Environmental stimuli previously paired with drug taking appear to play a critical role in
nicotine dependence. Converging anatomical, pharmacological, and behavioral evidence implicates
dopamine D3 receptors (D3Rs) in the mechanisms underlying stimulus-controlled drug-seeking behavior. This study assessed the effects of
BP 897, a D3R partial agonist and
ST 198, a D3R antagonist, on
nicotine-induced conditioned place preferences (CPPs), used as a measure of drug-seeking behavior, on food-maintained responding and on discrimination performance under a two-lever-choice
nicotine discrimination procedure.
BP 897 and
ST 198 both blocked the expression of
nicotine-induced
CPP at doses selective for D3R. They had no effect on locomotor activity in the
CPP apparatus and no significant effect on
nicotine discrimination performance or food-maintained responding under the discrimination procedure. Involvement of
antidepressant actions in the effects of
BP 897 and
ST 198 on
CPP is unlikely, since we found no effect of D3R blockade with
BP 897 or genetic depletion of D3Rs in a forced swimming test, used as a behavioral test for
antidepressant activity. This suggests that D3R
ligands reduce the motivational effects of
nicotine by a mechanism distinct from those of
nicotine replacement therapy and
bupropion, the two currently used
aids for smoking cessation in humans. These findings support the use of D3R
ligands as
aids for smoking cessation and indicate that their effects would be selective for those rewarding or reinforcing effects of
nicotine that contribute to the maintenance of tobacco-smoking behavior, without affecting subjective responses to
nicotine or producing any
antidepressant-like effects.