Blockade of dorsal hippocampal dopamine receptors inhibits state-dependent learning induced by cannabinoid receptor agonist in mice

Abstract

To clarify the interaction between cannabinnoid CB1 receptors and the dopaminergic system in memory processes, the effects of dopamine receptor agents on the state-dependent learning induced by the non-selective CB1/CB2 receptor agonist, WIN55,212-2 have been investigated in mice. Animals implanted with unilateral cannula at the CA1 region of the dorsal hippocampus and microinjected with WIN55,212-2 and/or dopaminergic agents, were tested using a single-trial step-down passive avoidance task. Intra-CA1 microinjections of WIN55,212-2 (0.1–1 μg/mouse) immediately after training, decreased the step-down latency, indicating an amnesic effect of the drug. The amnesia was reversed by pre-test administration of the drug, suggesting state-dependent learning by the cannabinoid. Pre-test microinjection of apomorphine, a D1/D2 dopamine receptor agonist (0.1–0.3 μg/mouse) into the CA1 region reversed the amnesia induced by post-training WIN55,212-2 (1 μg/mouse). Moreover, pre-test co-administration of apomorphine with an ineffective dose of WIN55,212-2 (0.01 μg/mouse), showed a reversion of the impairment on retention performance. Pre-test administration of the same doses of apomorphine did not show any response by itself. Pre-test intra-CA1 administration of a D1 dopamine receptor antagonist, SCH23390 (0.05–0.3 μg/mouse) or D2 dopamine receptor antagonist, sulpiride (0.125–0.5 μg/mouse) inhibited the expression of WIN55,212-2-induced state-dependent learning. Pre-test microinjection of the same doses of SCH23390 or sulpiride had no effect on WIN55,212-2-induced amnesia. Moreover, single injection of SCH23390 (0.2 and 0.3 μg/mouse) or sulpiride (0.125 μg/mouse) decreased memory retrieval. The results suggest that the dorsal hippocampal dopaminergic system participates in the modulation of WIN55,212-2-induced state-dependent learning.