Quik_2013_Biochem.Pharmacol_86(8)_1153

Accumulating evidence supports the idea that drugs acting at nicotinic acetylcholine receptors (nAChRs) may be beneficial for Parkinson's disease, a neurodegenerative movement disorder characterized by a loss of nigrostriatal dopaminergic neurons. Nicotine administration to parkinsonian animals protects against nigrostriatal damage. In addition, nicotine and nAChR drugs improve L-dopa-induced dyskinesias, a debilitating side effect of L-dopa therapy which remains the gold-standard treatment for Parkinson's disease. Nicotine exerts its antidyskinetic effect by interacting with multiple nAChRs. One approach to identify the subtypes specifically involved in L-dopa-induced dyskinesias is through the use of nAChR subunit null mutant mice. Previous work with beta2 and alpha6 nAChR knockout mice has shown that alpha6beta2* nAChRs were necessary for the development/maintenance of L-dopa-induced abnormal involuntary movements (AIMs). The present results in parkinsonian alpha4 nAChR knockout mice indicate that alpha4beta2* nAChRs also play an essential role since nicotine did not reduce L-dopa-induced AIMs in such mice. Combined analyses of the data from alpha4 and alpha6 knockout mice suggest that the alpha6alpha4beta2beta3 subtype may be critical. In contrast to the studies with alpha4 and alpha6 knockout mice, nicotine treatment did reduce L-dopa-induced AIMs in parkinsonian alpha7 nAChR knockout mice. However, alpha7 nAChR subunit deletion alone increased baseline AIMs, suggesting that alpha7 receptors exert an inhibitory influence on L-dopa-induced AIMs. In conclusion, alpha6beta2*, alpha4beta2* and alpha7 nAChRs all modulate L-dopa-induced AIMs, although their mode of regulation varies. Thus drugs targeting one or multiple nAChRs may be optimal for reducing L-dopa-induced dyskinesias in Parkinson's disease.