Hippocampal endocannabinoids inhibit spatial learning and limit spatial memory in rats.

RATIONALE: As exogenous cannabinoid agonists impair memory formation, could it be that antagonists have opposing effects and act as memory-enhancing drugs?
OBJECTIVES: Here, we studied the effects of the cannabinoid antagonist SR141716A (SR; Rimonabant) on spatial learning and memory formation and assessed the possible involvement of hippocampal CB(1) receptor in these actions.
MATERIALS AND METHODS: In the water maze, spatial reference memory was probed using different training protocols followed by assessment of behavioral flexibility. The CB(1) receptor antagonist SR (3 mg/kg) was intraperitoneally administered before or immediately after training in experiment 1, or via minipumps intrahippocampally (0.89 ng and 0.089 ng/day) either during or after spatial learning, or subcutaneously in experiment 2.
RESULTS: In experiment 1, systemic SR impaired spatial learning when given intraperitoneally (ip) before training coincident with increasing swim speed and thigmotaxis. Pretraining before drug treatment eliminated these effects while post-training injections had no effect. In experiment 2, intrahippocampal infusion of 0.089 ng SR during training enhanced acquisition learning, but did not affect long-term consolidation of spatial memory. In contrast, subcutaneous infusion of SR via minipumps had no effect. Post-training infusion of SR did not affect reversal learning, but short-term memory (1 h post-training) was weaker, and long-term memory for the reversal platform location was enhanced.
CONCLUSIONS: Systemic Rimonabant-induced deficits are due to anxiogenic properties of the drug. The difference between administration regimes is discussed in terms of CB(1) receptor blockade in multiple non-memory and memory-related brain regions and the possibility that selective inactivation of hippocampal CB(1) receptors may be memory enhancing.