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Baclofen attenuates cue-induced reinstatement of alcohol-seeking behavior in Sardinian alcohol-preferring (sP) rats

https://doi.org/10.1016/j.drugalcdep.2008.02.006Get rights and content

Abstract

The GABAB receptor agonist, baclofen, suppressed alcohol deprivation effect (a proposed experimental model of alcohol relapse) in Sardinian alcohol-preferring rats. The present study was designed to extend the characterization of the “anti-relapse” properties of baclofen to the reinstatement of alcohol-seeking behavior (another proposed model of alcohol relapse). Rats of the sP line were first trained to lever press for alcohol under a fixed ratio 4 schedule of reinforcement. Subsequently, rats were exposed to two within-session 70-min extinction/reinstatement tests with saline or baclofen administered in a counterbalanced, within-subject design. After a 60-min extinction phase, an alcohol-associated stimulus complex was presented (reinstatement phase). Saline or baclofen (3 mg/kg) were administered via a permanent intraperitoneal catheter, 30 min before the reinstatement phase. During the reinstatement phase, baclofen administration: (a) reduced by approximately 60% responses on the previously active lever, (b) increased latency to the first response and (c) decreased the response rate. These results indicate that baclofen reduced cue-induced reinstatement of alcohol-seeking behavior in sP rats.

Introduction

Relapse to alcohol use after periods of abstinence is considered the major problem in the treatment of alcohol dependence (O’Brein, 1997). In order to better understand the neurobiological bases of these phenomena and to possibly identify potential pharmacological remedies, two experimental procedures have been proposed to model alcohol relapses in laboratory animals: alcohol deprivation effect (i.e., the robust, although transient, increase in alcohol consumption after a period of abstinence) and reinstatement of alcohol-seeking behavior (i.e., the resumption of extinguished lever pressing for alcohol induced by alcohol-associated cues or environmental stressors) (Spanagel, 2005).

The GABAB receptor agonist, baclofen, has recently gained interest in the alcohol research field due to a demonstrated suppression of several alcohol-related behaviors, including alcohol drinking, alcohol reinforcing and motivational properties, alcohol-stimulated locomotor activity and alcohol-induced conditioned place preference in rodents (Colombo et al., 2000, Colombo et al., 2003b, Bechtholt and Cunningham, 2005, Maccioni et al., 2005, Walker and Koob, 2007). When tested in human alcoholics, baclofen reduced alcohol consumption and craving for alcohol (Addolorato et al., 2002, Flannery et al., 2004), generalizing – to some extent – the data obtained in rodents.

In experiments on alcohol deprivation effect, acute administration of baclofen resulted in the suppression of this extra-intake of alcohol in Sardinian alcohol-preferring (sP) rats (Colombo et al., 2003a, Colombo et al., 2006). The present study was designed to extend to the reinstatement model the investigation on the “anti-relapse” properties of baclofen in sP rats. To this aim, rats were first trained to lever press for alcohol and then exposed to a within-session reinstatement procedure (Bienkowski et al., 1999, Bienkowski et al., 2000, Maccioni et al., 2007). The baclofen dose (3 mg/kg, i.p.) was chosen on the basis of previous results demonstrating that it was totally devoid of sedative and motor-incoordinating effects while being particularly effective in suppressing different alcohol-related behaviors, including alcohol deprivation effect, in sP rats (Colombo et al., 2003a).

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Materials and methods

The experimental procedure was performed in accordance with the European Communities Council Directive (86/609/EEC) and the subsequent Italian Law on the “Protection of animals used for experimental and other scientific reasons”.

Results

Before the first extinction/reinstatement session, all rats responded stably and preferentially on the “active” lever (166.5 ± 18.6 responses/session during the seven post-surgery sessions, corresponding to an average alcohol self-administration of 0.99 ± 0.11 g/kg/session) over the “inactive” lever (0.9 ± 0.1).

Extinction responding on the “active” lever averaged approximately 70 presses/60 min, without any significant difference between the saline and baclofen condition (Fig. 1). Extinction responding

Discussion

The non-contingent presentation of the alcohol-associated stimulus complex reinstated a previously extinguished lever pressing for alcohol in saline-treated sP rats. These data confirm that presentation of a complex of stimuli associated to alcohol may trigger a robust reinstatement of alcohol-seeking behavior in this rat line (Maccioni et al., 2007).

Treatment with baclofen, administered when responding for alcohol was virtually extinguished, reduced this reinstatement of responding. The mean

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