nerve terminal function - Quik_2013_Neurobiol.Dis_50_30
Author(s) : Quik M , Mallela A , Chin M , McIntosh JM , Perez XA , Bordia T
Ref : Neurobiol Dis , 50 :30 , 2013
Abstract : L-dopa-induced dyskinesias (LIDs) are abnormal involuntary movements that develop with long term L-dopa therapy for Parkinson's disease. Studies show that nicotine administration reduced LIDs in several parkinsonian animal models. The present work was done to understand the factors that regulate the nicotine-mediated reduction in LIDs in MPTP-lesioned nonhuman primates. To approach this, we used two groups of monkeys, one with mild-moderate and the other with more severe parkinsonism rendered dyskinetic using L-dopa. In mild-moderately parkinsonian monkeys, nicotine pretreatment (300 mug/ml via drinking water) prevented the development of LIDs by ~75%. This improvement was maintained when the nicotine dose was lowered to 50 mug/ml but was lost with nicotine removal. Nicotine re-exposure again decreased LIDs. By contrast, nicotine treatment did not reduce LIDs in monkeys with more severe parkinsonism. We next determined how nicotine's ability to reduce LIDs correlated with lesion-induced changes in the striatal dopamine transporter and (3)H-dopamine release in these two groups of monkeys. The striatal dopamine transporter was reduced to 54% and 28% of control in mild-moderately and more severely parkinsonian monkeys, respectively. However, basal, K(+), alpha4beta2* and alpha6beta2* nAChR-evoked (3)H-dopamine release were near control levels in striatum of mild-moderately parkinsonian monkeys. By contrast, these same release measures were reduced to a significantly greater extent in striatum of more severely parkinsonian monkeys. Thus, nicotine best improves LIDs in lesioned monkeys in which striatal dopamine transmission is still relatively intact. These data suggest that nicotine treatment would most effectively reduce LIDs in patients with mild to moderate Parkinson's disease.
ESTHER : Quik_2013_Neurobiol.Dis_50_30
PubMedSearch : Quik_2013_Neurobiol.Dis_50_30
PubMedID: 23009753

Title : Varenicline is a potent partial agonist at alpha6beta2* nicotinic acetylcholine receptors in rat and monkey striatum - Bordia_2012_J.Pharmacol.Exp.Ther_342_327
Author(s) : Bordia T , Hrachova M , Chin M , McIntosh JM , Quik M
Ref : Journal of Pharmacology & Experimental Therapeutics , 342 :327 , 2012
Abstract : Extensive evidence indicates that varenicline reduces nicotine craving and withdrawal symptoms by modulating dopaminergic function at alpha4beta2* nicotinic acetylcholine receptors (nAChRs) (the asterisk indicates the possible presence of other nicotinic subunits in the receptor complex). More recent data suggest that alpha6beta2* nAChRs also regulate dopamine release and mediate nicotine reinforcement. The present experiments were therefore done to test the effect of varenicline on alpha6beta2* nAChRs and their function, because its interaction with this subtype is currently unclear. Receptor competition studies showed that varenicline inhibited alpha6beta2* nAChR binding (K(i) = 0.12 nM) as potently as alpha4beta2* nAChR binding (K(i) = 0.14 nM) in rat striatal sections and with approximately 20-fold greater affinity than nicotine. Functionally, varenicline was more potent in stimulating alpha6beta2* versus alpha4beta2* nAChR-mediated [(3)H]dopamine release from rat striatal synaptosomes with EC(50) values of 0.007 and 0.086 muM, respectively. However, it acted as a partial agonist on alpha6beta2* and alpha4beta2* nAChR-mediated [(3)H]dopamine release with maximal efficacies of 49 and 24%, respectively, compared with nicotine. We also evaluated varenicline's action in striatum of monkeys, a useful animal model for comparison with humans. Varenicline again potently inhibited monkey striatal alpha6beta2* (K(i) = 0.13 nM) and alpha4beta2* (K(i) = 0.19 nM) nAChRs in competition studies. Functionally, it potently stimulated both alpha6beta2* (EC(50) = 0.014 muM) and alpha4beta2* (EC(50) = 0.029 muM) nAChR-mediated [(3)H]dopamine release from monkey striatal synaptosomes, again acting as a partial agonist relative to nicotine at both subtypes. These data suggest that the ability of varenicline to interact at alpha6beta2* nAChRs may contribute to its efficacy as a smoking cessation aid.
