These data suggest that nicotine or selective nicotinic agonists may represent a useful treatment strategy to reduce levodopa-induced dyskinesias.

Parkinson's disease is a debilitating neurodegenerative movement disorder characterized by damage to the nigrostriatal dopaminergic system. Current therapies are symptomatic only and may be accompanied by serious side effects. There is therefore a continual search for novel compounds for the treatment of Parkinson's disease symptoms, as well as to reduce or halt disease progression. Nicotine administration has been reported to improve motor deficits that arise with nigrostriatal damage in parkinsonian animals and in Parkinson's disease. In addition, nicotine protects against nigrostriatal damage in experimental models, findings that have led to the suggestion that the reduced incidence of Parkinson's disease in smokers may be due to the nicotine in tobacco. Altogether, these observations suggest that nicotine treatment may be beneficial in Parkinson's disease. Nicotine interacts with multiple nicotinic receptor (nAChR) subtypes in the peripheral and central nervous system, as well as in skeletal muscle. Work to identify the subtypes affected in Parkinson's disease is therefore critical for the development of targeted therapies. Results show that striatal α6β2-containing nAChRs are particularly susceptible to nigrostriatal damage, with a decline in receptor levels that closely parallels losses in striatal dopamine. In contrast, α4β2-containing nAChRs are decreased to a much smaller extent under the same conditions. These observations suggest that development of nAChR agonists or antagonists targeted to α6β2-containing nAChRs may represent a particularly relevant target for Parkinson's disease therapeutics. Keywordsα-ConotoxinMII; Nicotine; Nicotinic; Parkinson's disease; Nigrostriatal; Striatum Parkinson's disease and the nicotinic cholinergic systemThe pathological hallmarks of Parkinson's disease are the presence of intracellular Lewy bodies and an extensive degeneration of the nigrostriatal dopaminergic system. [1][2][3][4]. There is a ≥70% decline in striatal dopamine and ≥50% loss of nigral dopaminergic neurons with the onset of clinical symptoms, which include bradykinesia, rigidity, and tremor [1][2][3][4].Although Parkinson's disease has primarily been considered a dopaminergic disorder, it is becoming increasingly clear that multiple CNS systems are involved in its pathogenesis [5][6][7]. Braak and coworkers have also identified Lewy bodies in numerous non-dopaminergic brain regions including the locus coeruleus, raphe nuclei, thalamus, amygdala, olfactory nuclei, pedunculopontine nucleus, and cerebral cortex [5,6]. These observations are in agreement with much earlier studies, which indicated that multiple CNS neuronal systems are affected in 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...

Accumulating evidence suggests that nicotine, a drug that stimulates nicotinic acetylcholine receptors, may be of therapeutic value in Parkinson’s disease. Beneficial effects may be several-fold. One of these is a protective action against nigrostriatal damage. This possibility stems from the results of epidemiological studies that consistently demonstrate an inverse correlation between tobacco use and Parkinson’s disease. This reduced incidence of Parkinson’s disease has been attributed to the nicotine in tobacco products, at least in part, based on experimental work showing a protective effect of nicotine against toxic insults. Second, several studies suggest a symptomatic effect of nicotine in Parkinson’s disease, although effects are small and somewhat variable. Third, recent data in nonhuman primates show that nicotine attenuates L-dopa-induced dyskinesias, a debilitating side effect that develops in the majority of patients on L-dopa therapy. Collectively, these observations suggest that nicotine or CNS selective nicotinic receptor ligands hold promise for Parkinson’s disease therapy to reduce disease progression, improve symptoms and/or decrease L-dopa-induced dyskinesias.

