Both GABA B receptor activation and blockade exacerbated anhedonic aspects of nicotine withdrawal in rats

Abstract

Nicotine dependence is maintained by the aversive, depression-like effects of nicotine withdrawal and the rewarding effects of acute nicotine. GABA B receptor antagonists exhibit antidepressant-like effects in rodents, whereas GABA B receptor agonists attenuate the rewarding effects of nicotine. Recent studies with GABA B receptor positive modulators showed that these compounds represent potentially improved medications for the treatment of nicotine dependence because of fewer side-effects than GABA B receptor agonists. Thus, GABA B receptor agonists and antagonists, and GABA B receptor positive modulators may have efficacy as smoking cessation aids by targeting different aspects of nicotine dependence and withdrawal. The present study assessed the effects of the GABA B receptor agonist CGP44532, the GABA B receptor antagonist CGP56433A, and the GABA B receptor positive modulator BHF177 on the anhedonic aspects of nicotine withdrawal. Rats were prepared with stimulating electrodes in the posterior lateral hypothalamus. After establishing stable intracranial self-stimulation (ICSS) thresholds, rats were prepared with subcutaneous osmotic minipumps delivering either nicotine or saline for 7 or 14 days. ICSS thresholds were assessed 6 h post-pump removal. Thirty hours after pump removal, CGP44532, CGP56433A, and BHF177 were administered 30 min prior to ICSS testing. Both GABA B receptor activation (CGP44532 and BHF177) and blockade (CGP56433A) elevated ICSS thresholds in all groups, resulting in exacerbated effects of nicotine withdrawal in the nicotine-treated groups. These similar effects of GABA B receptor activation and blockade on the anhedonic depression-like aspects of nicotine withdrawal were surprising and perhaps reflect differential efficacy of these compounds at presynaptic hetero- and autoreceptors, as well as postsynaptic, GABA B receptors.