ESTHER : Bordia_2012_J.Pharmacol.Exp.Ther_342_327
PubMedSearch : Bordia_2012_J.Pharmacol.Exp.Ther_342_327
PubMedID: 22550286

Title : Nicotine reduces antipsychotic-induced orofacial dyskinesia in rats - Bordia_2012_J.Pharmacol.Exp.Ther_340_612
Author(s) : Bordia T , McIntosh JM , Quik M
Ref : Journal of Pharmacology & Experimental Therapeutics , 340 :612 , 2012
Abstract : Antipsychotics are an important class of drugs for the management of schizophrenia and other psychotic disorders. They act by blocking dopamine receptors; however, because these receptors are present throughout the brain, prolonged antipsychotic use also leads to serious side effects. These include tardive dyskinesia, repetitive abnormal involuntary movements of the face and limbs for which there is little treatment. In this study, we investigated whether nicotine administration could reduce tardive dyskinesia because nicotine attenuates other drug-induced abnormal movements. We used a well established model of tardive dyskinesia in which rats injected with the commonly used antipsychotic haloperidol develop vacuous chewing movements (VCMs) that resemble human orofacial dyskinesias. Rats were first administered nicotine (minipump; 2 mg/kg per day). Two weeks later, they were given haloperidol (1 mg/kg s.c.) once daily. Nicotine treatment reduced haloperidol-induced VCMs by approximately 20% after 5 weeks, with a significant approximately 60% decline after 13 weeks. There was no worsening of haloperidol-induced catalepsy. To understand the molecular basis for this improvement, we measured the striatal dopamine transporter and nicotinic acetylcholine receptors (nAChRs). Both haloperidol and nicotine treatment decreased the transporter and alpha6beta2* nAChRs (the asterisk indicates the possible presence of other nicotinic subunits in the receptor complex) when given alone, with no further decline with combined drug treatment. By contrast, nicotine alone increased, while haloperidol reduced alpha4beta2* nAChRs in both vehicle and haloperidol-treated rats. These data suggest that molecular mechanisms other than those directly linked to the transporter and nAChRs underlie the nicotine-mediated improvement in haloperidol-induced VCMs in rats. The present results are the first to suggest that nicotine may be useful for improving the tardive dyskinesia associated with antipsychotic use.
ESTHER : Bordia_2012_J.Pharmacol.Exp.Ther_340_612
PubMedSearch : Bordia_2012_J.Pharmacol.Exp.Ther_340_612
PubMedID: 22144565

Title : Nicotine as a potential neuroprotective agent for Parkinson's disease - Quik_2012_Mov.Disord_27_947
Author(s) : Quik M , Perez XA , Bordia T
Ref : Movement Disorders , 27 :947 , 2012
Abstract : Converging research efforts suggest that nicotine and other drugs that act at nicotinic acetylcholine receptors (nAChRs) may be beneficial in the management of Parkinson's disease. This idea initially stemmed from the results of epidemiological studies that demonstrated that smoking is associated with a decreased incidence of Parkinson's disease. The subsequent finding that nicotine administration protected against nigrostriatal damage in parkinsonian animal models led to the idea that nicotine in tobacco products may contribute to this apparent protective action. Nicotine most likely exerts its effects by interacting at nAChRs. Accumulating research indicates that multiple subtypes containing nAChRs, including alpha4beta2, alpha6beta2, and/or alpha7, may be involved. Stimulation of nAChRs initially activates various intracellular transduction pathways primarily via alterations in calcium signaling. Consequent adaptations in immune responsiveness and trophic factors may ultimately mediate nicotine's ability to reduce/halt the neuronal damage that arises in Parkinson's disease. In addition to a potential neuroprotective action, nicotine also has antidepressant properties and improves attention/cognition. Altogether, these findings suggest that nicotine and nAChR drugs represent promising therapeutic agents for the management of Parkinson's disease.
