Original Investigation

Psychopharmacology

, Volume 186, Issue 1, pp 82-92

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

  • Anh Dzung LêAffiliated withDepartment of Neuroscience, Centre for Addiction and Mental HealthDepartment of Pharmacology, University of TorontoDepartment of Psychiatry, University of Toronto Email author 
  • , Douglas FunkAffiliated withDepartment of Neuroscience, Centre for Addiction and Mental Health
  • , Stephen HardingAffiliated withDepartment of Neuroscience, Centre for Addiction and Mental Health
  • , W. JuzytschAffiliated withDepartment of Neuroscience, Centre for Addiction and Mental Health
  • , Paul J. FletcherAffiliated withDepartment of Neuroscience, Centre for Addiction and Mental HealthDepartment of Psychiatry, University of TorontoDepartment of Psychology, University of Toronto
  • , Yavin ShahamAffiliated withBehavioral Neuroscience Branch, IRP/NIDA/NIH/DHHS

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Abstract

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.

Keywords

5-Hydroxytryptamine Reinstatement Footshock 5-HT3 receptors Relapse Stress