Nicotine Reduces L-DOPA-Induced Dyskinesias by Acting at

L-DOPA-induced dyskinesias or abnormal involuntary move-ments (AIMs) are a debilitating adverse complication associ-ated 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, because such knowledge would allow for the development of drugs that tar-get the relevant receptor population(s). To address this, we used 2 nAChR subunit knockout [2(/)] mice because 2-containing nAChRs are key regulators of nigrostriatal dopa-minergic function. All of the mice were lesioned by intracranial injection of 6-hydroxydopamine into the right medial forebrain bundle. Lesioning resulted in a similar degree of nigrostriatal damage and parkinsonism in 2(/) and wild-type mice. All of the mice then were injected with L-DOPA (3 mg/kg) plus bensera-zide (15 mg/kg) once daily for 4 weeks until AIMs were fully developed. L-DOPA-induced AIMs were approximately 40 % less in the 2(/) mice compared with the wild-type mice. It is interesting to note that nicotine (300 g/ml in drinking water) reduced L-DOPA-induced AIMs by 40 % in wild-type mice but had no effect in 2(/) mice with partial nigrostriatal damage. The nicotine-mediated decline in AIMs was much less pronounced in wild-type mice with near-complete degeneration, suggesting that presynaptic nAChRs on dopaminergic terminals have a major influence. These data demonstrate an essential role for 2* nAChRs in the antidyskinetic effect of nicotine and suggest that drugs targeting these subtypes may be useful for the manage-ment of L-DOPA-induced dyskinesias in Parkinson’s disease