Effects of β-adrenoceptor antagonists on alcohol drinking by alcohol-dependent rats

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.

Fig. 1

Mean (±SEM) fixed-ratio (FR-1) operant lever presses for ethanol (top panel) and water (bottom panel) by alcohol-dependent (black circles) and non-dependent (white circles) Wistar rats following injection of one of four propranolol doses (0.0, 2.5, 5.0, and 10.0 mg/kg). Operant tests occurred 6–8 h following termination of vapor exposure (i.e., 6–8 h withdrawal). *indicates p<0.05 significant difference from non-dependent control rats; # indicates p<0.05 significant difference from vehicle condition

Fig. 2

Mean (±SEM) cumulative ethanol responses across the 30-min operant session divided into 3-min bins. Fixed-ratio (FR-1) operant lever presses for ethanol by dependent (top panel) and non-dependent (bottom panel) Wistar rats following injection of one of four propranolol doses (0.0, 2.5, 5.0, and 10.0 mg/kg). Operant tests occurred 6–8 h following termination of vapor exposure (i.e., 6–8 h withdrawal). *p<0.005, all doses significantly lower than vehicle within bin (non-cumulative); #p<0.05, 2.5 and 10.0 mg/kg doses significantly lower than vehicle within bin (non-cumulative)

Fig. 3

Mean (±SEM) progressive ratio operant lever presses for ethanol during 11 baseline 90-min sessions by alcohol-dependent (black bars) and non-dependent (white bars) Wistar rats. Operant tests occurred 6–8 h following termination of vapor exposure (i.e. 6–8 h withdrawal)

Fig. 4

Mean (±SEM) operant lever presses for ethanol during the first 30 min (top panel) and the entire 90 min (bottom panel) of progressive ratio sessions. Alcohol-dependent (black circles) and non-dependent (white circles) Wistar rats responded for ethanol at the 6–8 h withdrawal time point following injection of one of four propranolol doses (0.0, 2.5, 5.0, and 10.0 mg/kg). # indicates p<0.05 significant difference from vehicle condition across all rats