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 14days. ICSS thresholds were assessed 6h post-pump removal. Thirty hours after pump removal, CGP44532, CGP56433A, and
BHF177 were administered 30min 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.