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-DOPAinduced 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 Ն2 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 Ն3 weeks to allow for the development of AIMs, with nicotine treatment continued. Both modes of nicotine administration resulted in Ն50% 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.Dyskinesias are a complication of L-DOPA treatment that eventually develop in the majority of patients with Parkinson's disease (Fabbrini et al., 2007;Singh et al., 2007;Santini et al., 2008). These abnormal movements can be quite debilitating and represent a major drawback to continued L-DOPA therapy. A variety of drugs targeting various neurotransmitter systems in the basal ganglia have been reported to exert beneficial effects against dyskinetic-like movements in parkinsonian animal models, including the glutamate, adenosine, noradrenaline, 5-hydroxytryptamine, cannabinoid, and opioid systems (Brotchie, 2005;Fox et al., 2006;Fabbrini et al., 2007). However, management of L-DOPA-induced side effects in patients with Parkinson's disease continues to represent a serious therapeutic challenge.Therefore, there is a continual search for new approaches and alternative agents that may reduce this side effect associated with L-DOPA therapy. One drug that has recently been shown to attenuate L-DOPA-induced dyskinetic-like movements in nonhuman primates is nicotine (Quik et al., 2007b). Nicotine may exert this effect by acting on nicotinic acetylcholine receptors, which are present on dopaminergic terminals in the striatum and ...

Nicotinic Receptor Agonists Reduce l-DOPA–Induced Dyskinesias in a Monkey Model of Parkinson's Disease

“…Nicotine treatment decreased LIDs in parkinsonian monkey, rat, and mouse models, suggesting that it may represent a useful treatment approach (Quik et al, 2007;Bordia et al, 2008Bordia et al, , 2010Huang et al, 2011a). Moreover, various modes of nicotine administration successfully attenuated LIDs, including injection, oral treatment, and minipump infusion, some of which could readily be used in the clinic.…”

“…Moreover, various modes of nicotine administration successfully attenuated LIDs, including injection, oral treatment, and minipump infusion, some of which could readily be used in the clinic. Tolerance to the effect of nicotine did not develop in any species with study periods up to 6 months (Quik et al, 2007;Bordia et al, 2008Bordia et al, , 2010Huang et al, 2011a).…”

Pathophysiology of Drug-Induced Dyskinesias

“…A number of studies have demonstrated that in 6-OHDA lesioned rats and MPTP dyskinetic monkeys, long term exposure to nicotine, which acts on nicotinic acetylcholine receptors, can reduce drug-induced dyskinesias. Interestingly, the nicotinic receptor antagonist mecamylamine can also provide similar effects Bordia et al, 2008;Bordia et al, 2010). It has been recently demonstrated that drug-induced dyskinesias can effectively be decreased by selective nicotinic receptor agonists in dyskinetic partially lesioned rats (Huang et al, 2011).…”

l-DOPA Impairs Proteasome Activity in Parkinsonism through D1Dopamine Receptor

“…However, in our study, we challenge the idea that in LID, the proteasome activity should instead be increased. Interestingly, the ubiquitin-proteasome system displays an increased activity in animals chronically exposed to nicotine (Kane et al, 2004), a drug that displays anti-dyskinetic activity (Quik et al, 2007;Bordia et al, 2008). Further exploration is now needed to fully understand the relationships between dopamine signaling, the mechanisms of proteasome regulation and proteasome targets in medium spiny striatal neurons.…”