WIN 55212-2 impairs contextual fear conditioning through the activation of CB1 cannabinoid receptors.

The memory deficits induced by cannabinoid agonists have been found in several behavioral paradigms. Nevertheless, there is evidence that not all types of memory are impaired after cannabinoid administration. The aim of this study was to investigate whether the cannabinoid agonist WIN 55212-2 (WIN) is able to influence the acquisition of fear conditioning using tone and contextual versions. For tone-fear conditioning, male Wistar rats were placed in the conditioning chamber and after 3 min, a sound (CS) was presented for 10s that terminated with a 1-s electric footshock (1.5 mA). For contextual-fear conditioning, a similar procedure was used but no sound was presented. Twenty-four hours after, the animals were re-exposed to the respective CS (tone or conditioning chamber) and the freezing behavior was registered. A subsequent experiment investigated a possible state-dependent effect of WIN by administering WIN or control solution 30 min before conditioning and before testing. WIN (2.5 and 5.0 mg/kg) administered i.p. 30 min before impaired contextual fear conditioning but did not modify the freezing behavior elicited by tone presentation. These animals did not show any state-dependent effects of WIN. Further, the impaired contextual conditioning was prevented by preadministration of SR141716A (1.0 mg/kg, i.p.) or SR147778 (1.0 mg/kg, i.p.), selective cannabinoid CB1 receptor antagonists. The present findings highlight that cannabinoid agonists effects are selective for the hippocampus-dependent aversive memories in rats. This effect appears to be related to the activation of CB1 cannabinoid receptors and confirms that cannabinoids might provide a novel approach for the treatment of unpleasant memories.