Molecular and Physiological Diversity of Nicotinic Acetylcholine Receptors in the Midbrain Dopaminergic Nuclei

Klink, Ruby; d’Exaerde, Alban de Kerchove; Zoli, Michèle; Changeux, Jean-Pierre

doi:10.1523/jneurosci.21-05-01452.2001

Cited by 600 publications

(753 citation statements)

References 57 publications

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“…The absence of M 5 receptors on the VTA likely accounts for the lower rate of cocaine self-administration in M 5 À/À rodents (Fink-Jensen et al, 2003; Thomsen et al, 2005). Although a 4-6 b 2 and a 4-5 b 2 nAChRs have been identified on VTA DANs (Klink et al, 2001), VTA mACh receptors appear to play a more prominent role in maintaining reward relative to nAChRs. Using lateral hypothalamic brain stimulation as the reward, Yeomans and Baptista (1997) found that the intra-VTA administration of an mAChR antagonist (atropine) produced a rightward shift in the dose-response curve of self-stimulation (signaling slower rates of responding at a given dose) four-fold greater than that of two nAChR antagonists (mecamylamine and dihydro-beta-erythroidine (DHbE)).…”

Section: Vta Acetylcholine and Rewardmentioning

confidence: 99%

“…Glutamate activates ionotropic glutamate receptors located on DA neurons, triggering the long-term molecular adaptations that underlie sensitization (Kalivas, 1995). nAChRs are expressed on VTA neurons as well as cortical glutamate afferents to the VTA; b 2 -containing nAChRs are expressed on DA and GABAergic neurons while a 7 nAChRs are primarily expressed on glutamatergic terminals (Klink et al, 2001). Both the heightened dopaminergic response and the psychomotor effects of cocaine-induced sensitization are prevented by mecamylamine, an nAChR antagonist that blocks both a 7 -and b 2 -containing VTA nAChRs (Schoffelmeer et al, 2002).…”

Section: Cocaine-induced Sensitizationmentioning

confidence: 99%

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The Role of Acetylcholine in Cocaine Addiction

Williams

Adinoff²

2007

Neuropsychopharmacol

157

138

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Central nervous system cholinergic neurons arise from several discrete sources, project to multiple brain regions, and exert specific effects on reward, learning, and memory. These processes are critical for the development and persistence of addictive disorders. Although other neurotransmitters, including dopamine, glutamate, and serotonin, have been the primary focus of drug research to date, a growing preclinical literature reveals a critical role of acetylcholine (ACh) in the experience and progression of drug use. This review will present and integrate the findings regarding the role of ACh in drug dependence, with a primary focus on cocaine and the muscarinic ACh system. Mesostriatal ACh appears to mediate reinforcement through its effect on reward, satiation, and aversion, and chronic cocaine administration produces neuroadaptive changes in the striatum. ACh is further involved in the acquisition of conditional associations that underlie cocaine self-administration and context-dependent sensitization, the acquisition of associations in conditioned learning, and drug procurement through its effects on arousal and attention. Long-term cocaine use may induce neuronal alterations in the brain that affect the ACh system and impair executive function, possibly contributing to the disruptions in decision making that characterize this population. These primarily preclinical studies suggest that ACh exerts a myriad of effects on the addictive process and that persistent changes to the ACh system following chronic drug use may exacerbate the risk of relapse during recovery. Ultimately, ACh modulation may be a potential target for pharmacological treatment interventions in cocaine-addicted subjects. However, the complicated neurocircuitry of the cholinergic system, the multiple ACh receptor subtypes, the confluence of excitatory and inhibitory ACh inputs, and the unique properties of the striatal cholinergic interneurons suggest that a precise target of cholinergic manipulation will be required to impact substance use in the clinical population.

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Section: Vta Acetylcholine and Rewardmentioning

confidence: 99%

Section: Cocaine-induced Sensitizationmentioning

confidence: 99%

The Role of Acetylcholine in Cocaine Addiction

Williams

Adinoff²

2007

Neuropsychopharmacol

157

138

View full text Add to dashboard Cite

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“…In the mouse, the midbrain DA areas express many nAChRs subunits, ␣3-␣7 and ␤2-␤4 (Hill et al, 1993;Cordero-Erausquin, 2000;Klink et al, 2001;Champtiaux et al, 2002). The ␤2* nAChRs are the most widely expressed in the mesostriatal DA system, and the ␣4 and ␣6 subunits are also highly expressed.…”

Section: Nicotinic Receptors In the Mesolimbic Dopamine System And Stmentioning

confidence: 99%

“…Genetic deletion of the ␤2 subunit results in a dramatic decrease or loss of nicotine-evoked effects in the midbrain DA areas and the striatum (Picciotto et al, 1998;Zhou et al, 2001). All DA neurons and many GABA neurons in the VTA and SN express ␤2* nAChRs (Picciotto et al, 1998;Jones et al, 2001;Klink et al, 2001). Activation of these somatic nAChRs increases the excitability, action potential firing, and Ca 2ϩ influx in these neurons (Pidoplichko et al, 1997;Picciotto et al, 1998;Klink et al, 2001).…”

