Converging research efforts suggest that nicotine and other drugs that act at nicotinic acetylcholine receptors (nAChRs) may be beneficial in the management of Parkinson’s disease. This idea initially stemmed from the results of epidemiological studies which demonstrate that smoking is associated with a decreased incidence of Parkinson’s disease. The subsequent finding that nicotine administration protected against nigrostriatal damage in parkinsonian animal models led to the idea that nicotine in tobacco products may contribute to this apparent protective action. Nicotine most likely exerts its effects by interacting at nAChRs. Accumulating research indicates that multiple subtypes, including α4β2, α6β2 and/or α7 containing nAChRs, may be involved. Stimulation of nAChRs initially activates various intracellular transduction pathways primarily via alterations in calcium signaling. Consequent adaptations in immune responsiveness and trophic factors may ultimately mediate nicotine’s ability to reduce/halt the neuronal damage that arises in Parkinson’s disease. In addition to a potential neuroprotective action, nicotine also has anti-depressant properties and improves attention/cognition. Altogether, these findings suggest that nicotine and nAChR drugs represent promising therapeutic agents for the management of Parkinson’s disease.

Nicotine treatment has long been associated with alterations in ␣4␤2* nicotinic acetylcholine receptor (nAChR) expression that modify dopaminergic function. However, the influence of longterm nicotine treatment on the ␣6␤2* nAChR, a subtype specifically localized on dopaminergic neurons, is less clear. Here we used voltammetry, as well as receptor binding studies, to identify the effects of nicotine on striatal ␣6␤2* nAChR function and expression. Long-term nicotine treatment via drinking water enhanced nonburst and burst endogenous dopamine release from rat striatal slices. In control animals, ␣6␤2* nAChR blockade with ␣-conotoxin MII (␣-CtxMII) decreased release with nonburst stimulation but not with burst firing. These data in control animals suggest that varying stimulus frequencies differentially regulate ␣6␤2* nAChR-evoked dopamine release. In contrast, in nicotine-treated rats, ␣6␤2* nAChR blockade elicited a similar pattern of dopamine release with nonburst and burst firing. To elucidate the ␣6␤2* nAChR subtypes altered with long-term nicotine treatment, we used the novel ␣-CtxMII analog E11A in combination with ␣4 nAChR knockout mice. 125 I-␣-CtxMII competition studies in striatum of knockout mice showed that nicotine treatment decreased the ␣6␣4␤2* subtype but increased the ␣6(non␣4)␤2* nAChR population. These data indicate that ␣6␤2* nAChR-evoked dopamine release in nicotine-treated rats is mediated by the ␣6(non␣4)␤2* nAChR subtype and suggest that the ␣6␣4␤2* nAChR and/or ␣4␤2* nAChR contribute to the differential effect of higher frequency stimulation on dopamine release under control conditions.

L-dopa-induced dyskinesias (LIDs) are a serious complication of L-dopa therapy for Parkinson's disease. Emerging evidence indicates that the nicotinic cholinergic system plays a role in LIDs, although the pathways and mechanisms are poorly understood. Here we used optogenetics to investigate the role of striatal cholinergic interneurons in LIDs. Mice expressing cre-recombinase under the control of the choline acetyltransferase promoter (ChAT-Cre) were lesioned by unilateral injection of 6-hydroxydopamine. AAV5-ChR2-eYFP or AAV5-control-eYFP was injected into the dorsolateral striatum, and optical fibers implanted. After stable virus expression, mice were treated with L-dopa. They were then subjected to various stimulation protocols for 2 h and LIDs rated. Continuous stimulation with a short duration optical pulse (1-5 ms) enhanced LIDs. This effect was blocked by the general muscarinic acetylcholine receptor (mAChR) antagonist atropine indicating it was mAChR-mediated. By contrast, continuous stimulation with a longer duration optical pulse (20 ms to 1 s) reduced LIDs to a similar extent as nicotine treatment (~50%). The general nicotinic acetylcholine receptor (nAChR) antagonist mecamylamine blocked the decline in LIDs with longer optical pulses showing it was nAChR-mediated. None of the stimulation regimens altered LIDs in control-eYFP mice. Lesion-induced motor impairment was not affected by optical stimulation indicating that cholinergic transmission selectively regulates LIDs. Longer pulse stimulation increased the number of c-Fos expressing ChAT neurons, suggesting that changes in this immediate early gene may be involved. These results demonstrate that striatal cholinergic interneurons play a critical role in LIDs and support the idea that nicotine treatment reduces LIDs via nAChR desensitization.

