bp-897 and Tobacco-Use-Disorder

The dopamine D3 receptor (DRD3) has been suggested to be involved in the mechanisms underlying stimulus-controlled drug-seeking behaviour. Ligands acting as DRD3 antagonists (SB 277011-A) or DRD3 partial agonists (BP 897) have shown some promise for reducing the influence of drug-associated cues on motivational behaviour. Here, effects of SB 277011-A and BP 897 were evaluated on cue-induced reinstatement of nicotine-seeking in rats. The effects of BP 897 on nicotine self-administration under a fixed-ratio 5 (FR5) schedule of reinforcement were also evaluated. SB 277011-A (1-10 mg/kg) was able to block cue-induced reinstatement of nicotine-seeking, indicating that DRD3 selective antagonism may be an effective approach to prevent relapse for nicotine. In contrast, BP 897 did not block the cue-induced reinstatement of nicotine-seeking or nicotine-taking under the FR5 schedule. In a control study, rats did not respond to the light stimuli without nicotine delivery, indicating that the responding for the drug-associated cues was induced by the previous pairing of light stimuli with nicotine's effects. These findings validate the role of DRD3 on reactivity to drug-associated stimuli and suggest that the DRD3 antagonist, but perhaps not the DRD3 partial agonist, could be used to prevent relapse in tobacco smokers.

Topics: Animals; Conditioning, Operant; Cues; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; Drug Partial Agonism; Male; Nicotine; Nicotinic Agonists; Nitriles; Piperazines; Rats; Rats, Long-Evans; Receptors, Dopamine D3; Reinforcement Schedule; Self Administration; Tetrahydroisoquinolines; Tobacco Use Disorder

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.

Topics: Acrylamides; Animals; Antidepressive Agents; Conditioning, Psychological; Discrimination, Psychological; Disease Models, Animal; Dopamine Agents; Dopamine Agonists; Dopamine Antagonists; Drug Interactions; Female; Isoquinolines; Ligands; Limbic System; Male; Mice; Mice, Knockout; Nicotine; Piperazines; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D2; Receptors, Dopamine D3; Spatial Behavior; Tobacco Use Disorder