Nicotinic receptor agonists decrease L-dopa-induced dyskinesias most effectively in partially lesioned parkinsonian rats
Highlights
► Varenicline and A-85380 reduce abnormal movements in partially lesioned rats. ► The α4β2* and α6β2* nAChRs are critical for nicotine’s antidyskinetic effect. ► β2* nAChR drugs may be useful in the treatment of dyskinesias.
Introduction
Dyskinesias are a complication of L-dopa treatment that eventually develops in the majority of patients with Parkinson’s disease (Jenner, 2008, Lang, 2009, Pezzoli and Zini, 2010). These abnormal involuntary movements (AIMs) can be quite debilitating and represent a major drawback to continued L-dopa therapy. A variety of drugs targeting different neurotransmitter systems in the basal ganglia have been reported to exert beneficial effects against AIMs in parkinsonian animal models, including the glutamate, adenosine, noradrenaline, 5-hydroxytryptamine, cannabinoid, and opioid systems (Fabbrini et al., 2007, Fox et al., 2008). However, management of L-dopa-induced dyskinesias continues to represent a serious therapeutic challenge in Parkinson’s disease patients.
Recent results showed that nicotine administration improves L-dopa-induced dyskinesias in parkinsonian animal models (Quik et al., 2009). Nicotine given in the drinking water reduced L-dopa-induced dyskinesias in both L-dopa naïve and L-dopa primed monkeys (Quik et al., 2007). Similar findings were obtained in parkinsonian rodent models of L-dopa-induced dyskinesias. Nicotine given via several modes of administration (drinking water, minipump or injection) significantly improved L-dopa-induced AIMs in parkinsonian rats and mice (Bordia et al., 2008, Huang et al., 2009). These treatment modalities readily lend themselves to use in Parkinson’s disease patients, for instance, as an oral formulation (pill or solution) or a slow release mode (nicotine patch). Importantly, nicotine did not modify the anti-parkinsonian effect of L-dopa in any parkinsonian animal model (Bordia et al., 2008, Bordia et al., 2010, Huang et al., 2009, Quik et al., 2007).
Although the mechanism whereby nicotine exerts its antidyskinetic effect remains to be elucidated, studies with the nAChR antagonist mecamylamine indicate that nicotine may exert its antidyskinetic effect via an interaction at nAChRs (Bordia et al., 2010). These receptors are pentameric ligand gated ion channels expressed throughout the body including the central and peripheral nervous system and the neuromuscular junction. Multiple nAChR subunits have been identified (α1–α10, β1–β4, γ, δ and ɛ) which co-assemble to form a diverse family of receptor subtypes (Albuquerque et al., 2009, Gotti et al., 2009, Millar and Gotti, 2009). Notably, the nAChRs throughout the body are distinct from one another. For instance, the α1, β1, γ, δ and ɛ are exclusively expressed at the neuromuscular junction. The primary nAChRs in the peripheral nervous system are α3β4* and α7 expressing receptors, while the α4β2*, α6β2* and α7 nAChRs predominate in the CNS. The asterisk indicates the possible presence of other subunits in the receptor complex. The α4β2* nAChR subtype may play a significant antidyskinetic role since it is widely distributed throughout the brain, and highly expressed in the striatum, a region critical in the pathology of Parkinson’s disease (Gotti et al., 2009, Millar and Gotti, 2009, Quik et al., 2009). In addition, the α6β2* nAChR population may be important as it has a restricted distribution to catecholaminergic systems, and plays a prominent role in modulating dopaminergic function in the nigrostriatal and mesolimbic pathways (Exley et al., 2008, Meyer et al., 2008, Perez et al., 2009, Perez et al., 2008). Although not densely express in striatum, α7 receptors may also be involved since they are located in numerous brain regions linked to the striatum (Gotti et al., 2009).
To directly elucidate whether nicotine exerts its ability to reduce AIMs or dyskinetic-like movements by acting at nAChRs, we tested varenicline and A-85380 in a well characterized rat model of L-dopa-induced dyskinesias. The nAChR agonist varenicline was selected because it interacts with multiple nAChRs, while 5-iodo-A-85380 (A-85380) was chosen because it acts selectively at α4β2* and α6β2* subtypes. In addition, we investigated the effect of partial and near-complete striatal dopaminergic damage to determine the involvement of presynaptic as compared to postsynaptic nAChRs in nicotine’s antidyskinetic effect. The results show that nAChR agonists best reduce L-dopa-induced dyskinesias in rats with only partial striatal dopamine damage. These data suggest that α4β2* and/or α6β2* nAChRs localized to presynaptic dopaminergic terminals are important for the antidyskinetic effect of nicotine.
Section snippets
6-Hydroxydopamine (6-OHDA) lesioning
Male Sprague–Dawley rats (∼250 g) were purchased from Charles River Laboratories, Gilroy, CA. They were group housed in a temperature- and humidity-controlled environment under a 12 h light/dark cycle with free access to food and water. After a 2–3 day acclimation period, they were unilaterally lesioned by intracranial administration of 6-OHDA (free base; Sigma-Aldrich Co., St. Louis, MO). Two injections of 2 μl each (3 μg free base/μl dissolved in 0.02% ascorbic acid, 0.9% saline) were
The nonselective nAChR agonist varenicline decreased L-dopa-induced AIMs with a partial but not with a near-complete striatal dopamine lesion
As a first approach to test whether nAChR agonists reduced L-dopa-induced AIMs, we used varenicline because this drug interacts with a variety of subtypes, including α3β4*, α4β2* and α7* nAChRs (Coe et al., 2005, Gonzales et al., 2006, Jorenby et al., 2006, Mihalak et al., 2006, Rollema et al., 2007a, Rollema et al., 2007b). In addition, our recent unpublished data indicate that varenicline inhibits 125I-conotoxinMII binding, which labels α6β2* nAChRs.
We first evaluated the antidyskinetic
Discussion
The present results are the first to show that nAChR subtype agonists reduce L-dopa-induced abnormal movements in a parkinsonian rat model. Varenicline and A-85380 both reduced L-dopa-induced AIMs, directly demonstrating a role for nAChRs against dyskinesias. The nAChRs most likely involved are the α4β2* and α6β2* subtypes based on findings that A-85380, which targets β2* nAChRs, reduces L-dopa-induced AIMs. In addition, the results show that the antidyskinetic effect of nAChR agonists is
Acknowledgements
This work was supported by grants from the Michael J Fox Foundation and the National Institutes of Health [NS42091, NS47162] to MQ, and by a fellowship from the California TRDRP [18FT-0058] to LH. The authors thank Y. Y. Lee for excellent technical assistance.
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