Continuous and Intermittent Nicotine Treatment Reduces l-3,4-Dihydroxyphenylalanine (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 [l-3,4-dihydroxyphenylalanine] 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. Therefore, we investigated whether constant nicotine administration reduced l-DOPA-induced AIMs in a rat parkinsonian model, with results compared with 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 weeks 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 weeks 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, whereas 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 patients with Parkinson's disease.