Drugs for Relapse Prevention of Alcoholism (Milestones in Drug Therapy)

Editors: Spanagel, Rainer; Mann, Karl F.

Title: Drugs for Relapse Prevention of Alcoholism, 1st Edition

Copyright 2005 Springer

> Table of Contents > Cannabinoid receptor antagonists: a perspective

Cannabinoid receptor antagonists: a perspective

Mauro A.M. Carai¹

Carla Lobina¹

Gian Luigi Gessa^{1, 2}

Giancarlo Colombo²

¹ Department of Neuroscience, University of Cagliari, Cagliari, Italy

² C.N.R. Institute of Neuroscience, Section of Cagliari, Viale Diaz 182, 09126 Cagliari, Italy

Introduction

Cannabinoid CB₁ receptors are G-protein coupled receptors, located in different brain areas, including the cerebral cortex, hippocampus, basal ganglia, limbic structures and cerebellum (see [1]). Together with their endogenous ligands (anandamide and 2-arachidonyl-glycerol- identified to date), cannabinoid CB₁ receptors constitute the so-called endocannabinoid system . When activated, cannabinoid CB₁ receptors suppress the neuronal release of different excitatory and inhibitory neurotransmitters, including acetylcholine, noradrenaline, dopamine, serotonin, GABA, glutamate and aspartate (see [1]). As a consequence, cannabinoid CB₁ receptors have been implicated in physiological functions such as cognition, control of movement, pain perception, and emotional responses as well as appetite (see [1]).

Furthermore, in recent years, accumulating lines of experimental evidence have suggested the possible involvement of the brain cannabinoid CB₁ receptor system in the neural circuitry controlling alcohol intake, including alcohol relapse-like drinking, and alcohol reinforcing properties. Specifically, the acute administration of cannabinoid receptor agonists CP 55,940 and WIN 55,212-2 has been found to stimulate alcohol intake in selectively bred Sardinian alcohol-preferring (sP) rats [2] and enhance the break-point for beer (i.e., an index of the appetitive or motivational properties of alcohol) in Wistar rats [3]. These effects were completely blocked via pre-treatment with the selective cannabinoid CB₁ receptor antagonist SR 141716, indicating that they were indeed mediated by the cannabinoid CB₁ receptor [2, 3].

Conversely, the administration of SR 141716 has repeatedly been reported to produce opposite effects. Specifically, SR 141716 has been found to:

• Reduce voluntary alcohol intake and alcohol preference under the home cage, 2-bottle alcohol versus water choice paradigm in alcohol-experienced C57BL/6 mice [4], sP rats [5] and Wistar rats [6], which may model the maintenance or active drinking phase of human alcoholism;

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• Suppress the acquisition of alcohol drinking behavior in alcohol-naive sP rats, that is rats which had never consumed alcohol before the start of the experiment [7];

• Suppress the alcohol deprivation effect (ADE; a model of alcohol relapses in human alcoholics) in sP rats (see below);

• Decrease the oral self-administration of alcohol in unselected rats tested under operant procedures (i.e., experimental paradigms in which rats were trained to press a lever to gain access to alcohol) [8] (see also L. Parsons and G. Koob's contribution to [9]);

• Attenuate the appetitive or motivational properties of alcohol, as revealed by a decrease in the probability of the completion of response requirements for alcohol in operant procedures using unselected rats [8, 10] and by the suppression of extinction responding for alcohol (i.e., the maximal amount of work which a rat trained to lever-press for alcohol is willing to perform to obtain alcohol) in sP rats [11].

In agreement with the above results on the effect of the pharmacological blockade of the cannabinoid CB₁ receptor by SR 141716, CB₁ receptor knockout mice tested under the 2-bottle choice paradigm displayed significantly lower levels of alcohol preference and consumption in comparison to the wild-type mice ([12, 13, 14 and 15]; see however [16]).

Taken together, these results suggest that the cannabinoid CB₁ receptor is one of multiple receptor systems implicated in the mediation of the behavioral responses to alcohol.

