The potential therapeutic benefits of cannabinoid compounds have raised interest in understanding the molecular mechanisms that underlie cannabinoid-mediated effects. We previously showed that the acute amnesic-like effects of delta9-tetrahydrocannabinol (THC) were prevented by the subchronic inhibition of the mammalian target of rapamycin (mTOR) pathway. In the present study, we assess the relevance of the mTOR pathway in other acute and chronic pharmacological effects of THC. The rapamycin derivative temsirolimus, an inhibitor of the mTOR pathway approved by the Food and Drug Administration, prevents both the anxiogenic- and the amnesic-like effects produced by acute THC. In contrast, THC-induced anxiolysis, hypothermia, hypolocomotion, and antinociception are not sensitive to the mTOR inhibition. In addition, a clear tolerance to THC-induced anxiolysis, hypothermia, hypolocomotion, and antinociception was observed after chronic treatment, but not to its anxiogenic- and amnesic-like effects. Temsirolimus pre-treatment prevented the amnesic-like effects of chronic THC without affecting the downregulation of CB1 receptors (CB1R) induced by this chronic treatment. Instead, temsirolimus blockade after chronic THC cessation did not prevent the residual cognitive deficit produced by chronic THC. Using conditional knockout mice lacking CB1R in GABAergic or glutamatergic neurons, we found that GABAergic CB1Rs are mainly downregulated under chronic THC treatment conditions, and CB1-GABA-KO mice did not develop cognitive deficits after chronic THC exposure. Therefore, mTOR inhibition by temsirolimus allows the segregation of the potentially beneficial effects of cannabinoid agonists, such as the anxiolytic and antinociceptive effects, from the negative effects, such as anxiogenic- and amnesic-like responses. Altogether, these results provide new insights for targeting the endocannabinoid system in order to prevent possible side effects.

EP and AB-G were recipients of a predoctoral fellowship, Ministerio de Educación y Cultura. This work was supported by grants from the Ministerio de Ciencia e Innovación (#SAF2009-07309 to AO and # SAF2011-29864 to RM), Instituto de Salud Carlos III (RD06/0001/0001 to RM), PLAN E/n(Plan Español para el Estímulo de la Economía y el Empleo), the European Commission/n(PHECOMP #LSHM-CT-2007-037669 to RM), Generalitat de Catalunya (SGR-2009-00731/nto RM), INSERM to GM, European Research Council (ENDOFOOD, ERC-2010-StG-/n260515, to GM), Fondation pour la Recherche Medicale to GM, and ICREA (Institució Catalana de Recerca i Estudis Avançats) Academia to RM