Effects of serotonin-3 receptor antagonists on the intracranial self-administration of ethanol within the ventral tegmental area of Wistar rats

Abstract

Rationale. Previous work from our laboratory indicated that Wistar rats will self-administer ethanol (EtOH) directly into the posterior ventral tegmental area (VTA) and that 5-HT₃ antagonists will inhibit EtOH-stimulated somatodendritic release of dopamine within the VTA.

Objectives. The objective of this study was to use the intracranial self-administration procedure to determine the involvement of 5-HT₃ receptors in mediating the reinforcing effects of EtOH within the VTA, and to increase our understanding of central nervous system mechanisms involved in the rewarding effects of EtOH.

Methods. Adult female Wistar rats were stereotaxically implanted with guide cannulae aimed at the posterior VTA. After 1 week, rats were placed into standard two-lever experimental chambers for a total of seven sessions (4-h sessions separated by 48 h) and allowed to self-administer vehicle alone, a 5-HT₃ antagonist alone, 200 mg% EtOH alone, or combinations of 200 mg% EtOH with different concentrations of a 5-HT₃ antagonist (n=6–9 per group).

Results. Throughout all seven sessions, Wistar rats self-infused more 200 mg% ETOH (25±5 infusions) than vehicle (5±4 infusions) or 5-HT₃ antagonist (6±4 infusions) (P<0.05), and responded significantly more (P<0.05) on the active than inactive lever (e.g., 50±12 vs 12±8 responses in session 1). Co-administration of 50 µM or 100 µM ICS 205,930 with 200 mg% EtOH completely prevented the acquisition and maintenance of EtOH self-infusion into the posterior VTA. Similarly, co-administration of either 25–100 µM LY-278–584 or 10–100 µM zacopride with 200 mg% EtOH completely blocked EtOH-maintained intracranial self-administration behavior.

Conclusions. The results of this study suggest that the reinforcing effects of EtOH within the posterior VTA of Wistar rats require activation of local 5-HT₃ receptors.