α6β2* and α4β2* Nicotinic Acetylcholine Receptors As Drug Targets for Parkinson's Disease

Quik, Maryka; Wonnacott, Susan

doi:10.1124/pr.110.003269

Cited by 175 publications

(191 citation statements)

References 341 publications

(496 reference statements)

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“…As mentioned earlier, there are multiple nAChRs throughout the body, with the predominant populations in the striatum being the a4b2* and a6b2* nAChR subtypes Millar and Gotti, 2009;Quik and Wonnacott, 2011). Although initial studies suggested that varenicline was selective for a4b2* nAChRs, subsequent work showed that it also interacted with a6b2*, a3b4*, and a7 nAChRs (Coe et al, 2005;Mihalak et al, 2006;Grady et al, 2010;Ween et al, 2010;Chatterjee et al, 2011;Bordia et al, 2012).…”

Section: Discussionmentioning

confidence: 98%

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Nicotinic Receptor Agonists Reduce l-DOPA–Induced Dyskinesias in a Monkey Model of Parkinson's Disease

Zhang

Mallela

Sohn

et al. 2013

J Pharmacol Exp Ther

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Abnormal involuntary movements or dyskinesias are a serious complication of long-term L-DOPA treatment of Parkinson's disease, for which there are few treatment options. Accumulating preclinical data show that nicotine decreases L-DOPAinduced dyskinesias (LIDs), suggesting that it may be a useful antidyskinetic therapy for Parkinson's disease. Here, we investigated whether nicotinic acetylcholine receptor (nAChR) agonists reduced LIDs in nonhuman primates. We first tested the nonselective nAChR agonist 1, 6,7,8,9-tetrahydro-6,10-methano-6H-pyrazino [2,3-h][3]benzazepine (varenicline), which offers the advantage that it is approved by the U.S. Food and Drug Administration for use in humans. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned monkeys (n 5 23) were first administered L-DOPA/carbidopa (10/2.5 mg/kg) twice daily 5 days/week until stably dyskinetic. Oral varenicline (0.03-0.10 mg/kg) decreased LIDs ∼50% compared with vehicle-treated monkeys, whereas nicotine treatment (300 mg/ml in drinking water) reduced LIDs by 70% in a parallel group of animals. We next tested the selective a4b2*/a6b2* nAChR agonist heptane] on LIDs in the same set of monkeys after a 10-week washout. We also tested TC-8831 in another set of MPTP-lesioned monkeys (n 5 16) that were nAChR drug-naïve. Oral TC-8831 (0.03-0.3 mg/kg) reduced LIDs in both sets by 30-50%. After a washout period, repeat TC-8831 dosing led to a greater decline in LIDs (60%) in both sets of monkeys that was similar to the effect of nicotine. Tolerance to any nAChR drug did not develop over the course of the study (3-4 months). NAChR drug treatment did not worsen parkinsonism or cognitive ability. These data suggest that nAChR agonists may be useful for the management of dyskinesias in L-DOPA-treated Parkinson's disease patients.

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Section: Discussionmentioning

confidence: 98%

“…The primary nAChRs in the basal ganglia are the a6b2* and a4b2* subtypes, with a smaller subset of a7 nAChRs (Millar and Gotti, 2009;Gotti et al, 2010;Quik and Wonnacott, 2011). Studies in parkinsonian null mutant mice suggest that nicotine may reduce LIDs by acting at one or several of these nAChR populations.…”

Section: Introductionmentioning

confidence: 99%

Nicotinic Receptor Agonists Reduce l-DOPA–Induced Dyskinesias in a Monkey Model of Parkinson's Disease

Zhang

Mallela

Sohn

et al. 2013

J Pharmacol Exp Ther

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“…Extensive investigations have identified the ␣6␤2␤3 and ␣6␣4␤2␤3 subtypes localized on dopaminergic neurons in the substantia nigra and ventral tegmental area as key modulators of dopamine release in striatum and nucleus accumbens (7)(8)(9)(10)(11)(12)(13)(14)(15)(16), making the receptors interesting in connection with Parkinson disease and nicotine addiction (4,6,17). Although not having been subjected to the same meticulous exploration as ␣6␤2* receptors, ␣6␤4* nAChRs have recently been reported to regulate norepinephrine release in mouse hippocampus (18), to play a major role for exocytosis in human adrenal gland chro-* This work was supported by the Lundbeck Foundation, The Aase and Ejner maffin cells (19), and to be expressed in rat dorsal root ganglia (20).…”

mentioning

confidence: 99%

Elucidation of Molecular Impediments in the α6 Subunit for in Vitro Expression of Functional α6β4* Nicotinic Acetylcholine Receptors

Jensen

Hoestgaard-Jensen

Jensen

2013

Journal of Biological Chemistry

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Background: Inefficient functional receptor expression in heterologous expression systems has hampered investigations of ␣6* nAChRs. Results: Determinants in the ␣6 subunit for ␣6␤4* functionality have been delineated. Conclusion: Phe 223 and the intracellular loop in ␣6 are molecular impediments to functional ␣6␤4* nAChR expression in vitro. Significance: The molecular basis for the inefficient functional expression of ␣6␤4* nAChRs in vitro has been elucidated.

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“…The asterisk indicates the possible presence of other subunits in the receptor complex. The ␣6␤2* nAChR subtypes have a restricted CNS distribution, including dopaminergic pathways, whereas the ␣4␤2* subtypes are widely distributed in the brain and also present on dopaminergic nerve terminals (Quik and Wonnacott, 2011;Threlfell and Cragg, 2011).…”

Section: Discussionmentioning

confidence: 99%

“…Nicotine is thought to exert this effect by acting at CNS nAChRs. These are pentameric ion channels composed of different ␣-subunits (␣2-␣10) or of ␣-and ␤-subunits (␤2-␤4) (Albuquerque et al, 2009;Gotti et al, 2009;Millar and Gotti, 2009;Changeux, 2010;Quik and Wonnacott, 2011). The principle subtypes in the peripheral nervous system are the ␣3␤4* and ␣7 nAChRs, whereas the ␣4␤2*, ␣6␤2*, and ␣7 nAChRs are the primary ones in the nigrostriatal pathway.…”

Section: Discussionmentioning

confidence: 99%

Nicotine Reduces Antipsychotic-Induced Orofacial Dyskinesia in Rats

Bordia

McIntosh²,

Quik

2011

J Pharmacol Exp Ther

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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 haloperidolinduced VCMs by ϳ20% after 5 weeks, with a significant ϳ60% 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 ␣6␤2* 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 ␣4␤2* nAChRs in both vehicle and haloperidoltreated 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.

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α6β2* and α4β2* Nicotinic Acetylcholine Receptors As Drug Targets for Parkinson's Disease

Cited by 175 publications

References 341 publications

Nicotinic Receptor Agonists Reduce l-DOPA–Induced Dyskinesias in a Monkey Model of Parkinson's Disease

Nicotinic Receptor Agonists Reduce l-DOPA–Induced Dyskinesias in a Monkey Model of Parkinson's Disease

Elucidation of Molecular Impediments in the α6 Subunit for in Vitro Expression of Functional α6β4* Nicotinic Acetylcholine Receptors

Nicotine Reduces Antipsychotic-Induced Orofacial Dyskinesia in Rats

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