ESTHER : Quik_2012_Mov.Disord_27_947
PubMedSearch : Quik_2012_Mov.Disord_27_947
PubMedID: 22693036

Title : Targeting nicotinic receptors for Parkinson's disease therapy - Quik_2011_CNS.Neurol.Disord.Drug.Targets_10_651
Author(s) : Quik M , Bordia T , Huang L , Perez XA
Ref : CNS Neurol Disord Drug Targets , 10 :651 , 2011
Abstract : A promising target for improved therapeutics in Parkinson's disease is the nicotinic acetylcholine receptor (nAChR). nAChRs are widely distributed throughout the brain, including the nigrostriatal system, and exert important modulatory effects on numerous behaviors. Accumulating evidence suggests that drugs such as nicotine that act at these sites may be of benefit for Parkinson's disease treatment. Recent work indicates that a potential novel therapeutic application is the use of nicotine to reduce levodopa-induced dyskinesias, a side effect of dopamine replacement therapy for Parkinson's disease. Several clinical trials also report that nicotine may diminish disease symptoms. Not only may nAChR drugs provide symptomatic improvement, but they may also attenuate the neurodegenerative process itself. This latter idea is supported by epidemiological studies which consistently demonstrate a approximately 50% reduced incidence of Parkinson's disease in smokers. Experimental work in parkinsonian animal models suggests that nicotine in tobacco may contribute to this protection. These combined findings suggest that nicotine and nAChR drugs offer the possibility of improved therapeutics for Parkinson's disease.
ESTHER : Quik_2011_CNS.Neurol.Disord.Drug.Targets_10_651
PubMedSearch : Quik_2011_CNS.Neurol.Disord.Drug.Targets_10_651
PubMedID: 21838678

Title : Nicotinic receptor-mediated reduction in L-DOPA-induced dyskinesias may occur via desensitization - Bordia_2010_J.Pharmacol.Exp.Ther_333_929
Author(s) : Bordia T , Campos C , McIntosh JM , Quik M
Ref : Journal of Pharmacology & Experimental Therapeutics , 333 :929 , 2010
Abstract : L-DOPA-induced dyskinesias in Parkinson's disease are a significant clinical problem for which few therapies are available. We recently showed that nicotine reduces L-DOPA-induced abnormal involuntary movements (AIMs) in parkinsonian animals, suggesting it may be useful for the treatment of L-DOPA-induced dyskinesias. The present experiments were performed to understand the mechanisms whereby nicotine reduces L-DOPA-induced AIMs. We used a well established model of dyskinesias, L-DOPA-treated unilateral 6-hydroxydopamine-lesioned rats. Dose-ranging studies showed that injection of 0.1 mg/kg nicotine once or twice daily for 4 or 10 days most effectively reduced AIMs, with no worsening of parkinsonism. Importantly, a single nicotine injection did not reduce AIMs, indicating that nicotine's effect is caused by long-term rather than short-term molecular changes. Administration of the metabolite cotinine did not reduce AIMs, suggesting a direct effect of nicotine. Experiments with the nicotinic receptor (nAChR) antagonist mecamylamine were done to determine whether nicotine acted via a receptor-mediated mechanism. Unexpectedly, several days of mecamylamine injection (1.0 mg/kg) alone significantly ameliorated dyskinesias to a comparable extent as nicotine. The decline in AIMs with combined nicotine and mecamylamine treatment was not additive, suggesting that nicotine exerts its effects via a nAChR interaction. This latter finding, combined with data showing that mecamylamine reduced AIMs to a similar extent as nicotine, and that nicotine or mecamylamine treatment both decreased alpha6beta2* and increased alpha4beta2* nAChR expression, suggests that the nicotine-mediated improvement in L-DOPA-induced AIMs may involve a desensitization block. These data have important implications for the treatment of L-DOPA-induced dyskinesias in Parkinson's disease.
