Differential effects of the dopamine D2/D3 receptor antagonist sulpiride on self-administration of morphine into the ventral tegmental area or the nucleus accumbens

Rationale: The involvement of dopamine neurotransmission in opiate reward remains controversial. Objective: To investigate the dopaminergic basis of opiate reward by comparing the effect of systemic injection of the D-2/D-3 antagonist sulpiride on morphine self-administration (ICSA) into the ventral tegmental area (VTA) or the nucleus accumbens (NAc) Methods: BALB/c mice were unilaterally implanted with a guide cannula 1.5 mm above either the VTA or the NAc. On experimental days, a stainless-steel injection cannula was inserted via the guide cannula, and mice were trained to discriminate the arm of a Y-maze reinforced by intracranial morphine microinjections (6.5 pmol or 65 pmol/50 nl) from the neutral arm (no injection). Following acquisition of morphine ICSA, the dopamine D-2/D-3 receptor antagonist sulpiride (50 mg/kg, i.p.) was administered 30 min before testing. Results: Sulpiride produced an extinction of intra-VTA, but not intra-NAC, morphine self-administration. Extinction in VTA subjects was followed by a reappearance of ICSA, although mice continued to receive sulpiride injections. Extinction was re-induced when the dose of sulpiride was raised to 100 mg/kg. whereas no effect of this dose was detected on intra-NAc self-administration. Conclusion: Maintenance of intra-VTA, but not intra-NAc, morphine self-administration depends acutely on D-2/D-3 receptors. However, the deleterious effect of sulpiride on intra-VTA morphine self-administration is transient. Reappearance of ICSA under neuroleptic treatment in VTA subjects may be related to the sensitization effect of intra-VTA morphine infusions, combined with an upregulation of D-2/D-3 receptors and alterations of DA metabolism by repeated sulpiride injections.