Effect of naltrexone on alcohol consumption during chronic alcohol drinking and after a period of imposed abstinence in free-choice drinking rhesus monkeys

Abstract

Relapse into problematic alcohol drinking is a serious problem in the treatment of alcoholism. Free-choice drinking rhesus monkeys show relapse-like behaviour after imposed abstinence of alcohol, by immediately reinitiating ethanol intake at an increased level. The relapse-like behaviour of the monkeys seems not induced by physical withdrawal, but rather argues for a resistance to extinction of ethanol-reinforced behaviour. It has been suggested that endogenous opioids play a role in the positive reinforcing effect of ethanol. In this study, the effect of the opiate antagonist naltrexone was investigated in eight adult male rhesus monkeys (Macaca mulatta) who had about 1 year experience with alcohol drinking, under two conditions: 1) (expt 1) during continuous and concurrent supply of drinking water and two ethanol/water solutions (16% and 32% (v/v], and 2) (expt 2) after 2 days of alcohol abstinence. In both experiments, each monkey received six doses of naltrexone (0.02, 0.06, 0.17, 0.5, 1.0, 1.5 mg.kg-1); each dose was paired with a placebo injection (im) in a cross-over design. Consumption was measured from 16.00 hours in the afternoon (30 min after injection) to 9.00 hours the next morning. In experiment 1 naltrexone reduced total net ethanol intake in a graded dose-dependent manner. The effect of naltrexone was apparent shortly after injection, and lasted until the following day. Consumption of drinking water was reduced only shortly after injection. In expt 2, reduction of net ethanol intake was largely restricted to the first few hours of reinitiation of alcohol drinking, i.e. the period in which the abstinence-induced increase was manifest. Consumption of drinking water was not affected by naltrexone. Naltrexone hardly influenced consumption of the non-preferred ethanol solution of 32%. It is postulated that the opioid modulation specifically interacted with positively reinforced behaviour. In expt 2 naltrexone reduced ethanol intake at a lower dose (0.17 mg.kg-1) compared to expt 1 (0.50 mg.kg-1), but net ethanol intakes however remained higher. It might be that alcohol abstinence resulted in altered opioid activity, leading to increased ethanol-seeking behaviour. The renewed presentation of ethanol solutions (also) might have stimulated reinitiation of alcohol drinking, representing conditioned incentive stimuli. The reported monkey model of relapse in alcohol drinking could be a useful tool to evaluate new hypotheses and experimental treatments with respect to human alcoholism.

Effects of alcohol and saccharin deprivations on concurrent ethanol and saccharin operant self-administration by alcohol-preferring (P) rats

“…The ADE has been used as model of alcohol craving to study the efficacy of drugs designed to prevent relapse drinking (Heyser et al, 1998;Kornet et al, 1991;Rodd et al, 2003Rodd et al, , 2004Rodd et al, , 2006Sinclair and Li, 1989;Spanagel and Zieglgansberger, 1997;Vengeliene et al, 2005).…”

Characterization of the ethanol-deprivation effect in substrains of C57BL/6 mice

“…Short (12-h or less; Sinclair and Li, 1989) or long (up to 75 days; Sinclair et al, 1973) deprivation intervals both produce an EDE in rats. Further validation of the EDE as a model for relapse comes from studies showing that pharmacological agents known to be effective in treating alcoholism will also decrease the EDE in animal models (Heyser et al, 1998;Kornet et al, 1991;Spanagel and Zieglgansberger, 1997).…”

Effects of Repeated Alcohol Deprivations on Operant Ethanol Self-Administration by Alcohol-Preferring (P) Rats

“…The ADE has been hypothesized to be an animal model of alcohol craving (Heyser et al, 1997;Sinclair and Li, 1989) and has been utilized to examine the efficacy of pharmacological agents to prevent relapse drinking (Heyser et al, 1998;Kornet et al, 1991;Spanagel and Zieglgansberger, 1997).…”