Deletion of α5 nicotine receptor subunits abolishes nicotinic aversive motivational effects in a manner that phenocopies dopamine receptor antagonism

Abstract

Nicotine addiction is a worldwide epidemic that claims millions of lives each year. Genetic deletion of α5 nicotinic acetylcholine receptor (nAChR) subunits has been associated with increased nicotine intake, however, it remains unclear whether acute nicotine is less aversive or more rewarding, and whether mice lacking the α5 nAChR subunit can experience withdrawal from chronic nicotine. We used place conditioning and conditioned taste avoidance paradigms to examine the effect of α5 subunit-containing nAChR deletion (α5 -/-) on conditioned approach and avoidance behaviour in nondependent and nicotine-dependent and -withdrawn mice, and compared these motivational effects with those elicited after dopamine receptor antagonism. We show that nondependent α5 -/- mice find low, non-motivational doses of nicotine rewarding, and do not show an aversive conditioned response or taste avoidance to higher aversive doses of nicotine. Furthermore, nicotine-dependent α5 -/- mice do not show a conditioned aversive motivational response to withdrawal from chronic nicotine, although they continue to exhibit a somatic withdrawal syndrome. These effects phenocopy those observed after dopamine receptor antagonism, but are not additive, suggesting that α5 nAChR subunits act in the same pathway as dopamine and are critical for the experience of nicotine's aversive, but not rewarding motivational effects in both a nondependent and nicotine-dependent and -withdrawn motivational state. Genetic deletion of α5 nAChR subunits leads to a behavioural phenotype that exactly matches that observed after antagonizing dopamine receptors, thus we suggest that modulation of nicotinic receptors containing α5 subunits may modify dopaminergic signalling, suggesting novel therapeutic treatments for smoking cessation.

Chrna5-Expressing Neurons in the Interpeduncular Nucleus Mediate Aversion Primed by Prior Stimulation or Nicotine Exposure

“…Here, we show that the IP neurons of ␣5 KO mice have a markedly attenuated physiological response to acetylcholine and nicotine, making the IP a strong candidate for mediating some of the behavioral effects of this nicotinic receptor subunit. We did not observe an attenuation in the nicotine response of MHbV neurons in ␣5 KO mice despite the prevailing idea that ␣5 expression is relevant to MHb function (Fowler et al, 2011;Frahm et al, 2011;Fowler and Kenny, 2014;Antolin-Fontes et al, 2015).…”

“…In other cell types, such as the VTA, information from outside the transgenic construct used here appears to be required for correct expression. These findings may help to provide a framework for the interpretation of the noncoding polymorphisms found in smoking-related haplotypes (Barrie et al, 2017).…”

“…The ␣5 subunit is also detected in the ventral tegmental area (VTA), where it regulates striatal nicotine effects (Exley et al, 2012), and in deep layers of the cerebral cortex, where loss of ␣5 may impair performance in attentional tests (Bailey et al, 2010). Genetic studies have shown that mice lacking the ␣5 subunit (␣5 KO mice) have attenuated somatic signs of nicotine withdrawal (Jackson et al, 2008;Salas et al, 2009) and show self-administration and place preference with high doses of nicotine that are usually aversive (Jackson et al, 2010;Fowler et al, 2011;Morel et al, 2014).…”

“…Pharmacological studies also support a role for the MHbV and/or IP as mediating behavioral responses to nicotine, including reinforcement, aversion, and withdrawal (Salas et al, 2009;Zhao-Shea et al, 2013Antolin-Fontes et al, 2015;Harrington et al, 2016), but are not by themselves sufficient to assess the role of the ␣5 subunit, which does not participate in the usual ligand binding site of nAChRs and thus has no specific agonist or antagonist. Here, we show that the IP neurons of ␣5 KO mice have a markedly attenuated physiological response to acetylcholine and nicotine, making the IP a strong candidate for mediating some of the behavioral effects of this nicotinic receptor subunit.…”

“…Prior studies have addressed ␣5 function in mice using BAC transgenic methods to manipulate the Chrna5/a3/b4 locus (Frahm et al, 2011;Hsu et al, 2013). However, this approach may misexpress the other genes in the ␣5 cluster, which can independently affect physiology and behavior.…”