ROLE OF MITOCHONDRIAL CB1 RECEPTORS IN ENDOCANNABINOID MODULATION OF INCIDENTAL ASSOCIATION FORMATION

Our daily choices rely on sensory inputs we receive from the environment. Sometimes, this sensory information is associated with an aversive or rewarding reinforcer. More often, however, our decision-making arises from the coupling of neutral environmental stimuli never paired with any reinforcer.
These non-reinforced associations, known as incidental associations (IAs), allow better predictions of future scenarios and appear altered in psychotic disorders. They are conserved across species and can be studied in rodents using sensory preconditioning paradigms. In these protocols, two low-salience stimuli (S1 and S2) are presented together in a preconditioning phase, followed by classical conditioning of S1 with a potent reinforcer. Consequently, animals show direct responses to S1 but also mediated responses to S2—the stimulus never explicitly reinforced—indicating previous IA formation. Unpaired S1-S2 control groups show that responses to S2 derive from specific S1-S2 association, rather than generalization. The endocannabinoid system, through type-1 cannabinoid receptors (CB1Rs) in the hippocampus, participates in IA-related processes. Interestingly, CB1Rs are found both on the plasma membrane and in mitochondria (mtCB1), where they regulate oxygen consumption and respiration.
Preliminary results show that activating CB1Rs through THC, the main psychoactive compound of cannabis, facilitates IA formation in wild-type animals but not in mice lacking CB1R specifically in mitochondria, suggesting a key role of mtCB1R in mediating THC’s effects on IAs. Ongoing studies are evaluating the change in hippocampal mitochondrial activity upon THC administration. Yet, future experiments will disentangle the mechanism by which hippocampal mtCB1Rs activated by THC are altering IA formation.