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Although a relative newcomer to the nicotinic acetylcholine receptor (nAChR) family, substantial evidence suggests that α6 containing nAChRs play a key role in CNS function. This subtype is unique in its relatively restricted localization to the visual system and catecholaminergic pathways. These latter include the mesolimbic and nigrostriatal dopaminergic systems, which may account for the involvement of α6 containing nAChRs in the rewarding properties of nicotine and in movement. Here, we review the literature on the role of α6 containing nAChRs with a focus on the striatum and nucleus accumbens. This includes molecular, electrophysiological and behavioral studies in control and lesioned animal models, as well as in different genetic models. Converging evidence suggest that the major α6 containing nAChRs subtypes in the nigrostriatal and mesolimbic dopamine system are the α6β2β3 and α6α4β2β3 nAChR populations. They appear to have a dominant role in regulating dopamine release, with consequent effects on nAChR-modulated dopaminergic functions such as reinforcement and motor behavior. Altogether these data suggest that drugs directed to α6 containing nAChRs may be of benefit for the treatment of addiction and for neurological disorders with locomotor deficits such as Parkinson’s disease.

There exists a remarkable diversity of neurotransmitter compounds in the striatum, a pivotal brain region in the pathology of Parkinson's disease, a movement disorder characterized by rigidity, tremor and bradykinesia. The striatal dopaminergic system, which is particularly vulnerable to neurodegeneration in this disorder, appears to be the major contributor to these motor problems. However, numerous other neurotransmitter systems in the striatum most likely also play a significant role, including the nicotinic cholinergic system. Indeed, there is an extensive anatomical overlap between dopaminergic and cholinergic neurons, and acetylcholine is well known to modulate striatal dopamine release both in vitro and in vivo. Nicotine, a drug that stimulates nicotinic acetylcholine receptors (nAChRs), influences several functions relevant to Parkinson's disease. Extensive studies in parkinsonian animals show that nicotine protects against nigrostriatal damage, findings that may explain the well-established decline in Parkinson's disease incidence with tobacco use. In addition, recent work shows that nicotine reduces L-dopa-induced abnormal involuntary movements, a debilitating complication of L-dopa therapy for Parkinson's disease. These combined observations suggest that nAChR stimulation may represent a useful treatment strategy for Parkinson's disease for neuroprotection and symptomatic treatment. Importantly, only selective nAChR subtypes are present in the striatum including the α4β2*, α6β2* and α7 nAChR populations. Treatment with nAChR ligands directed to these subtypes may thus yield optimal therapeutic benefit for Parkinson's disease, with a minimum of adverse side effects. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access OverviewThe basal ganglia are key in the pathogenesis of Parkinson's disease, a movement disorder characterized by a predominant loss of nigrostriatal dopaminergic neurons [1][2][3]. A major component of the basal ganglia is the striatum which receives projections from dopaminergic cell bodies in the substantia nigra. In addition to dopamine, the striatum contains a wide diversity of neuroactive substances including serotonin, glutamate, GABA, noradrenaline, cannabinoids, opioids, adenosine, and numerous neuropeptides, any of which may contribute to the regulation of dopaminergic activity [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18]. Furthermore, extensive evidence shows that acetylcholine influences striatal dopamine release predominantly through an action at nAChRs [19][20][21], and also muscarinic receptors to a l...

Background Dyskinesias are a disabling motor complication that arises with prolonged L-dopa treatment. Studies using D1 receptor drugs and genetically modified mice suggest that medium spiny neurons expressing D1 receptors play a primary role in L-dopa-induced dyskinesias. However, the specific role of these neurons in dyskinesias is not fully understood. Methods We used optogenetics, which allows for precise modulation of select neurons in vivo, to investigate whether striatal D1-expressing medium spiny neuron activity regulates abnormal involuntary movements or dyskinesia in parkinsonian mice. D1-cre mice unilaterally lesioned with 6-hydroxydopamine received striatal injections of cre-dependent channelrhodopsin2-virus or control-virus. After stable virus expression, the effect of optical stimulation on dyskinesia was tested in L-dopa-naïve and L-dopa-primed mice. Results Single pulse and burst optical stimulation of D1-expressing medium spiny neurons induced dyskinesias in L-dopa-naïve channelrhodopsin2 mice. In stably dyskinetic mice, L-dopa injection induced dyskinesia to a similar or somewhat greater extent than optical stimulation. Combined L-dopa administration and stimulation resulted in an additive increase in dyskinesias, indicating that other mechanisms also contribute. Molecular studies indicate that changes in extracellular signal-regulated kinase phosphorylation in D1-expressing medium spiny neurons are involved. Optical stimulation did not ameliorate parkinsonism in L-dopa-naïve mice. However, it improved parkinsonism in L-dopa-primed mice to a similar extent as L-dopa administration. None of the stimulation paradigms enhanced dyskinesia or modified parkinsonism in L-dopa-naïve or L-dopa-primed control-virus mice. Conclusion The data provide direct evidence that striatal D1-expressing medium spiny neuron stimulation is sufficient to induce dyskinesias and contributes to the regulation of motor control.

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