PRECLINICAL STUDY: Schedule‐induced alcohol drinking: non‐selective effects of acamprosate and naltrexone

Abstract

Acamprosate and naltrexone are therapeutically effective drugs that promote abstinence and prevent drinking relapse among alcohol-dependent patients, and dose-dependently decrease alcohol self-administration in animals. The purpose of this experiment was to investigate the behavioral specificity of acamprosate and naltrexone treatment in mice on alcohol drinking elicited in a schedule-induced polydipsia (SIP) task. Food-deprived male C57BL/6J (B6) mice were divided into three groups assigned to a 5% alcohol SIP, water SIP, or a 1-hour limited access regulatory water drinking task. Injections (intraperitoneal) of acute (0, 50, 100, 200, 400 mg/kg) and chronic (2 x 100 mg/kg, 10 days) acamprosate, or naltrexone (0, 1.0, 2.5, 5.0 mg/kg) were administered. Behavioral drug specificity was determined by comparing alterations in alcohol or water consumption in SIP with alterations in limited access drinking. Additionally, drug effects on drinking-specific measures (g/kg consumption and lick efficiency) were compared with those of non-drinking measures (head entries for food and locomotor activity) during SIP. In comparison with saline injections, acute acamprosate (400 mg/kg) reduced both alcohol and water drinking in both SIP and the regulatory drinking conditions, but had no significant effects on non-drinking measures. Chronic administration of acamprosate reduced both alcohol and water drinking during SIP, but did not significantly affect regulatory drinking or non-drinking measures. Naltrexone (1.0, 2.5, 5.0 mg/kg) reduced alcohol and water drinking in both paradigms, and at the highest dose, significantly reduced head entries for food. These results indicate that acamprosate (acute and chronic) and naltrexone are relatively non-selective in their effects on alcohol self-administration in this task.

Acute effects of Naltrexone and GBR 12909 on ethanol drinking-in-the-dark in C57BL/6J mice

“…Moreover, it points to a specific role for the opioid system in initiating high ethanol intake as compared to the intake of a sugar reward or plain water. This is important because other animal models of high ethanol drinking, such as schedule-induced polydipsia, fail to show specificity for effects of naltrexone on ethanol drinking as compared to plain water drinking (Escher and Mittleman 2006). This result is also significant because one feature that has not yet been clearly elucidated is how motivation for ethanol is different from motivation for natural rewards (Kelley and Berridge 2002).…”

Acamprosate attenuates cocaine- and cue-induced reinstatement of cocaine-seeking behavior in rats

“…In addition, doses of acamprosate of 400-450 mg/kg have been previously reported to produce reductions in general fluid consumption and body weight (Czachowski et al 2001;Escher and Mittleman 2006;Gewiss et al 1991;Heyser et al 1998;Hölter et al 1997;Le Magnen et al 1987).…”

“…Because we observed adverse effects of the high (500 mg/kg) dose of acamprosate (i.e., reductions in body weight and spontaneous locomotor activity as well as one case of mortality) and because previous reports have shown that doses of 400 and 450 mg/kg of acamprosate inhibit general behavioral output and reduce body weight in other rat strains and experimental settings (Czachowski et al 2001;Escher and Mittleman 2006;Gewiss et al 1991;Heyser et al 1998;Hölter et al 1997;Le Magnen et al 1987), we elected not to test any doses of acamprosate higher than 300 mg/kg on cocaine self-administration and reinstatement of cocaine-seeking behavior.…”

Schedule-induced polydipsia as a model of compulsive behavior: neuropharmacological and neuroendocrine bases

“…Moreover, in SIP, the substitution of water for ethanol solution-induced equivalent levels of consumption has been considered as a promising behavioral model of alcohol abuse, relating directly to the induction of compulsive alcohol drinking (Gilpin et al 2008;Mittleman et al 2003Mittleman et al , 2011Singer et al 1982;Singer and Wallace 1984;Wayner 2002). Schedule induction and ethanol polydipsia provide an opportunity to investigate the development of drinking typologies that lead to chronic, excessive voluntary alcohol consumption in animals (Colotla 1981;Falk and Tang 1988), as well as the neural substrates and pharmacology of alcohol addiction (Escher and Mittleman 2006;Mittleman et al 2011).…”