1. ¹Preclinical Pharmacology Section, Behavioral Neuroscience Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, Baltimore, MD, USA
2. ²Laboratoire de Biologie et Physiologie Cellulaires, CNRS-6187, University of Poitiers, Poitiers, France
3. ³Psychobiology Section, Medications Discovery Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, Baltimore, MD, USA
4. ⁴Center for Drug Discovery, Northeastern University, Boston, MA, USA

Correspondence: Dr SR Goldberg, Preclinical Pharmacology Section, Behavioral Neuroscience Research Branch, National Institute on Drug Abuse, Division of Intramural Research, National Institutes of Health, 5500 Nathan Shock Drive, Baltimore, MD 21224, USA. Tel: +410 550 1522; Fax: +410 550 1648; E-mail sgoldber@intra.nida.nih.gov

Received 14 February 2005; Revised 17 March 2005; Accepted 21 March 2005; Published online 4 May 2005.

Abstract

Accumulating evidence suggests that the endogenous cannabinoid system is involved in the reinforcing effects of heroin. In rats intravenously self-administering heroin, we investigated effects of cannabinoid CB₁ receptor agonists and compounds that block transport or metabolism of the endogenous cannabinoid anandamide. The natural cannnabinoid CB₁ receptor agonist delta-9-tetrahydrocannabinol (THC, 0.3–3 mg/kg i.p.) did not alter self-administration of heroin under a fixed-ratio one (FR1) schedule, except at a high 3 mg/kg dose which decreased heroin self-administration. Under a progressive-ratio schedule, however, THC dose-dependently increased the number of 50 g/kg heroin injections self-administered per session and the maximal ratio completed (break-point), with peak increases at 1 mg/kg THC. In addition, 1 mg/kg THC increased break-points and injections self-administered over a wide range of heroin injection doses (25-100 g/kg), indicating an increase in heroin's reinforcing efficacy and not its potency. The synthetic cannabinoid CB₁ receptor agonist WIN55,212–2 (0.3–3 mg/kg i.p.) had effects similar to THC under the progressive-ratio schedule. In contrast, AM-404 (1–10 mg/kg i.p.), an inhibitor of transport of anandamide, and URB-597 (0.01–0.3 mg/kg i.p.), an inhibitor of the enzyme fatty acid amide hydrolase (FAAH) that degrades anandamide, or their combination, did not increase reinforcing efficacy of heroin at any dose tested. Thus, activation of cannabinoid CB₁ receptors facilitates the reinforcing efficacy of heroin and this appears to be mediated by interactions between cannabinoid CB₁ receptors and mu-opioid receptors and their signaling pathways, rather than by an opioid-induced release of endogenous cannabinoids.