ABT-089, but not ABT-107, ameliorates nicotine withdrawal-induced cognitive deficits in C57BL6/J mice

Abstract

Nicotine withdrawal produces cognitive deficits that can predict relapse. Amelioration of these cognitive deficits emerges as a target in current smoking cessation therapies. In rodents, withdrawal from chronic nicotine disrupts contextual fear conditioning (CFC), whereas acute nicotine enhances this hippocampus-specific learning and memory. These modifications are mediated by β2-subunit-containing (β2*) nicotinic acetylcholine receptors in the hippocampus. We aimed to test ABT-089, a partial agonist of α4β2*, and ABT-107, an α7 nicotinic acetylcholine receptor agonist, for amelioration of cognitive deficits induced by withdrawal from chronic nicotine in mice. Mice underwent chronic nicotine administration (12.6 mg/kg/day or saline for 12 days), followed by 24 h of withdrawal. At the end of withdrawal, mice received 0.3 or 0.6 mg/kg ABT-089 or 0.3 mg/kg ABT-107 (doses were determined through initial dose–response experiments and prior studies) and were trained and tested for CFC. Nicotine withdrawal produced deficits in CFC that were reversed by acute ABT-089, but not ABT-107. Cued conditioning was not affected. Taken together, our results suggest that modulation of hippocampal learning and memory using ABT-089 may be an effective component of novel therapeutic strategies for nicotine addiction.

Basolateral amygdala, nicotinic cholinergic receptors, and nicotine: Pharmacological effects and addiction in animal models and humans

“…This impairment is mediated by β 2 ‐containing nAChRs and associated with upregulation of nAChRs in hippocampus (Kutlu et al., ; Portugal, Kenney, & Gould, ). ABT‐089A, a partial agonist of α 4 β 2 ‐containing nAChRs, but not an α 7 agonist, reversed this well‐known withdrawal‐induced deficit in fear extinction (Yildirim, Connor, & Gould, ).…”

Cholinergic regulation of fear learning and extinction

“…Nicotine's effects appear to be mediated via β2‐containing receptors because the ability of nicotine to enhance fear responses was blocked by the α4β2 antagonist DHβE, and contextual freezing was increased by administration of the partial α4β2 agonist ABT‐089 given both pretraining and pretesting (Davis and Gould, ; Yildirim et al, ). In contrast, varenicline, which is a partial α4β2 agonist but a full α7 agonist, failed to affect contextual freezing when given before testing, before training, or both (Raybuck et al, ).…”

“…Mice lacking the α7, β3, or β4 nAChR subunits did not show any deficits in contextual fear, although administration of the α7 selective antagonist methyllycaconitine (MLA) into the ventral hippocampus blocked the influences of systemic nicotine on contextual fear responses (Wehner et al, ; Kenney et al, ), and systemic administration of MLA (without nicotine) increased contextual fear responses (Davis and Gould, ). An agonist at homomeric α7 nAChRs (ABT‐107), however, failed to increase contextual fear (Yildirim et al, ). Decreased contextual fear responses were seen in mice during spontaneous or precipitated nicotine withdrawal, and this reduction during nicotine withdrawal was not seen in mice lacking the β2 nAChR subunit (Portugal et al, ).…”

Chronic fluoxetine ameliorates adolescent chronic nicotine exposure-induced long-term adult deficits in trace conditioning

“…For example, treatment with cholinergic agents can reduce the detrimental effects of immediate chronic nicotine withdrawal on cognition in adult animals (Poole et al, 2014; Yildirim et al, 2015). However, pharmacological treatments for the long-term effects of adolescent chronic nicotine exposure on hippocampal learning have not been similarly investigated.…”