Endogenous cannabinoids are not involved in cocaine reinforcement and development of cocaine-induced behavioural sensitization

https://doi.org/10.1016/j.euroneuro.2004.04.003Get rights and content

Abstract

The endogenous cannabinoid system is a relatively novel discovered system consisting of cannabinoid CB1 receptors, which are expressed both in the periphery and in the central nervous system, peripheral cannabinoid CB2 receptors and endogenous cannabinoids, which are anandamide and 2-arachidonyl glycerol. The cannabinoid CB1 receptors have recently been implicated in rewarding aspects of not only the cannabinoid drug Δ9-tetrahydrocannabinol (Δ9-THC), but also of other drugs of abuse, including cocaine. The present study was designed to further investigate the role of CB1 receptors in reward-related effects of cocaine. Using the CB1 receptor selective antagonist SR141716A, the involvement of CB1 receptors in cocaine reinforcement was determined by intravenous cocaine self-administration. In addition, the effects of the CB1 receptor selective antagonist SR141716A upon the development of cocaine-induced behavioural sensitization were investigated.

SR141716A did not affect cocaine reinforcement nor did it affect the development of behavioural sensitization to the locomotor stimulant effects of cocaine. These findings suggest that CB1 receptors are not involved in acute cocaine reinforcement nor in cocaine-induced behavioural sensitization.

Introduction

The endogenous cannabinoid system consists of cannabinoid type 1 receptors (CB1), CB2 receptors, which are restricted to the periphery, and the endogenous cannabinoids anandamide and 2-arachidonyl glycerol (2-AG) (Childers and Breivogel, 1998). Cannabinoid CB1 receptors have been implicated in the rewarding aspects not only of the Cannabis sativa-derived compound Δ9-tetrahydrocannabinol (Δ9-THC) (Maldonado and Rodriguez, 2002), but also of opiates such as heroin and morphine Chaperon et al., 1998, Navarro et al., 2001, Solinas et al., 2003, De Vries et al., 2003. Moreover, endogenous cannabinoids may be involved in reward-related effects of other drugs of abuse such as alcohol (Arnone et al., 1997, Gallate and McGregor, 1999, Serra et al., 2001, Lallemand et al., 2001, Freedland et al., 2001 but Vacca et al., 2002, Colombo et al., 2002, Wang et al., 2003), nicotine (Cohen et al., 2002), 3,4-methylenedioxymethamphetamine (MDMA) (Braida and Sala, 2002) and cocaine (Chaperon et al., 1998, De Vries et al., 2001 but Fattore et al., 1999).

Here we further investigated the role of CB1 receptors in acute and chronic reward-related effects of cocaine. For this purpose, we used the selective CB1 receptor antagonist SR141716A (N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxyamide hydrochloride (Rinaldi-Carmona et al., 1995). First, the involvement of CB1 receptors in the initiation of intravenous cocaine self-administration in drug-naive mice was studied. Initiation of cocaine self-administration is predominantly determined by the positive reinforcing properties of cocaine and is not or less influenced by effects of repeated drug administration (Van Ree et al., 1999). In a yoked-controlled self-administration paradigm, the effects of acute CB1 receptor blockade with SR141716A upon cocaine reinforcement were determined. In the second part of this study, the involvement of CB1 receptors in chronic effects of cocaine was determined. Prolonged exposure to cocaine, or other drugs of abuse, leads to sensitization of brain systems, which mediate incentive salience or ‘drug wanting’ (Robinson and Berridge, 2000). Here behavioural sensitization to the locomotor stimulant effects of cocaine, which is assumed to involve the same neural substrates, was studied for involvement of CB1 receptors. SR141716A or placebo was co-administered with repeated intermittent cocaine or saline sensitization injections for 11 subsequent days.

Section snippets

Animals

Male C57Bl/6Jico mice (Charles River, l'Arbresle, France) aged 2–3 months were group-housed (2–4) in extended Macrolon© type I cages with water and food pellets available ad libitum. Environmental conditions were controlled (22 °C and 50% humidity; lights on at 7:00 a.m. and lights off at 7:00 p.m., GDL Utrecht University). The experimental procedures were approved by the Ethical Committee for Animal Experiments of the University Medical Center Utrecht.

Effects of SR141716A upon intravenous cocaine self-administration

This experiment was designed to determine

Effects of SR141716A upon intravenous cocaine self-administration

Overall analysis of the nose pokes during the 10-min pre-test revealed no effect of SR141716A treatment nor were there differences between active and yoked control mice or between cocaine doses (Table 1), showing that during the initial pre-test all mice were equally active in their nose poke responding.

During the cocaine self-administration session, the active mice responded with significantly more nose pokes than the yoked control mice did (Fig. 1A, overall analysis, effect of type F

Discussion

Endogenous cannabinoid systems have been implicated in the rewarding aspects not only of the C. sativa derived compound Δ9-tetrahydrocannabinol (Δ9-THC), but also of opiates, alcohol and psychostimulants. Here we investigated the involvement of cannabinoid CB1 receptors in cocaine reinforcement and cocaine-induced behavioural sensitization. Neither cocaine self-administration in drug-naive mice nor cocaine-induced behavioural sensitization was affected by co-administration of the CB1 receptor

Acknowledgements

This work is supported by the Netherlands Organisation for Scientific Research (ZON-MW grant 985-01-004). Sanofi-synthelabo Recherche (Montpellier, France) kindly provided a sample of the CB1 antagonist SR141716A, which is gratefully acknowledged.

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