Effects of dexfenfluramine and 5-HT3 receptor antagonists on stress-induced reinstatement of alcohol seeking in rats

Rationale and objectives: We previously found that systemic injections of the 5-HT uptake blocker fluoxetine attenuate intermittent footshock stress-induced reinstatement of alcohol seeking in rats, while inhibition of 5-HT neurons in the median raphe induces reinstatement of alcohol seeking. In this study, we further explored the role of 5-HT in footshock stress-induced reinstatement of alcohol seeking by determining the effects of the 5-HT releaser and reuptake blocker dexfenfluramine, and the 5-HT receptor antagonists ondansetron and tropisetron, which decrease alcohol self-administration and anxiety-like responses in rats, on this reinstatement. Methods: Different groups of male Wistar rats were trained to self-administer alcohol (12% v/v) for 28-31 days (1 h/day, 0.19 ml per alcohol delivery) and then their lever responding for alcohol was extinguished over 9-10 days. Subsequently, the effect of systemic injections of vehicle or dexfenfluramine (0.25 or 0.5 mg/kg, i.p), ondansetron (0.001, 0.01, or 0.1 mg/kg, i.p), or tropisetron (0.001, 0.01, and 0.1 mg/kg, i.p) on reinstatement induced by 10 min of intermittent footshock (0.8 mA) was determined. Results: Systemic injections of dexfenfluramine, ondansetron or tropisetron attenuated footshock-induced reinstatement of alcohol seeking. Injections of dexfenfluramine, ondansetron, or tropisetron had no effect on extinguished lever responding in the absence of footshock. Conclusions: The present results provide additional support for the hypothesis that brain 5-HT systems are involved in stress-induced reinstatement of alcohol seeking. The neuronal mechanisms that potentially mediate the unexpected observation that both stimulation of 5-HT release and blockade of 5-HT3 receptors attenuate footshock-induced reinstatement are discussed.