ESTHER : Bordia_2010_J.Pharmacol.Exp.Ther_333_929
PubMedSearch : Bordia_2010_J.Pharmacol.Exp.Ther_333_929
PubMedID: 20200117

Title : alpha6ss2* and alpha4ss2* nicotinic receptors both regulate dopamine signaling with increased nigrostriatal damage: relevance to Parkinson's disease - Perez_2010_Mol.Pharmacol_78_971
Author(s) : Perez XA , Bordia T , McIntosh JM , Quik M
Ref : Molecular Pharmacology , 78 :971 , 2010
Abstract : Nicotinic receptors (nAChRs) are important modulators of dopaminergic transmission in striatum, a region critical to Parkinson's disease. The nAChRs mainly involved are the alpha6beta2* and alpha4beta2* subtypes. Lesion studies show that the alpha6beta2* receptor is decreased to a much greater extent with nigrostriatal damage than the alpha4beta2* subtype raising the question whether this latter nAChR population is more important with increased nigrostriatal damage. To address this, we investigated the effect of varying nigrostriatal damage on alpha6beta2* and alpha4beta2* receptor-modulated dopamine signaling using cyclic voltammetry. This approach offers the advantage that changes in dopamine release can be observed under different neuronal firing conditions. Total single-pulse-evoked dopamine release decreased in direct proportion to declines in the dopamine transporter and dopamine uptake. We next used alpha-conotoxinMII and mecamylamine to understand the role of the alpha4beta2* and alpha6beta2* subtypes in release. Single-pulse-stimulated alpha6beta2* and alpha4beta2* receptor dopamine release decreased to a similar extent with increasing nigrostriatal damage, indicating that both subtypes contribute to the control of dopaminergic transmission with lesioning. Total burst-stimulated dopamine release also decreased proportionately with nigrostriatal damage. However, the role of the alpha4beta2* and alpha6beta2* nAChRs varied with different degrees of lesioning, suggesting that the two subtypes play a unique function with burst firing, with a somewhat more prominent and possibly more selective role for the alpha6beta2* subtype. These data have important therapeutic implications because they suggest that drugs directed to both alpha4beta2* and alpha6beta2* nAChRs may be useful in the treatment of neurological disorders such as Parkinson's disease.
ESTHER : Perez_2010_Mol.Pharmacol_78_971
PubMedSearch : Perez_2010_Mol.Pharmacol_78_971
PubMedID: 20732972

Title : Nicotine is neuroprotective when administered before but not after nigrostriatal damage in rats and monkeys - Huang_2009_J.Neurochem_109_826
Author(s) : Huang LZ , Parameswaran N , Bordia T , McIntosh JM , Quik M
Ref : Journal of Neurochemistry , 109 :826 , 2009
Abstract : Nicotine reduces dopaminergic deficits in parkinsonian animals when administered before nigrostriatal damage. Here we tested whether nicotine is also beneficial when given to rats and monkeys with pre-existing nigrostriatal damage. Rats were administered nicotine before and after a unilateral 6-hydroxydopamine lesion of the medial forebrain bundle, and the results compared with those in which rats received nicotine only after lesioning. Nicotine pre-treatment attenuated behavioral deficits and lessened lesion-induced losses of the striatal dopamine transporter, and alpha6beta2* and alpha4beta2* nicotinic receptors (nAChRs). By contrast, nicotine administered 2 weeks after lesioning, when 6-hydroxydopamine-induced neurodegenerative effects are essentially complete, did not improve these same measures. Similar results were observed in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned monkeys. Nicotine did not enhance striatal markers when administered to monkeys with pre-existing nigrostriatal damage, in contrast to previous data that showed improvements when nicotine was given to monkeys before lesioning. These combined findings in two animal models suggest that nicotine is neuroprotective rather than neurorestorative against nigrostriatal damage. Receptor studies with (125)I-alpha-conotoxinMII and the alpha-conotoxinMII analog E11A were next performed to determine whether nicotine treatment pre- or post-lesioning differentially affected expression of alpha6alpha4beta2* and alpha6(nonalpha4)beta2* nAChR subtypes in striatum. The observations suggest that protection against nigrostriatal damage may be linked to striatal alpha6alpha4beta2* nAChRs.
