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

Abstract

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...

Protein kinase C epsilon modulates nicotine consumption and dopamine reward signals in the nucleus accumbens

“…*P < 0.05 by unpaired, two-tailed t tests. α 3 mRNA was not assessed in the striatum because α 3 -subunits are not found in nAChRs on dopaminergic terminals in that brain region (45).…”

Differential contribution of genetic variation in multiple brain nicotinic cholinergic receptors to nicotine dependence: recent progress and emerging open questions

“…30,132,226 Genetic support for the involvement of the CHRNA6-CHRNB3 cluster in ND has been reported in one GWAS and a large (B300) candidategene association study on the same sample, 76,78 and by several other candidate-gene studies analyzing ND and other smoking-related phenotypes. 90,108,109 Data from KO mice are supplementary: chrna6 KO nicotine-naive mice do not display self-administration of nicotine (in contrast to WT), but when the chrna6 gene is re-expressed in the a6À/À VTA, the reinforcement property of nicotine is restored.…”

“…18 For example, current knowledge indicates that DA nerve terminals in the striatum express as many as five different nAChR subtypes: a4b2, a4a5b2, a4a6b2b3, a6b2b3 and a6b2. 226 This functional diversity of nAChR receptors in terms of composition and role is highly influenced by the a3, a5-6 and b3-4 receptor subunits, not paid much of attention until recently ( Table 6).…”

Differential Roles of α6β2* and α4β2* Neuronal Nicotinic Receptors in Nicotine- and Cocaine-Conditioned Reward in Mice

“…Although a5 and a6 are co-expression in the substantia nigra and VTA, no direct evidence suggests co-assembly of these two subunits. Recent studies indicate possible functional interaction between a5 and a6 since with the genetic deletion of a5, there is an increase in a-conotoxinII-sensitive responses (dopamine release) Grady et al, 2007).…”

“…Of equal relevance, a4b2*-nAChRs are highly expressed in the midbrain (Klink et al, 2001). The a4* nicotinic receptor subtype has been shown to be sufficient (Tapper et al, 2004) and necessary (McGranahan et al, 2011;Pons et al, 2008) for nicotine reward and reinforcement as well as nicotine-induced DA release in rodents (Marubio et al, 2003;Salminen et al, 2007;Grady et al, 2007;Drenan et al, 2010).…”