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.

Cognitive impairments, e.g., reward learning, are present in various psychiatric disorders and warrant treatment. Improving reward-related learning could synergistically enhance psychosocial treatments and cognition generally. A critical first step is to understand the mechanisms underlying reward learning. The dopamine system has been implicated in such learning, but less known is how indirect activation of this system may affect reward learning. We determined the role of alpha7 nicotinic acetylcholine receptors (nAChR) on a probabilistic reversal learning task (PRLT) in mice that includes reward and punishment. Male alpha7 knockout (KO), heterozygous (HT), and wildtype (WT) littermate mice (n = 84) were treated with vehicle, 0.03, or 0.3 mg/kg nicotine. Two cohorts of C57BL/6NJ male mice were treated with various alpha7 nAChR ligands, including the full agonists PNU282877 and AR-R-17779, the positive allosteric modulator CCMI, the partial agonist SSR180711, and the antagonist methyllycaconitine. All mice were then tested in the PRLT. Nicotine (0.3 mg/kg) significantly improved initial reward learning in alpha7 WT and HT mice but did not improve learning in KO mice, suggesting an involvement of the alpha7 nAChR in the pro-learning effects of nicotine. Neither alpha7 nAChR treatments (PNU282987, AR-R-17779, CCMI, SSR180711, nor methyllycaconitine) affected mouse PRLT performance however. Nicotine improved reward learning via a mechanism that may include alpha7 nAChRs. This improvement unlikely relied solely on alpha7 nAChRs however, since no alpha7 nAChR ligand improved reward learning in normal mice. Future assessments of the effects of other nAChR subtypes on reward learning are needed.