Nicotinic receptors as CNS targets for Parkinson's disease

Abstract

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...

Continuous and Intermittent Nicotine Treatment Reduces l-3,4-Dihydroxyphenylalanine (l-DOPA)-Induced Dyskinesias in a Rat Model of Parkinson's Disease

“…Nicotine generally exerts its behavioral effects in vivo by interacting with neuronal nicotinic receptors (Gotti et al, 2006;Quik et al, 2007a). These pentameric ligand-gated ion channels may consist only of ␣-subunits, or of ␣-and ␤-subunits.…”

“…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 involved in regulating dopamine release (Gotti et al, 2006;Grady et al, 2007;Quik et al, 2007a). Nicotine reduces L-DOPA-induced dyskinetic-like movements in both L-DOPA naive and L-DOPA-primed monkeys when administered via the drinking water.…”

Prominent Role of α3/α6β2*nAChRs in Regulating Evoked Dopamine Release in Primate Putamen: Effect of Long-Term Nicotine Treatment

“…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%).…”

Long-Term Nicotine Treatment Differentially Regulates Striatal α6α4β2*and α6(Nonα4)β2*nAChR Expression and Function

“…One of these is the ␣4␤2* nAChR population, which consists of ␣4␤2 and ␣4␣5␤2 subtypes, as well as other minor subtypes (the asterisk indicates the possible presence of other nicotinic subunits in the receptor complex) (Gotti et al, 2007;Grady et al, 2007;Quik et al, 2007). It is noteworthy that long-term nicotine treatment differentially influences ␣4␤2* nAChR subtype expression, with an increase in ␣4␤2 sites and no change in ␣4␣5␤2 nAChRs (Mao et al, 2008).…”

“…Several major ␣6␤2* nAChRs have been identified in striatum, including the ␣6␣4␤2* and ␣6(non␣4)␤2* subtypes (Salminen et al, 2004;Gotti et al, 2007;Grady et al, 2007;Quik et al, 2007). These receptors are selectively localized to catecholaminergic regions and represent 20 to 45% of nAChRs in the mesolimbic and nigrostriatal systems, depending on species .…”