ESTHER : Huang_2009_J.Neurochem_109_826
PubMedSearch : Huang_2009_J.Neurochem_109_826
PubMedID: 19250334

Title : Multiple roles for nicotine in Parkinson's disease - Quik_2009_Biochem.Pharmacol_78(7)_677
Author(s) : Quik M , Huang LZ , Parameswaran N , Bordia T , Campos C , Perez XA
Ref : Biochemical Pharmacology , 78 :677 , 2009
Abstract : There exists a remarkable diversity of neurotransmitter compounds in the striatum, a pivotal brain region in the pathology of Parkinson's disease, a movement disorder characterized by rigidity, tremor and bradykinesia. The striatal dopaminergic system, which is particularly vulnerable to neurodegeneration in this disorder, appears to be the major contributor to these motor problems. However, numerous other neurotransmitter systems in the striatum most likely also play a significant role, including the nicotinic cholinergic system. Indeed, there is an extensive anatomical overlap between dopaminergic and cholinergic neurons, and acetylcholine is well known to modulate striatal dopamine release both in vitro and in vivo. Nicotine, a drug that stimulates nicotinic acetylcholine receptors (nAChRs), influences several functions relevant to Parkinson's disease. Extensive studies in parkinsonian animals show that nicotine protects against nigrostriatal damage, findings that may explain the well-established decline in Parkinson's disease incidence with tobacco use. In addition, recent work shows that nicotine reduces l-dopa-induced abnormal involuntary movements, a debilitating complication of l-dopa therapy for Parkinson's disease. These combined observations suggest that nAChR stimulation may represent a useful treatment strategy for Parkinson's disease for neuroprotection and symptomatic treatment. Importantly, only selective nAChR subtypes are present in the striatum including the alpha4beta2*, alpha6beta2* and alpha7 nAChR populations. Treatment with nAChR ligands directed to these subtypes may thus yield optimal therapeutic benefit for Parkinson's disease, with a minimum of adverse side effects.