Brain dopaminergic systems are critical in motor control as evidenced by findings that their disruption results in movement disorders such as Parkinson's disease. Nicotinic acetylcholine receptor (nAChR) activation plays an important role in regulating striatal dopaminergic function. Rodent studies show that short-term nicotine exposure influences stimulated striatal dopamine release with responsiveness dependent on neuronal activity. However, studies have not yet been done in nonhuman primates, nor has work been done to evaluate the effect of long-term nicotine exposure, which is relevant for therapies for chronic neurological disorders. Here, we used voltammetry to assess the role of nAChRs on evoked dopamine release from monkey putamen slices. In both ventral and dorsal putamen, ␣3/␣6␤2* nAChRs regulated Ն80% of non-burst-(single pulse) nAChR-modulated dopamine release, and ␣4␤2* nAChRs regulated the remainder. Similar results were observed with burstfiring in ventral but not dorsal putamen, indicating that nAChRmodulated effects on release depend on the subregion and firing frequency. Next, we investigated the consequence of long-term nicotine exposure via the drinking water on nAChR-modulated responsiveness. Nicotine treatment altered both non-burst-and burst-stimulated dopamine release in ventral but not dorsal putamen. Altogether, these data support a predominant role for ␣3/ ␣6␤2* nAChRs in the regulation of evoked dopamine release in nonhuman primate putamen. They also show that long-term nicotine treatment selectively modifies nAChR-modulated release in distinct striatal subregions. These findings have implications for the development of treatments for addiction and neurological disorders with nAChR dysfunction.The nigrostriatal dopaminergic system plays a critical role in motor function under physiological conditions and in neurodegenerative disorders such as Parkinson's disease. Striatal dopaminergic afferents are in intimate contact with numerous neuronal elements from other neurotransmitter systems, including those of the cholinergic system (Zhou et al., 2002;. Indeed, there exists an extensive overlap of dopaminergic and cholinergic markers in the striatum, providing the anatomical basis for the close functional interrelationship between these two neurotransmitter systems (Zhou et al., 2002).Acetylcholine, secreted from cholinergic interneurons, modulates striatal dopamine release primarily via activation of nicotinic acetylcholine receptors (nAChRs), which are pentameric ligand-gated ion channels. The principal nAChRs in the striatum are the ␣4␤2* and ␣6␤2* subtypes (the asterisk denotes the possible presence of other subunits in the receptor complex) Quik et al., 2007;. Receptor expression studies in rodents indicate that ␣4␤2* nAChRs are in the majority (ϳ85%) compared with the ␣6␤2* nAChR subtype (ϳ15%). However, functional studies (synaptosomal nAChR-evoked [ 3 H]dopamine release) show that ␣4␤2* nAChRs control only ϳ70% and ␣6␤2* nAChRs 30% of striatal dopamine release. This discrepa...

Abbreviations used: DAT, dopamine transporter; DOPAC, dihydroxyphenylacetic acid; HVA, homovanillic acid; PD, Parkinson's disease; RTI-121, 2b-carboxylic acid isopropyl ester-3b-(4-iodophenyl) tropane. AbstractDespite a dramatic loss of nigrostriatal dopaminergic neurons in Parkinson's disease, clinical symptoms only arise with 70-80% reduction of striatal dopamine. The mechanisms responsible for this functional compensation are currently under debate. Although initial studies showed an enhanced pre-synaptic dopaminergic function with nigrostriatal degeneration, more recent work suggests that functional compensation is not dopamine-mediated. To address this issue, we used cyclic voltammetry to directly measure endogenous dopamine release from striatal slices of control monkeys and animals with a moderate or severe MPTP-induced dopaminergic lesion. The moderately lesioned monkeys were asymptomatic, while the severely lesioned animals were parkinsonian. In monkeys with a moderate lesion, a 300% increase was obtained in endogenous striatal dopamine release. In contrast, in striatal slices from severely lesioned animals, a small % of evoked dopamine signals were similar in amplitude to control while the greater majority were undetectable. These findings suggest that pre-synaptic dopaminergic compensation develops in residual dopaminergic terminals with moderate lesioning, but that this response is lost with severe nigrostriatal damage. Such an interpretation is supported by the results of dopamine turnover studies. This enhanced pre-synaptic dopaminergic activity may be important in maintaining normal motor function during the initial stages of Parkinson's disease.

