Chronic cocaine sensitizes striatal GABAergic synapses to the stimulation of cannabinoid CB1 receptors Diego Centonze, 1,2 Silvia Rossi, 1,2 Valentina De Chiara, 1,2 Chiara Prosperetti, 1,2 Natalia Battista, 2,3 Giorgio Bernardi, 1,2 Nicola B. Mercuri, 1,2 Alessandro Usiello 4 and Mauro Maccarrone 2,3 1 Clinica Neurologica, Dipartimento di Neuroscienze, Universita ` Tor Vergata, Via Montpellier 1, 00133, Rome, Italy 2 Centro Europeo per la Ricerca sul Cervello (CERC) ⁄ Fondazione Santa Lucia, Rome, Italy 3 Dipartimento di Scienze Biomediche, Universita ` di Teramo, Teramo, Italy 4 Behavioural Neuroscience Laboratory, CEINGE – Biotecnologie Avanzate, Naples, Italy Keywords: addiction, dopamine, electrophysiology, habit, IPSC Abstract Behavioural studies indicate that cannabinoid receptors are implicated in cocaine addiction. The synaptic underpinning of cocaine– cannabinoid receptor interaction is however, obscure. We have studied electrophysiologically the sensitivity of cannabinoid receptors modulating synaptic transmission in the striatum of rats exposed to cocaine. One-day treatment with cocaine did not modify the synaptic response to HU210, a cannabinoid CB1 receptor agonist. Seven days cocaine-treatment, conversely, caused conditioned place preference, and sensitized striatal GABAergic synapses to the presynaptic effect of cannabinoid CB1 receptor stimulation. The cannabinoid receptor-induced modulation of glutamate transmission was unaltered by cocaine. Furthermore, the effects of chronic cocaine on cannabinoid-mediated regulation of striatal GABA synapses were attenuated one week after the discontinuation of cocaine, and absent two weeks later, indicating the progressive reversibility of the adaptations of cannabinoid system during abstinence of drug consumption. Our data support the concept that modulation of cannabinoid receptors might be useful against drug abuse. Introduction Evidence exists that cannabinoid receptors are implicated in cocaine addiction. D 9 -tetrahydrocannabinol (THC) consumption in monkeys is greatly facilitated after previous acquisition of cocaine self-adminis- tration (Tanda et al., 2000; Maldonado & Rodriguez de Fonseca, 2002), while blockade of cannabinoid CB1 receptors attenuates both the rewarding effects of cocaine (Chaperon et al., 1998), and the relapse to cocaine-seeking behaviour induced by re-exposure to cocaine-associated cues or cocaine itself (De Vries et al., 2001). Furthermore (AAT)n repeat in the cannabinoid receptor gene has been found to be associated with predisposition to cocaine dependency in humans (Ballon et al., 2006), while lack of CB1 receptors impairs cocaine self-administration in mice (Soria et al., 2005). The involvement of cannabinoid receptors in cocaine addiction is however, challenged by other findings. It has been reported, in fact, that pharmacological blockade of cannabinoid CB1 receptors does not affect cocaine reinforcement nor does it affect the development of behavioural sensitization to the locomotor stimulant effects of cocaine (Lesscher et al., 2005). Furthermore, deletion of CB1 receptors eliminates the rewarding effects of cannabinoids (Ledent et al., 1999) and of opiates (Ledent et al., 1999; Martin et al., 2000; Cossu et al., 2001), but leaves the rewarding effects of psychostimulants intact (Martin et al., 2000; Cossu et al., 2001). Finally, CB1 receptor ablation does not modify the locomotion elicited by cocaine (Houchi et al., 2005), and CB1 receptor agonist and heroin, but not cocaine, reinstate cannabinoid-seeking behaviour in rats (Spano et al., 2004). From these data, it is therefore evident that further experimental work is necessary to clarify the putative role of cannabinoid receptors in cocaine addiction. One physiological study addressed the possible synaptic basis of cocaine–cannabinoid interaction. In that study, a single cocaine exposure in vivo was found to abolish endocannabinoid-mediated long-term depression (LTD) in the nucleus accumbens (Fourgeaud et al., 2004), identifying synaptic plasticity in dopaminoceptive areas of the reward system as the substrate of such interaction. Besides their role in synaptic plasticity, cannabinoid receptors modulate transmitter release at both excitatory and inhibitory synapses (Piomelli, 2003; Parolaro et al., 2005), raising the possibility that altered regulation of these synapses contributes to the central effects of cocaine exposure. In the present study therefore we investigated the sensitivity of both glutamate and GABA synapses to cannabinoid receptor stimulation in the striatum of cocaine-treated rats. The striatum is an ideal structure to study the possible cocaine–cannabinoid interaction, as this brain area plays a central role in psychostimulant addiction (Kelly et al., 1975; Amalric & Koob, 1993; Berke & Hyman, 2000; Gerdeman et al., 2003; Volkow et al., 2006), and contains high levels of cannabinoid receptors (Piomelli, 2003). Materials and methods Adult male Wistar rats (150–250 g) were used for all the experiments. All procedures were approved by the Institutional Animal Care and Use Committee of the University of Tor Vergata, Rome, and were in Correspondence: Dr Diego Centonze, 1 Clinica Neurologica, as above. E-mail: centonze@uniroma2.it Received 18 August 2006, revised 22 January 2007, accepted 23 January 2007 European Journal of Neuroscience, Vol. 25, pp. 1631–1640, 2007 doi:10.1111/j.1460-9568.2007.05433.x ª The Authors (2007). Journal Compilation ª Federation of European Neuroscience Societies and Blackwell Publishing Ltd