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.

Fig. 1

Dose–response of acute ABT-089 in contextual fear conditioning. ABT-089 enhances freezing to context at all doses tested. *Significant difference from vehicle group (P < 0.05). Error bars indicate SEM. For all fear conditioning data, the vertical axis is the percent freezing for each period. CS, conditioned stimulus.

Fig. 2

A dose of (a) 0.3 mg/kg ABT-089 and (b) 0.6 mg/kg ABT-089 ameliorates nicotine withdrawal-induced cognitive deficits in contextual fear conditioning. *Significant difference from the withdrawal from the saline + vehicle group (P < 0.05); **significant difference from the withdrawal from the nicotine + vehicle group and from the saline + vehicle group (P < 0.05). Error bars indicate SEM. CS, conditioned stimulus; W/D, withdrawal.

Fig. 3

Dose–response of acute ABT-107 in contextual fear conditioning. ABT-107 does not enhance freezing to context at any of the doses tested compared with vehicle. *Significant between the 0.03 and the 0.3 mg/kg ABT-107 groups (P < 0.05). Error bars indicate SEM. CS, conditioned stimulus.

Fig. 4

A dose of 0.3 mg/kg ABT-107 does not ameliorate nicotine withdrawal-induced cognitive deficits in contextual fear conditioning. *Significant difference as compared with withdrawal from chronic nicotine (P < 0.05). Error bars indicate SEM. CS, conditioned stimulus; W/D, withdrawal.

Fig. 5

Withdrawal did not alter performance in the 5-CSRTT. No difference in the percentage of correct responses was found across the 4 days of testing after cessation of chronic nicotine treatment (P > 0.05). Error bars indicate SEM. CS, conditioned stimulus; 5-CSRTT, five-choice serial reaction time task; W, withdrawal.