ESTHER : Quik_2009_Biochem.Pharmacol_78(7)_677
PubMedSearch : Quik_2009_Biochem.Pharmacol_78(7)_677
PubMedID: 19433069

Title : Nigrostriatal damage preferentially decreases a subpopulation of alpha6beta2* nAChRs in mouse, monkey, and Parkinson's disease striatum - Bordia_2007_Mol.Pharmacol_72_52
Author(s) : Bordia T , Grady SR , McIntosh JM , Quik M
Ref : Molecular Pharmacology , 72 :52 , 2007
Abstract : Parkinson's disease is a neurodegenerative movement disorder characterized by a loss of substantia nigra dopamine neurons, and corresponding declines in molecular components present on striatal dopaminergic nerve terminals. These include the alpha6beta2(*) nicotinic acetylcholine receptors (nAChRs), which are localized exclusively on dopamine terminals in striatum ((*)denotes the presence of possible additional subunits). In this study, we used a novel alpha-conotoxin MII (alpha-CtxMII) analog E11A to further investigate alpha6beta2(*) nAChR subtypes in mouse, monkey, and human striatum. Receptor competition studies with (125)I-alpha-CtxMII showed that E11A inhibition curves were biphasic, suggesting the presence of two distinct alpha6beta2(*) nAChR subtypes. These include a very high (femtomolar) and a high (picomolar) affinity site, with approximately 40% of the sites in the very high affinity form. It is noteworthy that only the high-affinity form was detected in alpha4 nAChR-null mutant mice. Because (125)I-alpha-CtxMII binds primarily to alpha6alpha4beta2beta3 and alpha6beta2beta3 nAChR subtypes in mouse striatum, these data suggest that the population lost in the alpha4 knockout mice was the alpha6alpha4beta2beta3 subtype. We next investigated the effect of nigrostriatal lesioning on these two striatal alpha6beta2(*) populations in two animal models and in Parkinson's disease. There was a preferential loss of the very high affinity subtype in striatum of mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), monkeys treated with MPTP, and patients with Parkinson's disease. These data suggest that dopaminergic terminals expressing the alpha6alpha4beta2beta3 population are selectively vulnerable to nigrostriatal damage. This latter nAChR subtype, identified with alpha-CtxMII E11A, may therefore provide a unique marker for dopaminergic terminals particularly sensitive to nigrostriatal degeneration in Parkinson's disease.
ESTHER : Bordia_2007_Mol.Pharmacol_72_52
PubMedSearch : Bordia_2007_Mol.Pharmacol_72_52
PubMedID: 17409284

Title : Nicotinic receptors as CNS targets for Parkinson's disease - Quik_2007_Biochem.Pharmacol_74(8)_1224
Author(s) : Quik M , Bordia T , O'Leary K
Ref : Biochemical Pharmacology , 74 :1224 , 2007
Abstract : Parkinson's disease is a debilitating neurodegenerative movement disorder characterized by damage to the nigrostriatal dopaminergic system. Current therapies are symptomatic only and may be accompanied by serious side effects. There is therefore a continual search for novel compounds for the treatment of Parkinson's disease symptoms, as well as to reduce or halt disease progression. Nicotine administration has been reported to improve motor deficits that arise with nigrostriatal damage in parkinsonian animals and in Parkinson's disease. In addition, nicotine protects against nigrostriatal damage in experimental models, findings that have led to the suggestion that the reduced incidence of Parkinson's disease in smokers may be due to the nicotine in tobacco. Altogether, these observations suggest that nicotine treatment may be beneficial in Parkinson's disease. Nicotine interacts with multiple nicotinic receptor (nAChR) subtypes in the peripheral and central nervous system, as well as in skeletal muscle. Work to identify the subtypes affected in Parkinson's disease is therefore critical for the development of targeted therapies. Results show that striatal alpha6beta2-containing nAChRs are particularly susceptible to nigrostriatal damage, with a decline in receptor levels that closely parallels losses in striatal dopamine. In contrast, alpha4beta2-containing nAChRs are decreased to a much smaller extent under the same conditions. These observations suggest that development of nAChR agonists or antagonists targeted to alpha6beta2-containing nAChRs may represent a particularly relevant target for Parkinson's disease therapeutics.
