title: Chronic treatment with prazosin or duloxetine lessens concurrent anxiety-like behavior and alcohol intake: evidence of disrupted noradrenergic signaling in anxiety-related alcohol use.
abstract: BACKGROUND
  Alcohol use disorders have been linked to increased anxiety, and enhanced central noradrenergic signaling may partly explain this relationship. Pharmacological interventions believed to reduce the excitatory effects of norepinephrine have proven effective in attenuating ethanol intake in alcoholics as well as in rodent models of ethanol dependence. However, most preclinical investigations into the effectiveness of these drugs in decreasing ethanol intake have been limited to acute observations, and none have concurrently assessed their anxiolytic effects. The purpose of these studies was to examine the long-term effectiveness of pharmacological interventions presumed to decrease norepinephrine signaling on concomitant ethanol self-administration and anxiety-like behavior in adult rats with relatively high levels of antecedent anxiety-like behavior.
  
  
  METHODS
  Adult male Long-Evans rats self-administered ethanol on an intermittent access schedule for eight to ten weeks prior to being implanted with osmotic minipumps containing either an a1-adrenoreceptor antagonist (prazosin, 1.5 mg/kg/day), a β1/2-adrenoreceptor antagonist (propranolol, 2.5 mg/kg/day), a serotonin/norepinephrine reuptake inhibitor (duloxetine, 1.5 mg/kg/day) or vehicle (10% dimethyl sulfoxide). These drugs were continuously delivered across four weeks, during which animals continued to have intermittent access to ethanol. Anxiety-like behavior was assessed on the elevated plus maze before treatment and again near the end of the drug delivery period.
  
  
  RESULTS
  Our results indicate that chronic treatment with a low dose of prazosin or duloxetine significantly decreases ethanol self-administration (P < 0.05). Furthermore, this decrease in drinking is accompanied by significant reductions in the expression of anxiety-like behavior (P < 0.05).
  
  
  CONCLUSIONS
  These findings suggest that chronic treatment with putative inhibitors of central noradrenergic signaling may attenuate ethanol intake via a reduction in anxiety-like behavior.
authors.affiliation: Department of Physiology and Pharmacology, Wake Forest School of Medicine, Medical Center Boulevard Winston-Salem, North Carolina, 27157.
authors.forename: Mary J
authors.initials: MJ
authors.lastname: Skelly
authors.affiliation: Department of Physiology and Pharmacology, Wake Forest School of Medicine, Medical Center Boulevard Winston-Salem, North Carolina, 27157.
authors.forename: Jeff L
authors.initials: JL
authors.lastname: Weiner
mesh_terms: D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D058668:Adrenergic alpha-1 Receptor Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D000428:Alcohol Drinking / Q000188:drug therapy*; D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology / Q000627:therapeutic use; D001007:Anxiety / Q000188:drug therapy*; D001522:Behavior, Animal / Q000187:drug effects*; D000068736:Duloxetine Hydrochloride; D000431:Ethanol / Q000008:administration & dosage*; D008297:Male; D011224:Prazosin / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D020318:Rats, Long-Evans; D012646:Self Administration; D013876:Thiophenes / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D018759:Adrenergic Uptake Inhibitors; D058668:Adrenergic alpha-1 Receptor Antagonists; D014151:Anti-Anxiety Agents; D013876:Thiophenes; D000431:Ethanol; D000068736:Duloxetine Hydrochloride; D011224:Prazosin
keywords: Duloxetine; osmotic minipump; plus maze; prazosin; propranolol; stress