Resumo

Introduction: drugs of abuse, including cocaine, increase dopamine levels in the nucleus accumbens producing, in rodents, locomotor stimulation, a behavior which is sensitized after repeated administration. This sensitization has been proposed to share neuronal mechanisms with drug craving. The aim of this study was to investigate if repeated treatment with the cannabinoid receptor antagonist rimonabant is able to inhibit cocaine-induced behavioral sensitization previously developed in mice. The role of environmental context in the behavioral sensitization phenomenon was also investigated (Ethic committee number: 470/07). Methods: In the first experiment, Swiss mice received intraperitoneally (ip) 10mg/kg of cocaine or saline every other day for 15 days (8 injections). Five minutes after each injection the animals were exposed to an open field (OF) for 10 min. Locomotor activity (LA) was measured on the 1st and 15th days. On the 17th day the animals began to be treated with vehicle or rimonabant (1 or 10mg/kg) ip during 8 consecutive days and 30 min after each injection were placed in the OF for 10 min (being LA quantified on the 17th and 24th days). On the 30th day all the animals were challenged ip with 10mg/kg cocaine and their LA was quantified for 10 min in the OF. Therefore, the following groups (n=14) were formed: Saline-Vehicle-Cocaine (Sal-Veh-Coc); Saline-Rimonabant1-Cocaine (Sal-Rim1-Coc); Saline-Rimonabant10-Cocaine (Sal-Rim10-Coc); Cocaine-Vehicle-Cocaine (Coc-Veh-Coc); Cocaine-Rimonabant1-Cocaine (Coc-Rim1-Coc); Cocaine-Rimonabant10-Cocaine (Coc-Rim10-Coc). In the second and third experiments the same protocol was used except that mice received vehicle or rimonabant in their home cages or in the activity box respectively. Results: The first cocaine injection increased LA of the cocaine groups (Coc-Veh-Coc: 192±33; Coc-Rim1-Coc: 218±36; Coc-Rim10-Coc: 208±48), compared to saline groups (Sal-Veh-Coc: 84±14; Sal-Rim1-Coc: 75±11; Sal-Rim10-Coc: 87±21). This effect was potentiated with repeated administration (Coc-Veh-Coc: 329±46 on the 15th day), revealing the development of behavioral sensitization (BS). During the subsequent treatment, rimonabant did not modify LA of animals. However, after cocaine challenge injection (day 30), two-way ANOVA revealed significant effects of cocaine previous treatment, rimonabant previous treatment as well as cocaine x rimonabant interaction. Indeed, cocaine previous treatment potentiated the hyperlocomotion induced by cocaine challenge injection (Sal-Veh-Coc: 163±29; Coc-Veh-Coc: 483±64), once again demonstrating the BS phenomenon. This BS to cocaine was inhibited by rimonabant previous treatment (Coc-Rim10-Coc: 262±33). Concerning experiment 2 and experiment 3, cocaine-induced behavioral sensitization was also demonstrated but it was not inhibited by home-cage or activity box rimonabant previous treatment. Conclusion: rimonabant treatment was able to inhibit locomotor sensitization previously developed to cocaine treatment, but this inhibition was dependent on the environmental context in which it was administered.