Ž . European Journal of Pharmacology 376 1999 23–26 www.elsevier.nlrlocaterejphar Short communication Dependence of mesolimbic dopamine transmission on D 9 -tetrahydrocannabinol Gianluigi Tanda, Patrizio Loddo, Gaetano Di Chiara ) Department of Toxicology and Consiglio Nazionale delle Ricerche, Center for Neuropharmacology, UniÕersity of Cagliari, Viale A. Diaz 182, 09126 Cagliari, Italy Received 18 May 1999; accepted 21 May 1999 Abstract Ž . 9 Ž 9 . Rats were administered daily for 8 days with increasing doses 2–12 mgrkgrday of D -tetrahydrocannabinol D -THC and than challenged with different doses of SR141716A, an antagonist of cannabinoid receptors. SR141716A dose dependently reduced dialysate Ž . dopamine DA in the nucleus accumbens shell and precipitated a physical withdrawal syndrome. No such effects were obtained after administration of SR141716A to saline controls. q 1999 Elsevier Science B.V. All rights reserved. Keywords: D 9 -Tetrahydrocannabinol; Dopamine; Microdialysis; Nucleus accumbens; Rat; SR141716A 1. Introduction 9 Ž 9 . D -Tetrahydrocannabinol D -THC , the active principle of Cannabis, resembles heroin in the property of stimulat- Ž . ing dopamine DA transmission in the nucleus accumbens shell and in being antagonized in this action by naloxone, Ž . the prototypical opiate antagonist Tanda et al., 1997 . Moreover, after chronic cannabinoid exposure, the syn- thetic cannabinoid receptor antagonist SR141716A Ž . Rinaldi-Carmona et al., 1994 precipitates a physical ab- stinence syndrome and elicits changes in brain corti- cotropin releasing factor that resemble those associated to Ž . opiate withdrawal De Fonseca et al., 1997 . We now provide evidence that in rats, a relatively mild and short- lasting schedule of exposure to D 9 -THC induces a state of dependence of in vivo DA transmission in the nucleus accumbens shell as estimated by microdialysis. 2. Materials and methods 2.1. Animals Ž Male Sprague–Dawley rats Charles River, Calco, . Como, Italy of 250 g were housed for at least a week, before use, in group of six under standard conditions of ) Corresponding author. Tel.: q0039-00-303819; fax: q0039-00- 300740; E-mail: diptoss@tin.it temperature and humidity, in an artificial light–dark cycle Ž . light on 8:00 a.m., off 8:00 p.m. . They had free access to food and water. All animal experimentation was approved by the local committee, in accordance with European Economic Community guidelines for care and use of ex- perimental animals. 2.2. Experimental procedure Thirty rats were divided into two groups. The first Ž . group n s 15 was administered intraperitoneally twice a Ž . 9 day ; 8:00 a.m. and ; 8:00 p.m. with D -THC, for a total daily dose of 2 mgrkg on the 1st day, 4 mgrkg on the 2nd day, 8 mgrkg on the 3rd day and 12 mgrkg from Ž . the 4th to the 8th day. The second group of rats n s 15 Ž was administered intraperitoneally twice a day 8:00 a.m. . and 8:00 p.m. with saline for 8 days. On the 8th day, 3 h after the first daily dose of D 9 -THC or saline, the rats were implanted with microdialysis probes in the nucleus accum- bens shell in order to estimate changes in extracellular DA as an index of in vivo DA transmission. Dialysate DA was monitored the next day, about 12 h after the last dose of D 9 -THC and about 24 h after probe implant. Saline con- trols were run in parallel. 2.3. Probe preparation Concentric dialysis probes were prepared with AN 69 Ž . fibers Hospal Dasco, Italy as described by Tanda and Di Ž . Chiara 1998 . 0014-2999r99r$ - see front matter q 1999 Elsevier Science B.V. All rights reserved. Ž . PII: S0014-2999 99 00384-2