1. ¹Clinica Neurologica, Dipartimento di Neuroscienze, Università Tor Vergata & IRCCS Fondazione Santa Lucia, Rome, Italy
2. ²Dipartimento di Medicina Sperimentale e Scienze Biochimiche, Università Tor Vergata, Rome, Italy
3. ³Dipartimento di Scienze Biomediche, Università di Teramo, Teramo, Italy
4. ⁴IRCCS Centro per la Neurobiologia Sperimentale C Mondino, Mondino-Tor Vergata-Santa Lucia, Rome, Italy

Correspondence: P Calabresi, Dipartimento di Neuroscienze, Università Tor Vergata, Via Montpellier 1, 00133 Rome, Italy. Tel: +39 06 7259 6010; Fax: +39 06 7259 6006; E-mail: paolo.calabresi@uniroma2.it; M Maccarrone, Dipartimento di Scienze Biomediche, Università di Teramo, Piazza A Moro 45, 64100 Teramo, Italy. Tel: +39 0861 266 875; Fax: +39 06 7259 6468; E-mail: maccarrone@vet.unite.it

⁵These authors should be considered equal senior authors

Received 9 September 2003; Revised 4 March 2004; Accepted 5 March 2004; Published online 21 April 2004.

Abstract

Compelling evidence indicates that endocannabinoids are implicated in drug addiction. In the present study, we have addressed the interaction between cocaine and endocannabinoid system by means of neurochemical and neurophysiological experiments in rat brain slices. Using gas chromatography–electron impact mass spectrometry, we have found that cocaine increased the levels of the endocannabinoid anandamide in the striatum, a brain area primarily involved in the compulsive drug-seeking and drug-taking behaviors typical of addiction. This effect was attenuated by pharmacological inhibition of D2-like receptors but not D1-like receptors, and it was mimicked by D2-like but not D1-like receptor stimulation. The cocaine-induced increase in anandamide concentrations was attributable to both stimulation of its synthesis and inhibition of its degradation, as suggested by the ability of cocaine and quinpirole, a D2-like receptor agonist, to enhance the activity of NAPE-phospholipase D and to inhibit fatty acid amide hydrolase. By means of electrophysiological recordings from single striatal neurons, we have then observed that the ability of cocaine to inhibit, via D2-like receptors, GABA transmission was partially prevented following blockade of cannabinoid receptors, suggesting that endocannabinoids may act as downstream effectors in the action of cocaine in the striatum. Understanding the molecular and physiological effects of drugs of abuse in the brain is essential for the development of effective strategies against addiction.