Nicotine withdrawal-induced inattention is absent in alpha7 nAChR knockout mice

Abstract

Rationale Smoking is the leading cause of preventable death in the U.S., but quit attempts result in withdrawal-induced cognitive dysfunction and predicts relapse. Greater understanding of the neural mechanism(s) underlying these cognitive deficits is required to develop targeted treatments to aid quit attempts. Objectives We examined nicotine withdrawal-induced inattention in mice lacking the α7 nicotinic acetylcholine receptor (nAChR) using the 5-choice continuous performance test (5C-CPT). Methods Mice were trained in the 5C-CPT prior to osmotic minipump implantation containing saline or nicotine. Experiment 1 used 40 mg/kg/day nicotine treatment and tested C57BL/6 mice 4, 28, and 52 h after pump removal. Experiment 2 used 14 and 40 mg/kg/day nicotine treatment in α7 nAChR knockout (KO) and wildtype (WT) littermates tested 4 h after pump removal. Subsets of WT mice were sacrificed before and after pump removal to assess changes in receptor expression associated with nicotine administration and withdrawal. Results Nicotine withdrawal impaired attention in the 5C-CPT, driven by response inhibition and target detection deficits. The overall attentional deficit was absent in α7 nAChR KO mice despite response disinhibition in these mice. Synaptosomal glutamate mGluR5 and dopamine D4 receptor expression were reduced during chronic nicotine but increased during withdrawal, potentially contributing to cognitive deficits. Conclusions The α7 nAChR may underlie nicotine withdrawal-induced deficits in target detection but is not required for response disinhibition deficits. Alterations to the glutamatergic and dopaminergic pathways may also contribute to withdrawal-induced attentional deficits, providing novel targets to alleviate the cognitive symptoms of withdrawal during quit attempts.

Pharmacological modulation of the α7 nicotinic acetylcholine receptor in a mouse model of mecamylamine-precipitated nicotine withdrawal

“…Studies by our group and others have been performed utilizing null mutant α7 mice in nicotine withdrawal. α7 knockout (KO) mice undergoing nicotine withdrawal showed a reduction in hyperalgesia (Grabus et al 2005; Jackson et al 2008), no alterations in their somatic signs upon withdrawal (Grabus et al 2005; Jackson et al 2008),the absence of attentional deficits (Higa et al 2017) and attenuated anxiety-like behavior compared to their wild type counterparts (Stoker et al 2012). Pharmacological blockade of the α7 receptor with methyllycaconitine (MLA) has been shown in some studies to precipitate a subset of nicotine withdrawal somatic signs in rats and mice (Nomikos et al 1999; Damaj et al 2003; Salas et al 2007) while in other studies, MLA was found to be ineffective at inducing nicotine withdrawal signs (Markou and Paterson 2001).…”

Persistent cognitive and affective alterations at late withdrawal stages after long-term intermittent exposure to tobacco smoke or electronic cigarette vapour: Behavioural changes and their neurochemical correlates

“…Only a few studies have investigated attention deficits during nicotine WDW, none of which did so for an extended period. However, one study of the 5-CSRTT in rats that had received nicotine 3.16 mg/kg/day for seven days found an increase in the percentage of omissions after 10 and 16 h of nicotine abstinence that progressively recovered within 106 h of WDW [15], and a similar attention deficit has been found in mice after four but not 52 h of nicotine WDW using the same task [48]. The main differences between these studies and our model are the lower nicotine dose and the much shorter period of nicotine exposure, which suggests that persistent attentional alterations during WDW require neuro-adaptations that develop over a longer period of exposure that is more similar to that experienced by human smokers or vapers.…”

Exploring Neurobehaviour in Zebrafish Embryos as a Screening Model for Addictiveness of Substances

“…Fundamental characterization of the (embryonic) zebrafish model has revealed that the cholinergic system is present, with a comparable role and function of the several subtypes of the nAChR to those in humans [ 17 , 46 ]. Subtypes of the nAChR considered to play a role in addictive behavior in humans include the α4β2 and α7 [ 24 , 47 ]. The α4β2 is present in high numbers in the mesolimbic structures of the human brain, mainly the striatum, where it plays a critical role in nicotinic reward and reinforcement through its effect on dopamine release.…”