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

Abstract

Mesolimbic a6* nicotinic acetylcholine receptors (nAChRs) are thought to have an important role in nicotine behavioral effects. However, little is known about the role of the various a6*-nAChRs subtypes in the rewarding effects of nicotine. In this report, we investigated and compared the role of a6*-nAChRs subtypes and their neuro-anatomical locus in nicotine and cocaine reward-like effects in the conditioned place preference (CPP) paradigm, using pharmacological antagonism of a6b2* nAChRs and genetic deletion of the a6 or a4 subunits in mice. We found that a6 KO mice exhibited a rightward shift in the nicotine dose-response curve compared with WT littermates but that a4 KO failed to show nicotine preference, suggesting that a6a4b2*-nAChRs are involved. Furthermore, a6b2* nAChRs in nucleus accumbens were found to have an important role in nicotine-conditioned reward as the intra-accumbal injection of the selective a6b2* a-conotoxin MII [H9A; L15A], blocked nicotine CPP. In contrast to nicotine, a6 KO failed to condition to cocaine, but cocaine CPP in the a4 KO was preserved. Intriguingly, a-conotoxin MII [H9A; L15A], blocked cocaine conditioning in a4 KO mice, implicating a6b2* nAChRs in cocaine reward. Importantly, these effects did not generalize as a6 KO showed both a conditioned place aversion to lithium chloride as well as CPP to palatable food. Finally, dopamine uptake was not different between the a6 KO or WT mice. These data illustrate that the subjective rewarding effects of both nicotine and cocaine may be mediated by mesolimbic a6b2* nAChRs and that antagonists of these receptor subtypes may exhibit therapeutic potential.

Nicotinic Receptor Contributions to Smoking: Insights from Human Studies and Animal Models

“…In addition, α4 β2*nAChR gain-of-function mice with a single point mutation in the α4 subunit (L9A) show leftward shifts in nicotine CPP and associated DAergic neuron firing [93], suggesting that activation of α4*nAChRs is sufficient for nicotine reinforcement and reward. Similarly, α6KO mice fail to develop nicotine self-administration or nicotine CPP and delivery of selective α6β2*nAChR α-conotoxin MII antagonists (CTX) into the VTA or NAc blocks nicotine self-administration and CPP, suggesting that activation of mesolimbic α6β2*nAChRs is critical for nicotine reinforcement and reward [83, 90, 94–97]. Recent ex vivo studies suggest that α4α6β2*nAChRs make up a subclass of nAChRs in the VTA which are highly sensitive to physiologically relevant doses of nicotine [98], presumably due to binding at the α4-α6 interface.…”

High affinity α3β4 nicotinic acetylcholine receptor ligands AT-1001 and AT-1012 attenuate cocaine-induced conditioned place preference and behavioral sensitization in mice

“…Several nAChR subtypes are thought to mediate the cholinergic mechanisms that underlie cocaine dependence. Mice null for the β2 nAChR subunit show decreased cocaine CPP [8] whereas α6 knockout mice do not develop cocaine CPP [13]. Interestingly, Sanjakdar and colleagues also reported that the α6β2* nAChR-selective antagonist, α-conotoxin MII blocked cocaine CPP both in α4 knockout and wild-type mice, further corroborating the importance of the β2 and the α6 nAChR subunit in mediating cocaine’s rewarding effects.…”

“…The nonselective nAChR antagonist mecamylamine has also been shown to decrease cocaine CPP in mice [8] as well as cocaine self-administration in rats [11, 12]. More recently, it was shown that nAChRs containing the α6-subunit, but not the α4 subunit, are important for the induction of cocaine-conditioned reward [13]. …”

Nicotine pretreatment reduced cocaine-induced CPP and its reinstatement in a sex- and dose-related manner in adult C57BL/6J mice

“…A novel finding of the present study is that pretreatment with the lower dose of nicotine blunted the rewarding action of acute cocaine in both male and female mice. Although the underlying mechanism of blunted cocaine-induced CPP with the lower dose of nicotine is not clear, it is possible that nicotine may have caused desensitization of certain nicotinic acetylcholine receptor, which are shown to be important in mediating the rewarding action of cocaine (Sanjakdar et al, 2015). Indeed, differences in the affinity of nicotine for different subtype (α7, α4β2) of nicotinic acetylcholine receptors as well as differences in the rate of desensitization of different subtypes by nicotine (Buccafusco et al, 2009;Giniatullin et al, 2005;Lewis and Picciotto, 2013;Papke et al, 2009) have been reported in the literature, which may explain the results of the current study.…”