Effects of nicotine in the dopaminergic system of mice lacking the alpha4 subunit of neuronal nicotinic acetylcholine receptors

Abstract

The mesostriatal dopaminergic system influences locomotor activity and the reinforcing properties of many drugs of abuse including nicotine. Here we investigate the role of the alpha4 nicotinic acetylcholine receptor (nAChR) subunit in mediating the effects of nicotine in the mesolimbic dopamine system in mice lacking the alpha4 subunit. We show that there are two distinct populations of receptors in the substantia nigra and striatum by using autoradiographic labelling with 125I alpha-conotoxin MII. These receptors are comprised of the alpha4, beta2 and alpha6 nAChR subunits and non-alpha4, beta2, and alpha6 nAChR subunits. Non-alpha4 subunit-containing nAChRs are located on dopaminergic neurons, are functional and respond to nicotine as demonstrated by patch clamp recordings. In vivo microdialysis performed in awake, freely moving mice reveal that mutant mice have basal striatal dopamine levels which are twice as high as those observed in wild-type mice. Despite the fact that both wild-type and alpha4 null mutant mice show a similar increase in dopamine release in response to intrastriatal KCl perfusion, a nicotine-elicited increase in dopamine levels is not observed in mutant mice. Locomotor activity experiments show that there is no difference between wild-type and mutant mice in basal activity in both habituated and non-habituated environments. Interestingly, mutant mice sustain an increase in cocaine-elicited locomotor activity longer than wild-type mice. In addition, mutant mice recover from depressant locomotor activity in response to nicotine at a faster rate. Our results indicate that alpha4-containing nAChRs exert a tonic control on striatal basal dopamine release, which is mediated by a heterogeneous population of nAChRs.

Genetic variability in nicotinic acetylcholine receptors and nicotine addiction: Converging evidence from human and animal research

“…Furthermore, α4 and β2 KO mice do not show nicotine-induced increases in striatal DA, whereas their respective WT littermates do [109,130]. However, basal striatal DA levels were significantly greater in α4 KO mice than in WT mice [109]. An additional abnormality in dopaminergic function has been reported: α4 KO mice have reduced DA transporter function when compared to WT mice [126].…”

“…For instance, both α4 and β2 KO mice do not have high affinity binding sites for nicotine [108,129], exhibited a reduced antinociceptive effect in a hot-plate test [108], and showed reduced sensitivity to the effects of nicotine on locomotor activity and nicotine-induced hypothermia [113,168,174]. Furthermore, α4 and β2 KO mice do not show nicotine-induced increases in striatal DA, whereas their respective WT littermates do [109,130]. However, basal striatal DA levels were significantly greater in α4 KO mice than in WT mice [109].…”

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

“…146 Similar to b2-KO mice, a4-KO exhibit striatal DA levels that do not increase in response to nicotine, supporting the notion that a4b2* nAChRs are necessary for DA release. 147 Morphological changes in nigrostriatal dopaminergic neurons in drug-naive adult a4(À/À)-mice have been described; KO mice had significantly larger terminal arbors than WT. 148 In addition, KO mice had impaired DA transporter levels and impairment in locomotor activity in response to DA agonist and antagonist.…”

Overview of the pharmacogenomics of cigarette smoking

“…132 Both subunits are upregulated by chronic nicotine treatment and their absence in knockout mice results in a lack of nicotine selfadministration and nicotine-induced dopamine release in the VTA. [132][133][134][135] Tapper et al 136 genetically altered the a 4 -subunit to make it hypersensitive; low doses of nicotine that selectively activate nAChRs containing these mutated subunits produced reinforcement, tolerance and sensitization without having such effects in wild-type mice. CHRNA4 encodes the a 4 subunit, and several genetic variants have been associated with smoking.…”