The nicotine metabolite cotinine is an abundant long-lived bioactive compound that may contribute to the overall physiological effects of tobacco use. Although its mechanism of action in the central nervous system has not been extensively investigated, cotinine is known to evoke dopamine release in the nigrostriatal pathway through an interaction at nicotinic receptors (nAChRs). Because considerable evidence now demonstrates the presence of multiple nAChRs in the striatum, the present experiments were done to determine the subtypes through which cotinine exerts its effects in monkeys, a species that expresses similar densities of striatal ␣4␤2* (nAChR containing the ␣4 and ␤2 subunits, but not ␣3 or ␣6) and ␣3/␣6␤2* (nAChR composed of the ␣3 or ␣6 subunits and ␤2) nAChRs. Competition binding studies showed that cotinine interacts with both ␣4␤2* and ␣3/␣6␤2* nAChR subtypes in the caudate, with cotinine IC 50 values for inhibition of 5-[ ]dopamine release from two ␣3/␣6␤2* nAChR populations, one of which was sensitive to cotinine and the other was not. This cotinine-insensitive subtype was only present in the medial caudate and was preferentially lost with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced nigrostriatal damage. In contrast, cotinine and nicotine elicited equivalent levels of ␣4␤2* nAChR-mediated dopamine release. These data demonstrate that cotinine functionally discriminates between two ␣3/␣6␤2* nAChRs in monkey striatum, with the cotinine-insensitive ␣3/␣6␤2* nAChR preferentially vulnerable to nigrostriatal damage.Cotinine is one of the major metabolites of nicotine in a number of mammalian species, including humans (Fig. 1). Cotinine has a much longer pharmacokinetic half-life (15-19 h) than nicotine (2-3 h), which results in plasma cotinine levels 5 to 10-fold greater than those of the parent compound (Hukkanen et al., 2005). These observations raise the question of whether cotinine is pharmacologically active in vivo, thereby contributing to the overall effects of tobacco exposure. Indeed, numerous studies indicate that cotinine influences autonomic functions including heart rate, blood pressure, respiration, and hormone regulation (Borzelleca et al., 1962;Dominiak et al., 1985;Andersson et al., 1993;Buccafusco et al., 2007), and it also affects behavioral and cognitive task performance (Risner et al., 1985;Buccafusco and Terry, 2003;Terry et al., 2005).The cotinine-induced changes described above seem to be independent of, and frequently opposite to, those of nicotine. However, like nicotine, they seem to be mediated by interaction with nicotinic acetylcholine receptors (nAChRs), pentameric ligand-gated ion channels composed of various combinations of ␣ and ␤ subunits. Cotinine displaces binding of various radiolabeled nAChR ligands to rat whole brain, hippocampal, and cortical membrane preparations, with a potency ϳ100-fold less than that of nicotine (Sloan et al., 1984;Anderson and Arneric, 1994;Vainio and Tuominen, 2001). This interaction is of functional relevance because coti...

Presynaptic modulation of synaptic transmission is the primary function of central nicotinic acetylcholine receptors (nAChRs) in developing and adult brain. nAChR activation regulates release of various neurotransmitters, including norepinephrine (NA). Given evidence that NA may serve a critical functional role in cerebellar development, we have undertaken studies to determine whether nAChRs modulate NA release in developing cerebellum. In vitro experiments using cerebellar slices examined the effects of nAChR stimulation on release of radiolabeled NA (

Nicotinic acetylcholine receptors (nAChRs) mediate numerous visceral functions via medullary catecholamine (CA) neurons found in the nucleus tractus solitarius (NTS), dorsal motor nucleus of the vagus (DMV), and ventrolateral medulla (VLM). However, the nAChR subtypes involved are not known. We have therefore characterized expression of nine nAChR subunit mRNAs in adult and developing rat medullary CA nuclei using combined isotopic/nonisotopic in situ hybridization. Tyrosine hydroxylase (TH) mRNA, the CA-synthesizing enzyme, was used as a marker for CA neurons, because these nuclei consist of heterogeneous populations of cells. Subunit mRNA expression varied within and between nuclei, along the rostrocaudal axis, between cell types, and across development. All CA neurons expressed beta2 mRNA, whereas alpha2 mRNA was completely absent. alpha6 And beta3 mRNA expression were restricted mainly to the VLM. alpha4, alpha5, And alpha7 mRNA expression was significantly greater in the rostral than in the caudal VLM. alpha3 And beta4 mRNAs were highly expressed in the dorsal region of the NTS, whereas dense alpha7 mRNA expression was restricted to the DMV and ventral NTS. The remaining subunit mRNAs were detected to some degree in both DMV and NTS. Except for alpha4 mRNA, which peaked prenatally, expression levels of subunit transcripts in the NTS and DMV were lower during development compared with adults. In the VLM, alpha3, alpha4, and alpha5 mRNAs expression peaked perinatally, whereas alpha6 and beta3 levels increased with age. These variations in nAChR subunit mRNA expression suggest that different receptor subtypes may produce function-specific regulation of medullary CA systems.