Resumo

Associative fear memories are acquired by the pairing of an aversive stimulus (usually a footshock) with a conditioned stimulus (CS). Extinction of such memories occur following repeated non-reinforced presentations of the CS, with the formation of an inhibitory memory trace signaling that CS no longer predicts the footshock (CS – "no shock" trace). We and others already showed that CB1 cannabinoid receptors modulate the extinction of conditioned fear in rats (Pamplona et al, 2006). However, it is not known whether the endocannabinoid system specifically modulates the formation of inhibitory memory traces (Marsicano et al, 2002), contributes to fear habituation (Kamprath et al, 2006) or it could modulate learning flexibility in general. We used a 2nd-order fear conditioning protocol to address this question. Male Wistar rats were placed in a conditioning chamber and 3 min after received a footshock (1.5mA, 1s). At the 2nd day, they were injected i.p. with previously validated doses of the cannabinoid agonist WIN55212-2 (WIN; 0.25 – 2.50 mg/kg) 30 min before being exposed to the conditioning chamber for 3 min. By the end of the session, the animals received one 10-s tone presentation (60dB, 110Hz), but no footshock. At the 3rd day, the rats were placed in a new context and 3 min later, the tone was presented 6 times, with 20s-intervals. Time spent in freezing (s) was registered during chamber/tone presentation as an index of aversive memory. There were no differences between groups during the 1st 3-min context re-exposure (retrieval of primary contextual memory). Additionally, WIN-treated rats expressed more tone-related freezing compared to controls in the new context (retrieval of secondary associative memory). The present results suggest that the cannabinoid receptors modulate 2nd-order learning, giving support to the idea that not only extinction, but the general learning flexibility is influenced by the activation of cannabinoid receptors.