Considerable evidence demonstrates that
cannabinoid agonists impair whereas
cannabinoid antagonists improve memory and plasticity. However, recent studies suggest that the effects of
cannabinoids on learning do not necessarily follow these simple patterns, particularly when emotional memory processes are involved. We investigated the involvement of the
cannabinoid system in hippocampal learning and plasticity using the fear-related inhibitory avoidance (IA) and the non-fear-related spatial learning paradigms, and cellular models of learning and memory, i.e., long-term potentiation (LTP) and long-term depression (LTD). We found that microinjection into the CA1 of the CB1/
CB2 receptor agonist WIN55,212-2 (5 μg/side) and an inhibitor of
endocannabinoid reuptake and breakdown
AM404 (200 ng/side) facilitated the extinction of IA, while the
CB1 receptor antagonist
AM251 (6 ng/side) impaired it. WIN55,212-2 and
AM251 did not affect IA conditioning, while
AM404 enhanced it, probably due to a
drug-induced increase in
pain sensitivity. However, in the water maze, systemic or local CA1
injections of
AM251, WIN55,212-2, and
AM404 all impaired spatial learning. We also found that i.p. administration of WIN55,212-2 (0.5 mg/kg),
AM404 (10 mg/kg), and
AM251 (2 mg/kg) impaired LTP in the Schaffer collateral-CA1 projection, whereas
AM404 facilitated LTD. Our findings suggest diverse effects of the
cannabinoid system on CA1 memory and plasticity that cannot be categorized simply into an impairing or an enhancing effect of
cannabinoid activation and deactivation, respectively. Moreover, they provide preclinical support for the suggestion that targeting the
endocannabinoid system may aid in the treatment of disorders associated with impaired extinction-like processes, such as
post-traumatic stress disorder.