Effect of SR 141716 on relapse-like behavior in alcohol-preferring rats

The possible anti-relapse properties of SR 141716 have been tested by investigating its effect on ADE in alcohol-preferring sP rats. ADE is defined as the transient increase in alcohol intake which occurs in several animal species after a period of abstinence from alcohol, and ADE has been proposed to model the loss of control over alcohol and the episodes of alcohol relapse of human alcoholics (see [17, 18]). Notably, ADE is a relevant feature of alcohol drinking behavior of sP rats. Indeed, after a proper period of exposure to alcohol and a subsequent period of alcohol deprivation, sP rats display a pronounced ADE during the first hour of re-access to alcohol [19, 20]. Furthermore, ADE in sP rats is reduced by the anti-relapse agent naltrexone (this laboratory, unpublished observations). These results make sP rats a suitable animal model, with predictive validity for pharmacological investigations on ADE.

In the experiment with SR 141716 [21], adult male sP rats were individually housed and continuously (24 h/day) offered alcohol (10%, v/v) and water under the standard home cage 2-bottle choice paradigm with unlimited access for 4 consecutive weeks. Subsequently, rats were divided into two groups

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The results of the study showed that alcohol intake was approximately two times higher in vehicle-treated alcohol-deprived rats than in vehicle-treated alcohol-nondeprived rats, indicative of the development of a robust ADE (Fig. 1). This extra intake of alcohol was, however, eliminated by all doses of SR 141716 (Fig. 1). Indeed, alcohol intake in the alcohol-deprived rat groups treated with all doses of SR 141716 was a) significantly lower than that recorded in alcohol-deprived vehicle-dosed rats, and b) not significantly different from that recorded in the corresponding alcohol-nondeprived SR 141716-treated groups.

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These results suggest that the cannabinoid CB₁ receptor is likely part of a neural substrate mediating ADE. These results, together with the apparent safety and potential use in humans of SR 141716 (Rimonabant) [22], also suggest that SR 141716 should be tested for its ability in preventing alcohol relapse in human alcoholics.

Effect of the combination of SR 141716 plus naloxone on relapse-like behavior in alcohol-preferring rats

Recent clinical surveys suggest that positive therapeutic outcomes in the treatment of alcohol relapse may be achieved by using a combination of drugs. For example, a recent, double-blind placebo-controlled study demonstrated that the combination of naltrexone and acamprosate tended to be more effective than the single application of either drug in the prevention of alcohol relapse in alcoholics [23]. Following this line of thought, this laboratory recently tested the hypothesis that a combination of SR 141716 with the opioid receptor antagonist naloxone would result in a potentiation of the reducing effect of each single drug on ADE in alcohol-preferring sP rats.

The procedure employed in this experiment was similar to that used in the study testing SR 141716 alone (see above). Specifically, adult male sP rats were singly housed and continuously (24 h/day) offered alcohol (10%, v/v) and water under the home cage 2-bottle regimen for 8 consecutive weeks. After the initial period of access to alcohol and water, rats were divided into two groups matched for similar daily alcohol consumption and preference over the last 7 days. One group was deprived of alcohol for 14 consecutive days, during which water was the sole fluid available (alcohol-deprived rats). The second group continued to have unlimited access to alcohol and water (alcohol-nondeprived rats). At the end of the deprivation phase, rats of both groups were divided into four subgroups (n = 16), matched for body weight, and acutely treated with: a) SR 141716 vehicle plus naloxone vehicle; b) 0.05 mg/kg SR 141716 plus naloxone vehicle; c) SR 141716 vehicle plus 0.01 mg/kg naloxone; d) 0.05 mg/kg SR 141716 plus 0.01 mg/kg naloxone. The SR 141716 and naloxone doses were chosen so as to be ineffective when given alone. Drugs were administered intraperitoneally 30 min before alcohol presentation (which coincided with lights off). Alcohol was re-presented at lights off. Alcohol intake was recorded 60 min later. Standard rat chow was available throughout the study.

As expected, after alcohol re-presentation, alcohol intake was higher by approximately 50% in control alcohol-deprived rats as compared to control alcohol-nondeprived rats (Fig. 2), indicating the development of ADE. When given alone, neither 0.05 mg/kg SR 141716 nor 0.01 mg/kg naloxone affected the extra amount of alcohol intake, which constitutes ADE. In contrast, their combination reduced ADE by approximately 30% (Fig. 2).

These results are in close agreement with those of recent studies, demonstrating that SR 141716 and the opioid receptor antagonist naltrexone synergistically

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The possible generalization to human alcoholics of the reducing effect of the combination of SR 141716 and naloxone on alcohol relapse-like drinking in sP rats would indicate a new therapeutic strategy.

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