Neuronal and astrocytic CB1R signaling differentially modulates goal-directed behavior and working memory by distinct temporal mechanisms

Several cognitive processes, including instrumental behavior and working memory, are controlled by endocannabinoids acting on cannabinoid receptor 1 (CB1R) in the brain through retrograde and presynaptic inhibition of GABA or glutamate release. However, the temporal mechanisms underlying the control of these cognitive processes by CB1Rs remain largely unknown. Here, we have developed a light-sensitive CB1R chimera (optoCB1R) by replacing the intracellular domains of bovine rhodopsin with those of human CB1R. We demonstrated that light stimulation of optoCB1R triggered canonical CB1R signaling by inhibiting cAMP (but not cGMP or IP1) signaling and activating the MAPK pathway in vitro or in vivo. Moreover, light stimulation of optoCB1R in corticostriatal glutamatergic neurons could temporally inhibit excitatory postsynaptic currents (EPSCs) at the level of seconds. Importantly, transient (3 s) and “time-locked”, but not random, activation of optoCB1R signaling in corticostriatal neurons at the time of reward affected animal sensitivity to outcome devaluation and inhibited goal-directed behavior. However, prolonged (~30 min) but not transient (10 or 30 s) activation of astrocytic CB1R signaling in the hippocampus impaired working memory. Consequently, neuronal and astrocytic CB1R signaling differentially regulate working memory and goal-directed behavior through distinct temporal and cellular mechanisms. Ultimately, the pharmacological blockade of adenosine A 2A R improved the neuronal and astrocytic CB1R-induced impairments in goal-directed behavior and working memory, possibly through modulation of EPSCs and c-Fos, respectively. Therefore, A 2A R may represent a promising target for managing cognitive dysfunction resulting from the use of CB1R drugs.