Targeted Deletion of the Mouse α2 Nicotinic Acetylcholine Receptor Subunit Gene (Chrna2) Potentiates Nicotine-Modulated Behaviors

Abstract

Baseline and nicotine-modulated behaviors were assessed in mice harboring a null mutant allele of the nicotinic acetylcholine receptor (nAChR) subunit gene α2 (Chrna2). Homozygous Chrna2−/− mice are viable, show expected sex and Mendelian genotype ratios, and exhibit no gross neuroanatomical abnormalities. A broad range of behavioral tests designed to assess genotype-dependent effects on anxiety (elevated plus maze and light/dark box), motor coordination (narrow bean traverse and gait), and locomotor activity revealed no significant differences between mutant mice and age-matched wild-type littermates. Furthermore, a panel of tests measuring traits, such as body position, spontaneous activity, respiration, tremors, body tone, and startle response, revealed normal responses for Chrna2-null mutant mice. However, Chrna2−/− mice do exhibit a mild motor or coordination phenotype (a decreased latency to fall during the accelerating rotarod test) and possess an increased sensitivity to nicotine-induced analgesia in the hotplate assay. Relative to wild-type, Chrna2−/− mice show potentiated nicotine self-administration and withdrawal behaviors and exhibit a sex-dependent enhancement of nicotine-facilitated cued, but not trace or contextual, fear conditioning. Overall, our results suggest that loss of the mouse nAChR α2 subunit has very limited effects on baseline behavior but does lead to the potentiation of several nicotine-modulated behaviors.

Nicotine Addiction and Psychiatric Disorders

“…Furthermore, there is evidence suggesting that systemic administration of a high-affinity nAChR antagonist, DhβE, reverses the effects of nicotine, while a low-affinity α7 nAChR antagonist, MLA, has no effect (Davis, Kenney, & Gould, 2007). Similarly, several studies using knockout (KO) mice have shown that animals lacking β2 nAChRs did not show enhancement of contextual (Davis & Gould, 2007) or trace fear conditioning (Davis & Gould, 2007; Lotfipour et al, 2013) by nicotine. These results suggest that nicotine enhances hippocampal-dependent fear memories through activation of β2-containing nAChRs.…”

Nicotine Withdrawal

“…In rodents, α2 mRNA levels are highest in the interpeduncular nucleus (IPN), with more restricted expression in scattered neurons within the amygdala, hippocampus, cortex, retina, spinal cord, and cerebellum (Lotfipour et al 2013). Analyses of withdrawal symptoms in α2 KO mice have shown that the physical manifestations of nicotine abstinence are context-dependent, as α2 KO mice exhibit more somatic symptoms of withdrawal in novel environments (Lotfipour et al 2013), but display no somatic signs of withdrawal in habituated environments (i.e., the home cage) (Salas et al 2009).…”

“…Analyses of withdrawal symptoms in α2 KO mice have shown that the physical manifestations of nicotine abstinence are context-dependent, as α2 KO mice exhibit more somatic symptoms of withdrawal in novel environments (Lotfipour et al 2013), but display no somatic signs of withdrawal in habituated environments (i.e., the home cage) (Salas et al 2009). Additionally, the lack of α2 is sufficient to abolish somatic symptoms of precipitated nicotine withdrawal (Salas et al 2009).…”

“…Additionally, the lack of α2 is sufficient to abolish somatic symptoms of precipitated nicotine withdrawal (Salas et al 2009). In male mice, Chrna2 deletion also produces nicotine withdrawal-induced deficits of cued FC (Lotfipour et al 2013). α2 KO mice also self-administer higher doses of nicotine than WT controls (Lotfipour et al 2013).…”

“…In male mice, Chrna2 deletion also produces nicotine withdrawal-induced deficits of cued FC (Lotfipour et al 2013). α2 KO mice also self-administer higher doses of nicotine than WT controls (Lotfipour et al 2013). It should be noted that in a study of European Americans and African-Americans, CHRNA2 showed a strong association with the Fagerström Test for Nicotine Dependence (FTND) after correction for multiple testing (Wang et al 2014).…”