Role for the nicotinic cholinergic system in movement disorders; therapeutic implications

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 α4β2*, α6β2* and α7 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.

Keywords: Ataxia; Nicotine; Nicotinic acetylcholine receptors; Tardive dyskinesia; Tourette's syndrome; l-dopa-induced dyskinesias.

Fig. 1

Nicotine and nAChR drugs reduce L-dopa-induced dyskinesias in parkinsonian monkeys. MPTP-lesioned monkeys were treated with L-dopa (10 mg/kg) and carbidopa (2.5 mg/kg) twice daily until stably dyskinetic. They were then given the indicated drugs immediately prior to L-dopa gavage. The bars are representative of the maximal decline in LIDs with the optimal drug dose as follows: nicotine, 300 μg/ml in the drinking water; varenicline, 0.03 mg/kg orally; TC-8831, 0.05 mg/kg orally; ABT-089, 0.1 mg/kg orally; and ABT-894, 0.01 mg/kg orally. The drug doses of nicotine, varenicline, ABT-089 and ABT-894 were within the range of those used in clinical trials. Several weeks of treatment were required for a maximal antidyskinetic effect. Tolerance did not develop to any of the nAChR drugs with months of treatment. Drug washout (lower panel) led to a return of LIDs to values similar to those in vehicle-treated monkeys. Values are the mean ± SEM of 5–12 animals per group. Significance of difference from vehicle-treated, **p < 0.01, ***p < 0.001 using Student’s t-test. Data taken in modified form from (D. Zhang, et al., 2014; D. Zhang, et al., 2013).

Fig. 2

Studies with nAChR null mutant mice indicate that receptors containing α4, α6 or α7 nAChR subunits all play a role in the occurrence of LIDs. Studies with genetically modified mice, nAChR subtype-specific antibodies and drugs, as well as nAChR subunit chimeras and concatamers show that the principle receptors in striatum are the α6β2*, α4β2* and α7 subtypes (Millar & Gotti, 2009; Quik & Wonnacott, 2011). The α6β2* nAChRs are present primarily on dopaminergic terminals originating in the substantia nigra. The α4β2* nAChRs are expressed on dopaminergic terminals and also on GABA interneurons and medium spiny neurons in striatum. By contrast, striatal α7 nAChRs are primarily localized to glutamatergic afferents from the cortex. Experiments with α4, α6 and α7 nAChR subunit knockout mice show that α6β2* and α7 nAChRs are involved in the development of LIDs, as the absence of these receptors decreases and increases baseline LID expression, respectively. In addition, the α6β2* and α4β2* nAChR subtypes are involved in the antidyskinetic effect of nicotine since deletion of the α6 and α4 nAChR subunit prevents nicotine from decreasing LIDs. Data taken in modified form from (L. Huang, et al., 2011; Quik, Campos, & Grady, 2013b; Quik, Park, et al., 2012).

Fig. 3

Nicotine treatment reduces vacuous chewing movements (VCMs) in a well-established rodent model of tardive dyskinesia. Rats or mice were pretreated with vehicle or nicotine given via minipump (A) or the drinking water (B and C). Two weeks later, they were treated with haloperidol via injection or surgically implanted with sub-dermal pellets that may mimic depot delivery of haloperidol in humans. Both forms of haloperidol treatment led to the development of VCMs, a motor side effect of antipsychotic therapy. (A–C) Chronic nicotine treatment reduced VCMs compared to vehicle-treated animals in rats and mice with either mode of haloperidol administration (injection or pellet), demonstrating the robustness of this effect. (B) The general nAChR agonist varenicline also reduced haloperidol-induced VCMs, indicating the reduction in VCMs is nAChR-mediated. Values are the mean ± SEM of 6–12 animals per group. Significance of difference from the vehicle-treated control, #p < 0.05, ###p < 0.001: from the vehicle-haloperidol-treated group, *p < 0.05, **p < 0.01, ***p < 0.001 using two-way ANOVA followed by a Bonferroni post hoc test or using one-way ANOVA followed by a Dunnett’s post hoc test. Data taken in modified form from (Bordia, et al., 2013; Bordia, McIntosh, et al., 2012).