L-dopa-induced dyskinesias or abnormal involuntary movements (AIMs) are a debilitating adverse side-effect associated with prolonged L-dopa administration for Parkinson's disease. Few treatments are currently available for dyskinesias. Our recent data showed that nicotine reduced L-dopa-induced AIMs in parkinsonian animal models. An important question is the nicotinic acetylcholine receptor (nAChR) subtypes through which nicotine exerts this beneficial effect, as such knowledge would allow for the development of drugs that target the relevant receptor population(s). To address this, we used β2 nAChR subunit knockout (β2 (-/-)) mice because β2-containing nAChRs are key regulators of nigrostriatal dopaminergic function. Mice were lesioned by intracranial injection of 6-hydroxydopamine into the right medial forebrain bundle. Lesioning resulted in a similar degree of parkinsonism in β2 (-/-) mice and wildtype littermates. All mice were then injected with L-dopa (3 mg/kg) plus benserazide (15 mg/kg) for 4 wk until AIMs were fully developed. L-dopa-induced AIMs were about 40% less in the β2 (-/-) compared to the wildtype mice. Interestingly, nicotine (300 µg/ml in drinking water) reduced L-dopa-induced AIMs by 40% in wildtype mice, but had no effect in β2 (-/-) mice with partial nigrostriatal damage. The nicotine-mediated decline in AIMs was much less pronounced in mice with near-complete degeneration, suggesting that presynaptic nAChRs on dopaminergic terminals have a major influence. These data demonstrate an essential role for β2* nAChRs in the antidyskinetic effect of nicotine and suggest that drugs targeting these subtypes may be useful for the management of L-dopa-induced dyskinesias in Parkinson's disease.
- Received April 13, 2011.
- Revision received June 9, 2011.
- Accepted June 9, 2011.
- The American Society for Pharmacology and Experimental Therapeutics