ESTHER : Quik_2007_Biochem.Pharmacol_74(8)_1224
PubMedSearch : Quik_2007_Biochem.Pharmacol_74(8)_1224
PubMedID: 17631864

Title : Increases in alpha4* but not alpha3*\/alpha6* nicotinic receptor sites and function in the primate striatum following chronic oral nicotine treatment - McCallum_2006_J.Neurochem_96_1028
Author(s) : McCallum SE , Parameswaran N , Bordia T , Fan H , Tyndale RF , Langston JW , McIntosh JM , Quik M
Ref : Journal of Neurochemistry , 96 :1028 , 2006
Abstract : Knowledge of the effects of chronic nicotine is critical considering its widespread use in tobacco products and smoking cessation therapies. Although nicotine is well known to up-regulate alpha4* nAChR sites and function in the cortex, its actions in the striatum are uncertain because of the presence of multiple subtypes with potentially opposing effects. We therefore investigated the effect of long-term nicotine treatment on nAChR sites and function in the primate striatum, which offers the advantage of similar proportions of alpha3*/alpha6* and alpha4* nAChRs. Nicotine was given in drinking water, which resembles smoking in its intermittent but chronic delivery. Plasma nicotine and cotinine levels were similar to smokers. Chronic nicotine treatment (> 6 months) enhanced alpha4* nAChR-evoked [(3)H]dopamine release in striatal subregions, with an overall pattern of increase throughout the striatum when normalized to uptake. This increase correlated with elevated striatal alpha4* nAChRs. Under the same conditions, striatal alpha3*/alpha6* nAChR sites and function were decreased or unchanged. These divergent actions of chronic nicotine treatment on alpha4* versus alpha6* nAChRs, as well as effects on dopamine uptake, allow for a complex control of striatal activity to maintain dopaminergic function. Such knowledge is important for understanding nicotine dependence and the consequences of nicotine administration for the treatment of neurological disorders.
ESTHER : McCallum_2006_J.Neurochem_96_1028
PubMedSearch : McCallum_2006_J.Neurochem_96_1028
PubMedID: 16412091

Title : Chronic oral nicotine treatment protects against striatal degeneration in MPTP-treated primates - Quik_2006_J.Neurochem_98_1866
Author(s) : Quik M , Parameswaran N , McCallum SE , Bordia T , Bao S , McCormack A , Kim A , Tyndale RF , Langston JW , Di Monte DA
Ref : Journal of Neurochemistry , 98 :1866 , 2006
Abstract : The present studies were done to investigate the effect of long-term nicotine treatment against nigrostriatal damage in non-human primates. Monkeys were administered nicotine in drinking water for 6 months to provide chronic but intermittent delivery as with smoking. Plasma nicotine levels ranged from 10 to 15 ng/mL, which were within the range in cigarette smokers. Animals were then lesioned with low doses of the dopaminergic neurotoxin MPTP for several months while nicotine was continued. The results showed that levels of striatal tyrosine hydroxylase, dopamine transporter, vesicular monoamine transporter, dopamine and nicotinic receptors were greater in nicotine-treated MPTP-lesioned primates than in lesioned animals not receiving nicotine. Nicotine had no effect in unlesioned animals. Monoamine oxidase activity was similar in unlesioned and lesioned animals treated with or without nicotine, suggesting that nicotine did not exert its effects through changes in MPTP or dopamine metabolism. MPTP-induced cell loss in the substantia nigra was unaffected by nicotine treatment, indicating that nicotine acts at the striatal level to restore/maintain dopaminergic function. These data further support the possibility that nicotine contributes to the lower incidence of Parkinson's disease in smokers.
