title: Effects of prazosin and doxazosin on yohimbine-induced reinstatement of alcohol seeking in rats.
abstract: 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.
  
  
  
  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.
  
  
  
  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).
  
  
  
  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.
authors.affiliation: Neurobiology of Alcohol Laboratory, Campbell Family Mental Health Research Institute, Center for Addiction and Mental Health, 33 Russell Street, Toronto, Ontario, M5S 2S1, Canada. Douglas.Funk@camh.ca.
authors.forename: D
authors.initials: D
authors.lastname: Funk
authors.affiliation: Neurobiology of Alcohol Laboratory, Campbell Family Mental Health Research Institute, Center for Addiction and Mental Health, 33 Russell Street, Toronto, Ontario, M5S 2S1, Canada.
authors.forename: K
authors.initials: K
authors.lastname: Coen
authors.affiliation: Neurobiology of Alcohol Laboratory, Campbell Family Mental Health Research Institute, Center for Addiction and Mental Health, 33 Russell Street, Toronto, Ontario, M5S 2S1, Canada.
authors.forename: S
authors.initials: S
authors.lastname: Tamadon
authors.affiliation: Neurobiology of Alcohol Laboratory, Campbell Family Mental Health Research Institute, Center for Addiction and Mental Health, 33 Russell Street, Toronto, Ontario, M5S 2S1, Canada.
authors.forename: Z
authors.initials: Z
authors.lastname: Li
authors.affiliation: Neurobiology of Alcohol Laboratory, Campbell Family Mental Health Research Institute, Center for Addiction and Mental Health, 33 Russell Street, Toronto, Ontario, M5S 2S1, Canada.
authors.forename: A
authors.initials: A
authors.lastname: Loughlin
authors.affiliation: Neurobiology of Alcohol Laboratory, Campbell Family Mental Health Research Institute, Center for Addiction and Mental Health, 33 Russell Street, Toronto, Ontario, M5S 2S1, Canada.|Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada.|Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada.
authors.forename: A D
authors.initials: AD
authors.lastname: Lê
mesh_terms: D058668:Adrenergic alpha-1 Receptor Antagonists / Q000494:pharmacology*; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000428:Alcohol Drinking / Q000523:psychology*; D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects; D017292:Doxazosin / Q000494:pharmacology*; D005108:Extinction, Psychological / Q000187:drug effects; D016762:Genes, fos / Q000187:drug effects; D007276:Injections, Intraventricular; D008297:Male; D011224:Prazosin / Q000494:pharmacology*; D051381:Rats; D020318:Rats, Long-Evans; D017207:Rats, Sprague-Dawley; D012646:Self Administration; D015016:Yohimbine / Q000494:pharmacology*
chemical_list: D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists; D015016:Yohimbine; D017292:Doxazosin; D011224:Prazosin
keywords: Alcohol self-administration; Alpha-1 adrenoceptors; Fos; Noradrenaline; Relapse; Stress