Received for publication May 7, 2008.
Revised July 21, 2008.
Accepted for publication July 22, 2008.

Continuous and intermittent nicotine treatment reduces L-dopa-induced dyskinesias in a rat model of Parkinson's disease

Abstract

The development of abnormal involuntary movements (AIMs) or dyskinesias is a serious complication of L-dopa therapy for Parkinson's disease. Our previous work had shown that intermittent nicotine dosing reduced L-dopa-induced dyskinetic-like movements in nonhuman primates. A readily available nicotine formulation is the nicotine patch, which provides a constant source of nicotine. However, constant nicotine administration more readily desensitizes nicotinic receptors, to possibly yield alternate behavioral outcomes. We therefore investigated whether constant nicotine administration reduced L-dopa-induced AIMs in a rat parkinsonian model, with results compared to those with intermittent nicotine dosing. Rats with a unilateral 6-hydroxydopamine (6-OHDA) lesion were exposed to either intermittent (drinking water) or constant (minipump) nicotine for 2 wk at doses that yielded plasma levels of the nicotine metabolite cotinine similar to those in smokers. The rats were next treated with L-dopa/benserazide (8 or 12 mg/kg/15 mg/kg) for 3 wk to allow for the development of AIMs, with nicotine treatment continued. Both modes of nicotine administration resulted in 50% decline in L-dopa-induced AIMs. Nicotine treatment also significantly reduced AIMs in L-dopa primed rats using either dosing regimen, while nicotine removal led to an increase in AIMs. There was no effect of nicotine on various measures of motor performance in 6-OHDA-lesioned rats. In summary, nicotine provided either via the drinking water or minipump reduced L-dopa-induced AIMs in a rat model of Parkinson's disease. These results suggest that either intermittent or constant nicotine treatment may be useful in the treatment of L-dopa-induced dyskinesias in Parkinson's disease patients.

Key words: L-dopa, Parkinson's disease, dyskinesias, nicotine, nicotinic, nigrostriatal