ESTHER : Quik_2006_J.Neurochem_98_1866
PubMedSearch : Quik_2006_J.Neurochem_98_1866
PubMedID: 16882311

Title : Subunit composition of nicotinic receptors in monkey striatum: effect of treatments with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine or L-DOPA - Quik_2005_Mol.Pharmacol_67_32
Author(s) : Quik M , Vailati S , Bordia T , Kulak JM , Fan H , McIntosh JM , Clementi F , Gotti C
Ref : Molecular Pharmacology , 67 :32 , 2005
Abstract : Nicotinic acetylcholine receptors (nAChRs) represent an important modulator of striatal function both under normal conditions and in pathological states such as Parkinson's disease. Because different nAChR subtypes may have unique functions, immunoprecipitation and ligand binding studies were done to identify their subunit composition. As in the rodent, alpha2, alpha4, alpha6, beta2, and beta3 nAChR subunit immunoreactivity was identified in monkey striatum. However, distinct from the rodent, the present results also revealed the novel presence of alpha3 nAChR subunit-immunoreactivity in this same region, but not that for alpha5 and beta4. Relatively high levels of alpha2 and alpha3 subunits were also identified in monkey cortex, in addition to alpha4 and beta2. Experiments were next done to determine whether striatal subunit expression was changed with nigrostriatal damage. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine treatment decreased alpha6 and beta3 subunit immunoreactivity by approximately 80% in parallel with the dopamine transporter, suggesting that they are predominantly expressed on nigrostriatal dopaminergic projections. In contrast, alpha3, alpha4, and beta2 subunit immunoreactivity was decreased approximately 50%, whereas alpha2 was not changed. These data, together with those from dual immunoprecipitation and radioligand binding studies ([(3)H]cytisine, (125)I-alpha-bungarotoxin, and (125)I-alpha-conotoxin MII) suggest the following: that alpha6beta2beta3, alpha6alpha4beta2beta3, and alpha3beta2* nAChR subtypes are present on dopaminergic terminals and that the alpha4beta2 subtype is localized on both dopaminergic and nondopaminergic neurons, whereas alpha2beta2* and alpha7 receptors are localized on nondopaminergic cells in monkey striatum. Overall, these results suggest that drugs targeting non-alpha7 nicotinic receptors may be useful in the treatment of disorders characterized by nigrostriatal dopaminergic damage, such as Parkinson's disease.
ESTHER : Quik_2005_Mol.Pharmacol_67_32
PubMedSearch : Quik_2005_Mol.Pharmacol_67_32
PubMedID: 15470079

Title : Decrease in alpha3*\/alpha6* nicotinic receptors but not nicotine-evoked dopamine release in monkey brain after nigrostriatal damage - McCallum_2005_Mol.Pharmacol_68_737
Author(s) : McCallum SE , Parameswaran N , Bordia T , McIntosh JM , Grady SR , Quik M
Ref : Molecular Pharmacology , 68 :737 , 2005
Abstract : Nicotinic acetylcholine receptors (nAChRs) are decreased in the striata of patients with Parkinson's disease (PD) or in experimental models after nigrostriatal damage. Because presynaptic nAChRs on striatal dopamine terminals mediate dopamine release, receptor loss may contribute to behavioral deficits in PD. The present experiments were done to determine whether nAChR function is affected by nigrostriatal damage in nonhuman primates, because this model shares many features with PD. Initial characterization of nicotine-evoked [3H]dopamine release from monkey striatal synaptosomes revealed that release was calcium-dependent and inhibited by selective nAChR antagonists. It is noteworthy that a greater proportion (approximately 70%) of release was inhibited by the alpha3*/alpha6* antagonist alpha-conotoxinMII (alpha-CtxMII) compared with rodents. Monkeys were lesioned with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), and [3H]dopamine release, dopamine transporter, and nAChRs were measured. As anticipated, lesioning decreased the transporter and alpha3*/alpha6* nAChRs in caudate and putamen. In contrast, alpha3*/alpha6* nAChR-evoked [3H]dopamine release was reduced in caudate but not putamen, demonstrating a dissociation between nAChR sites and function. A different pattern was observed in the mesolimbic dopamine system. Dopamine transporter levels in nucleus accumbens were not reduced after MPTP, as expected; however, there was a 50% decline in alpha3*/alpha6* nAChR sites with no decrease in alpha3*/alpha6* receptor-evoked dopamine release. No declines in alpha-CtxMII-resistant nAChR (alpha4*) binding or nicotine-evoked release were observed in any region. These results show a selective preservation of alpha3*/alpha6* nAChR-mediated function in the nigrostriatal and mesolimbic dopamine systems after nigrostriatal damage. Maintenance of function in putamen, a region with a selective loss of dopaminergic terminals, may be important in PD.
ESTHER : McCallum_2005_Mol.Pharmacol_68_737
PubMedSearch : McCallum_2005_Mol.Pharmacol_68_737
PubMedID: 15933214