Dorsolateral striatal CB1 receptors contribute to spatial memory optimization

Cannabinoid receptor 1 (CB1-R), the primary receptor of the endocannabinoid system, plays a critical role in cognitive function. Elevated CB1-R activity has been shown to impair spatial working memory and fear extinction in rodents; however, its contribution to distinct memory stages, and its impact on remote spatial memory is unclear. To investigate CB1-R involvement in remote spatial memory, we systemically administered the CB1-R inverse agonist rimonabant (3mg/kg) to male CD1 mice either pre-training, post-training, or pre-test using a massed Morris Water Maze (MWM) protocol. Memory retention was assessed at 14d after training. Systemic CB1-R inactivation did not affect recall. In contrast, pre-training and post-training inactivation significantly enhanced memory performance. These results suggest that modulation of CB1-R signaling can promote the consolidation of remote spatial memories. CB1-R expression follows a mediolateral gradient within the striatum, with higher receptor density in the dorsolateral (DLS) compared to dorsomedial striatum (DMS). This difference is parallelled functionally by the ability of the DLS in promoting memory stability. Based on this, we tested whether the effects observed after systemic rimonabant administration could be mediated by CB1-R signaling in the DLS. Consistently, post-training focal rimonabant administration (1ug/side) in the DLS increased memory retention at 14d. Together, these findings highlight a role for CB1-R signaling in reducing memory abilities, and identify the DLS as a key region mediating CB1-R-dependent memory processes. Future studies will assess the contribution of CB1-R blockade in the DMS to further clarify region-specific mechanisms of memory consolidation.