Effects of dexfenfluramine and 5-HT3 receptor antagonists on stress-induced reinstatement of alcohol seeking in rats
- 118 Downloads
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.
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.
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.
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.
Keywords5-Hydroxytryptamine Reinstatement Footshock 5-HT3 receptors Relapse Stress
This work was supported by a grant from the NIAAA (AA13108) to A.D. Le.
- Hajos-Korcsok E, Robinson DD, Yu JH, Fitch CS, Walker E, Merchant KM (2003) Rapid habituation of hippocampal serotonin and norepinephrine release and anxiety-related behaviors, but not plasma corticosterone levels, to repeated footshock stress in rats. Pharmacol Biochem Behav 74:609–616PubMedCrossRefGoogle Scholar
- Kandel DB, Johnson JG, Bird HR, Canino G, Goodman SH, Lahey BB, Regier DA, Schwab-Stone M (1997) Psychiatric disorders associated with substance use among children and adolescents: findings from the Methods for the Epidemiology of Child and Adolescent Mental Disorders (MECA) Study. J Abnorm Child Psychol 25:121–132PubMedCrossRefGoogle Scholar
- Le AD, Poulos CX, Harding S, Watchus W, Juzytsch W, Shaham Y (1999) Effects of naltrexone and fluoxetine on alcohol self-administration and reinstatement of alcohol seeking induced by priming injections of alcohol and exposure to stress in rats. Neuropsychopharmacology 21:435–444PubMedCrossRefGoogle Scholar
- McKenzie-Quirk SD, Miczek KA (2003) 5-HT1A agonists: alcohol drinking in rats and squirrel monkeys. Psychopharmacology (Berl) 167:145–152Google Scholar
- Stewart J, de Wit H (1987) Reinstatement of drug-taking behavior as a method of assessing incentive motivational properties of drugs. In: Bozarth MA (ed) Methods of assessing the reinforcing properties of abused drugs. Springer, Berlin Heidelberg New York, pp 211–227Google Scholar