Nicotinic acetylcholine subunit mRNA expression in dopaminergic neurons of the rat substantia nigra and ventral tegmental area

Charpantier, Eric; Barnéoud, Pascal; Moser, Paul; Besnard, François; Sgard, Frédéric

doi:10.1097/00001756-199809140-00033

Cited by 155 publications

(112 citation statements)

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“…The use of other ligands such as radiolabeled nicotine, α-bungarotoxin and α-conotoxinMII has helped identify nAChR subtypes, including those containing the α4, α6 and α7 subunits [67,69,71]. These findings from receptor binding studies are in agreement with the results of in situ hybridization and RT-PCR work, which demonstrate the presence of α2 through α7 and β2 through β4 nAChR subunit transcripts in the striatum and/or substantia nigra [72][73][74][75][76][77]. The results of immunoprecipitation studies using subunit-selective nAChR antibodies suggest that the greater majority of these transcripts are translated into protein to form receptors [64,78].…”

supporting

confidence: 62%

Nicotinic receptors as CNS targets for Parkinson's disease

Quik

Bordia

O’Leary

2007

Biochemical Pharmacology

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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...

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supporting

confidence: 62%

Nicotinic receptors as CNS targets for Parkinson's disease

Quik

Bordia

O’Leary

2007

Biochemical Pharmacology

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“…VTA DA neurons express mRNAs for many different nAChR subunits. Within the DA neuron population there is variation in the prevalence and amount of nAChR subunit expression, but ␣2-␣7 and ␤2-␤4 mRNAs are all expressed by these neurons (Charpantier et al, 1998;Klink et al, 2001). They give rise to three pharmacologically identifiable nAChRs, one that is likely a homomeric ␣7 receptor and two that do not contain ␣7.…”

Section: Vta Nachrs and Behaviormentioning

confidence: 99%

Cellular and synaptic mechanisms of nicotine addiction

2002

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ABSTRACT:The tragic health effects of nicotine addiction highlight the importance of investigating the cellular mechanisms of this complex behavioral phenomenon. The chain of cause and effect of nicotine addiction starts with the interaction of this tobacco alkaloid with nicotinic acetylcholine receptors (nAChRs). This interaction leads to activation of reward centers in the CNS, including the mesoaccumbens DA system, which ultimately leads to behavioral reinforcement and addiction. Recent findings from a number of laboratories have provided new insights into the biologic processes that contribute to nicotine self-administration.Examination of the nAChR subtypes expressed within the reward centers has identified potential roles for these receptors in normal physiology, as well as the effects of nicotine exposure. The high nicotine sensitivity of some nAChR subtypes leads to rapid activation followed in many cases by rapid desensitization. Assessing the relative importance of these molecular phenomena in the behavioral effects of nicotine presents an exciting challenge for future research efforts.

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“…The identity of the corresponding a-subunits of the specific nAChRs that participate in the effects of nicotine within striatum are unresolved. Rodent striatal DA axon terminals contain b2 subunits coexpressed predominantly with a4, or a6, a5 and also b3 subunits within at least three types of heteromeric pentamers, including a4b2, a6b2b3, and a6a4b2b3 (Champtiaux et al, 2003;Charpantier et al, 1998;Cui et al, 2003;Exley and Cragg, in press;Grady et al, 2002;Klink et al, 2001;Quik and McIntosh, 2006;Quik et al, 2005;Salminen et al, 2004;Zoli et al, 2002). Unlike other subunits, expression of the a6 subunit is relatively restricted to catecholaminergic (and some visual system) neurons (Le Novere et al, 1996;Quik et al, 2001Quik et al, , 2002.…”

Section: Introductionmentioning

confidence: 99%

α6-Containing Nicotinic Acetylcholine Receptors Dominate the Nicotine Control of Dopamine Neurotransmission in Nucleus Accumbens

Exley

Clements

Hartung

et al. 2007

Neuropsychopharmacol

227

262

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Modulation of striatal dopamine (DA) neurotransmission plays a fundamental role in the reinforcing and ultimately addictive effects of nicotine. Nicotine, by desensitizing b2 subunit-containing (b2*) nicotinic acetylcholine receptors (nAChRs) on striatal DA axons, significantly enhances how DA is released by reward-related burst activity compared to nonreward-related tonic activity. This action provides a synaptic mechanism for nicotine to facilitate the DA-dependent reinforcement. The subfamily of b2*-nAChRs responsible for these potent synaptic effects could offer a molecular target for therapeutic strategies in nicotine addiction. We explored the role of a6b2*-nAChRs in the nucleus accumbens (NAc) and caudate-putamen (CPu) by observing action potential-dependent DA release from synapses in real-time using fast-scan cyclic voltammetry at carbon-fiber microelectrodes in mouse striatal slices. The a6-specific antagonist a-conotoxin-MII suppressed DA release evoked by single and low-frequency action potentials and concurrently enhanced release by high-frequency bursts in a manner similar to the b2*-selective antagonist dihydro-b-erythroidine (DHbE) in NAc, but less so in CPu. The greater role for a6*-nAChRs in NAc was not due to any confounding regional difference in ACh tone since elevated ACh levels (after the acetylcholinesterase inhibitor ambenonium) had similar outcomes in NAc and CPu. Rather, there appear to be underlying differences in nAChR subtype function in NAc and CPu. In summary, we reveal that a6b2*-nAChRs dominate the effects of nicotine on DA release in NAc, whereas in CPu their role is minor alongside other b2*-nAChRs (eg a4*), These data offer new insights to suggest striatal a6*-nAChRs as a molecular target for a therapeutic strategy for nicotine addiction.

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Nicotinic acetylcholine subunit mRNA expression in dopaminergic neurons of the rat substantia nigra and ventral tegmental area

Cited by 155 publications

References 7 publications

Nicotinic receptors as CNS targets for Parkinson's disease

Nicotinic receptors as CNS targets for Parkinson's disease

Cellular and synaptic mechanisms of nicotine addiction

α6-Containing Nicotinic Acetylcholine Receptors Dominate the Nicotine Control of Dopamine Neurotransmission in Nucleus Accumbens

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