Effects of prazosin and doxazosin on yohimbine-induced reinstatement of alcohol seeking in rats

• Published in: Psychopharmacology Vol. 233; no. 11; pp. 2197 - 2207
• Main Authors: Funk, D., Coen, K., Tamadon, S., Li, Z., Loughlin, A., Lê, A. D.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.06.2016; Springer; Springer Nature B.V
• Subjects: Adrenergic alpha-1 Receptor Antagonists - pharmacology; Adrenergic alpha-Antagonists - pharmacology; Alcohol Drinking - psychology; Alcohol use; Alcoholism; Animals; Biomedical and Life Sciences; Biomedicine; Brain Chemistry - drug effects; Dosage and administration; Doxazosin - pharmacology; Drug interactions; Drug therapy; Extinction, Psychological - drug effects; Genes, fos - drug effects; Hormones; Injections, Intraventricular; Male; Neurosciences; Observations; Original Investigation; Pharmacology/Toxicology; Prazosin; Prazosin - pharmacology; Psychiatry; Psychopharmacology; Rats; Rats, Long-Evans; Rats, Sprague-Dawley; Self Administration; Stress response; Yohimbine - pharmacology; Alcohol self-administration; Alpha-1 adrenoceptors; Relapse; Fos; Noradrenaline; Stress
• ISSN: 0033-3158; 1432-2072
• DOI: 10.1007/s00213-016-4273-2

Rationale and objectives Alpha-1 adrenoceptor antagonists, such as prazosin, show promise in treating alcoholism. In rats, prazosin reduces alcohol self-administration and relapse induced by footshock stress and the alpha-2 antagonist yohimbine, but the processes involved in these effects of prazosin are not known. Here, we present studies on the central mechanisms underlying the effects of prazosin on yohimbine-induced reinstatement of alcohol seeking. Methods In experiment 1, we trained rats to self-administer alcohol (12 %  w / v , 1 h/day), extinguished their responding, and tested the effects of prazosin, administered ICV (2 and 6 nmol) or systemically (1 mg/kg) on yohimbine (1.25 mg/kg)-induced reinstatement. In experiment 2, we determined potential central sites of action by analyzing effects of prazosin (1 mg/kg) on yohimbine (1.25 mg/kg)-induced Fos expression. In experiment 3, we determined the effects of doxazosin (1.25, 2.5, and 5 mg/kg), an alpha-1 antagonist with a longer half-life on yohimbine-induced reinstatement. Results Yohimbine-induced reinstatement of alcohol seeking was reduced significantly by ICV and systemic prazosin (50 and 69 % decreases, respectively). Systemic prazosin reduced yohimbine-induced Fos expression in the prefrontal cortex, accumbens shell, ventral bed nucleus of the stria terminalis, and basolateral amygdala (46–67 % decreases). Doxazosin reduced yohimbine-induced reinstatement of alcohol seeking (78 % decrease). Conclusions Prazosin acts centrally to reduce yohimbine-induced alcohol seeking. The Fos mapping study suggests candidate sites where it may act. Doxazosin is also effective in reducing yohimbine-induced reinstatement. These data provide information on the mechanisms of alpha-1 antagonists on yohimbine-induced alcohol seeking and indicate their further investigation for the treatment of alcoholism.