Rewarding effects elicited by cocaine microinjections into the ventral tegmental area of C57BL/6 mice: involvement of dopamine D1 and serotonin1Breceptors

Rationale The role of ventral tegmental area (VTA) in mediating the rewarding effects of cocaine has not been extensively studied.Objectives We used the intracranial self-administration (ICSA) procedure to assess the involvement of the VTA in the rewarding effects of cocaine, and the effect of dopamine (DA) D₁- and serotonin (5-HT)_1B-receptor antagonists on ICSA of cocaine.Methods Adult male C57BL/6 mice were stereotaxically implanted, unilaterally, with a guide cannula either 1.5 or 2.3 mm above the VTA. After 1 week, mice were trained to discriminate between the two arms of a Y-maze over seven daily sessions, one arm being reinforced by intracranial cocaine microinjections. Starting from session 8, the D₁ and 5-HT_1B-receptor antagonists were injected IP pre-test each day over five consecutive sessions.Results Mice injected into the VTA rapidly exhibited a preference for the cocaine-reinforced arm, whatever the dose of cocaine available (30 pmol or 150 pmol per injection), reaching optimum ICSA performance within 5 days. In contrast, mice injected 0.8 mm above the VTA did not discriminate between the arms of the maze and performed at random, except for one subject. Once the ICSA response was acquired, systemic pre-injections of either the D₁ (SCH23390; 25 g/kg IP) or 5-HT_1B (GR127935; 0.5 mg/kg IP) antagonist disrupted this behavior. Replacement of each antagonist by vehicle led to the reinstatement of intra-VTA cocaine self-administration.Conclusions The results of the present study suggest that VTA neurons play a critical role in mediating the rewarding effects of acute cocaine and that both D₁ and 5-HT_1B receptors modulate these effects.