Section: Nicotinic Receptors In the Mesolimbic Dopamine System And Stmentioning

confidence: 99%

Cholinergic interneuron characteristics and nicotinic properties in the striatum

2002

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ABSTRACT:The neostriatum (dorsal striatum) is composed of the caudate and putamen. The ventral striatum is the ventral conjunction of the caudate and putamen that merges into and includes the nucleus accumbens and striatal portions of the olfactory tubercle. About 2% of the striatal neurons are cholinergic. Most cholinergic neurons in the central nervous system make diffuse projections that sparsely innervate relatively broad areas. In the striatum, however, the cholinergic neurons are interneurons that provide very dense local innervation. The cholinergic interneurons provide an ongoing acetylcholine (ACh) signal by firing action potentials tonically at about 5 Hz. A high concentration of acetylcholinesterase in the striatum rapidly terminates the ACh signal, and thereby minimizes desensitization of nicotinic acetylcholine receptors. Among the many muscarinic and nicotinic striatal mechanisms, the ongoing nicotinic activity potently enhances dopamine release. This process is among those in the striatum that link the two extensive and dense local arbors of the cholinergic interneurons and dopaminergic afferent fibers. During a conditioned motor task, cholinergic interneurons respond with a pause in their tonic firing. It is reasonable to hypothesize that this pause in the cholinergic activity alters action potential dependent dopamine release. The correlated response of these two broad and dense neurotransmitter systems helps to coordinate the output of the striatum, and is likely to be an important process in sensorimotor planning and learning.

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“…More than half of these neurons also expressed the α3 and α7 mRNAs and less than 10% expressed β4 mRNA. The second approach used single-cell reverse transcriptase polymerase chain reaction (RT-PCR) method to determine nAChR subunit gene mRNA expression in rat VTA and SN dopaminergic neurons [67]. This method detected α4 mRNA in virtually every SN and VTA dopaminergic cell body.…”

mentioning

confidence: 99%

The subtypes of nicotinic acetylcholine receptors on dopaminergic terminals of mouse striatum

Grady

Salminen

Laverty

et al. 2007

Biochemical Pharmacology

229

223

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This review summarizes studies that attempted to determine the subtypes of nicotinic acetylcholine receptors (nAChR) expressed in the dopaminergic nerve terminals in the mouse. A variety of experimental approaches has been necessary to reach current knowledge of these subtypes, including in situ hybridization, agonist and antagonist binding, function measured by neurotransmitter release from synaptosomal preparations, and immunoprecipitation by selective antibodies. Early developments that facilitated this effort include the radioactive labeling of selective binding agents, such as [ 125 I]-α-bungarotoxin and [ 3 H]-nicotine, advances in cloning the subunits, and expression and evaluation of function of combinations of subunits in Xenopus oocytes. The discovery of epibatidine and α-conotoxin MII (α-CtxMII), and the development of nAChR subunit null mutant mice have been invaluable in determining which nAChR subunits are important for expression and function in mice, as well as allowing validation of the specificity of subunit specific antibodies. These approaches have identified five nAChR subtypes of nAChR that are expressed on dopaminergic nerve terminals. Three of these contain the α6 subunit (α4α6β2β3, α6β2β3, α6β2) and bind α-CtxMII with high affinity. One of these three subtypes (α4α6β2β3) also has the highest sensitivity to nicotine of any native nAChR that has been studied, to date. The two subtypes that do not have high affinity for α-CtxMII (α4β2, α4α5β2) are somewhat more numerous than the α6* subtypes, but do bind nicotine with high affinity. Given that our first studies detected readily measured differences in sensitivity to agonists and antagonists among these five nAChR subtypes, it seems likely that subtype selective compounds could be developed that would allow therapeutic manipulation of diverse nAChRs that have been implicated in a number of human conditions. Alterations in nicotinic cholinergic receptor (nAChRs) number or function have been implicated in psychopathologies such as anxiety, attention deficit hyperactivity disorder, depression, schizophrenia (reviewed in [1,2,3]), at least one form of familial epilepsy [4], and Parkinson's and Alzheimer's diseases [5]. It is not particularly surprising that nAChRs might play important roles in modulating several human diseases given that binding sites for nicotinic ligands such as [ 125 I]-α-bungarotoxin [6,7,8], [ 3 H]-nicotine [7,8] Corresponding author: Sharon R Grady e-mail: sharon.grady@colorado.edu phone: 303-492-9677 fax: 303-492-8063 mailing address: Institute for Behavioral Genetics University of Colorado 447UCB Boulder, CO 80309. 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 w...

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Molecular and Physiological Diversity of Nicotinic Acetylcholine Receptors in the Midbrain Dopaminergic Nuclei

Cited by 600 publications

References 57 publications

The Role of Acetylcholine in Cocaine Addiction

The Role of Acetylcholine in Cocaine Addiction

Cholinergic interneuron characteristics and nicotinic properties in the striatum

The subtypes of nicotinic acetylcholine receptors on dopaminergic terminals of mouse striatum

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