Abstract Rationale: The rewarding properties of ∆9- tetrahydrocannabinol (THC) are difficult to demonstrate in rodents using standard procedures. Objective: To eval- uate the motivational responses of THC in the place con- ditioning paradigm in mice after minimizing the dyspho- ric effects of the first drug exposure and/or the conse- quences of its pharmacokinetic properties. Methods: Mice were conditioned to THC (1 or 5 mg/kg) using an unbiased procedure with an elevated number of pairings and long conditioning time. Results: A place aversion was observed with 5 mg/kg THC using a standard proto- col. Similar results were obtained when the CB-1 recep- tor antagonist SR 141716A (1 mg/kg) was administered immediately after each THC conditioning period. How- ever, mice receiving a priming THC injection and condi- tioned 24 h later showed a place preference with 1 mg/kg THC and no effect with 5 mg/kg THC. Conclusion: THC produces a clear place preference in mice by using a long period of conditioning and avoiding the possible dyspho- ric consequences of the first drug exposure. Key words ∆9-Tetrahydrocannabinol · Mouse · Reward · Place preference · SR 141716A Introduction ∆9-tetrahydrocannabinol (THC) is the psychoactive con- stituent of Cannabis sativa, the most widely consumed illicit drug (Adams and Martin 1996). However, the re- warding properties of THC in the currently used rodent models are controversial. Thus, cannabinoid agonists fail to induce self-administration behaviour in rats (Leite and Carlini 1974; Van Ree et al. 1978), but some agonists of the CB-1 receptors (Devane et al. 1988), such as WIN 55212-2 (D’Ambra et al. 1992), can be self- administered in mice (Martellota et al. 1998). In the place preference paradigm, cannabinoid administration has been shown to produce place aversion in rats (Parker and Gillies 1995; McGregor et al. 1996; Sañudo-Peña et al. 1997; Mallet and Beninger 1998) and mice (Hutcheson et al. 1998), although one early study has reported the occurrence of place preference in rats under particular experimental conditions (Lepore et al. 1995). Various possibilities have been proposed to explain the failure to find a clear rewarding effect of THC in these models. One possibility is the pharmacokinetic profile of the drug, which has a relatively long half-life (McGregor et al. 1996). Another possible explanation is that the first exposure to cannabinoids would produce important dys- phoric actions which mask the rewarding effects of the drug (Parker and Gillies 1995; McGregor et al. 1996). The purpose of this study was to test the possibility of revealing rewarding effects of THC in the place prefer- ence paradigm in mice by minimizing the dysphoric ef- fects and the consequences of its pharmacokinetic prop- erties. Materials and methods Male CD1 mice (Charles River, France) weighing 22–24 g were housed ten per cage and acclimatized to the laboratory conditions (12 h light: 12 h dark cycle, 21±1°C room temperature) 1 week before the experiment. Food and water were available ad libitum. Behavioural tests and animal care were conducted in accordance with the standard ethical guidelines (NIH, publication no. 85-23, revised 1985) and approved by the local ethical committee. THC (Sigma, UK) was dissolved in a solution of 5% ethanol, 5% cre- mophor El and 90% distilled water, and injected in a volume of 0.1 ml per 10 g body weight. The CB-1 receptor antagonist SR 141716A (Sanofi Recherche, France) (Rinaldi-Carmona et al. 1994) was dissolved in a solution of 10% ethanol, 10% cremophor El and 80% distilled water, and injected in a volume of 0.2 ml per 10 g body weight. An unbiased place conditioning procedure was used to evaluate the rewarding properties of THC. The apparatus E. Valjent · R. Maldonado ( ✉ ) Laboratori de Neurofarmacologia, Facultat de Cienciès de la Salut i de la Vida, Universitat Pompeu Fabra, E-08003 Barcelona, Spain e-mail: rafael.maldonado@cexs.upf.es E. Valjent Laboratoire Neurochimie-Anatomie, Institut des Neurosciences, UMR 7624 CNRS, Université Pierre et Marie Curie, F-75005 Paris, France Psychopharmacology (2000) 147:436–438 © Springer-Verlag 2000 RAPID COMMUNICATION Emmanuel Valjent · Rafael Maldonado A behavioural model to reveal place preference to ∆9-tetrahydrocannabinol in mice Received: 12 August 1999 / Final version: 28 September 1999