Nicholas W Gilpin1, George F Koob. 1. Committee on Neurobiology of Addictive Disorders, The Scripps Research Institute, SP30-2400 10550 N. Torrey Pines Rd, La Jolla, CA 92037, USA. nickg@scripps.edu
Abstract
RATIONALE: Alcohol-dependent animals display enhanced stress responsivity, reward thresholds, and alcohol self-administration during alcohol withdrawal, and some of these aspects of alcohol dependence may be mediated by activation of brain norepinephrine (NE) systems. OBJECTIVES: This study examined the effects of propranolol, a β-adrenoceptor antagonist, on operant alcohol-reinforced responding by alcohol-dependent and non-dependent rats. METHODS: Adult male Wistar rats were trained to respond for alcohol in an operant conditioning paradigm on fixed-ratio-1 (FR-1) and progressive ratio (PR) reinforcement schedules. Rats were either made dependent on alcohol via chronic intermittent (14 h ON/10 h OFF) alcohol vapor inhalation or were not exposed to alcohol vapor. Rats were tested for the effects of propranolol (0-10 mg/kg) or nadolol (0-20 mg/kg) on operant alcohol-reinforced responding at the time point corresponding to 6-8 h withdrawal in dependent animals. RESULTS: All doses of propranolol suppressed FR-1 operant alcohol-reinforced responding in alcohol-dependent rats, but only the highest dose suppressed FR-1 responding by controls. No dose of propranolol affected water responding. Nadolol did not affect operant behavior. Propranolol suppressed PR operant alcohol-reinforced responding across groups, an effect attributable to significant suppression of alcohol responding at the highest dose. CONCLUSIONS: Following development of alcohol dependence, rats exhibit hypersensitivity to the suppressive effects of propranolol on operant alcohol-reinforced responding. This effect is mediated by central actions of the drug, is not attributable to motor effects, and may reflect activation of brain NE systems that contributes to withdrawal-induced negative emotional states and drives alcohol drinking in the dependent organism.
RATIONALE: Alcohol-dependent animals display enhanced stress responsivity, reward thresholds, and alcohol self-administration during alcohol withdrawal, and some of these aspects of alcohol dependence may be mediated by activation of brain norepinephrine (NE) systems. OBJECTIVES: This study examined the effects of propranolol, a β-adrenoceptor antagonist, on operant alcohol-reinforced responding by alcohol-dependent and non-dependent rats. METHODS: Adult male Wistar rats were trained to respond for alcohol in an operant conditioning paradigm on fixed-ratio-1 (FR-1) and progressive ratio (PR) reinforcement schedules. Rats were either made dependent on alcohol via chronic intermittent (14 h ON/10 h OFF) alcohol vapor inhalation or were not exposed to alcohol vapor. Rats were tested for the effects of propranolol (0-10 mg/kg) or nadolol (0-20 mg/kg) on operant alcohol-reinforced responding at the time point corresponding to 6-8 h withdrawal in dependent animals. RESULTS: All doses of propranolol suppressed FR-1 operant alcohol-reinforced responding in alcohol-dependent rats, but only the highest dose suppressed FR-1 responding by controls. No dose of propranolol affected water responding. Nadolol did not affect operant behavior. Propranolol suppressed PR operant alcohol-reinforced responding across groups, an effect attributable to significant suppression of alcohol responding at the highest dose. CONCLUSIONS: Following development of alcohol dependence, rats exhibit hypersensitivity to the suppressive effects of propranolol on operant alcohol-reinforced responding. This effect is mediated by central actions of the drug, is not attributable to motor effects, and may reflect activation of brain NE systems that contributes to withdrawal-induced negative emotional states and drives alcohol drinking in the dependent organism.
Authors: Nicholas W Gilpin; Amanda D Smith; Maury Cole; Friedbert Weiss; George F Koob; Heather N Richardson Journal: Alcohol Clin Exp Res Date: 2009-09-09 Impact factor: 3.455