THE ROLE OF THE ENDOCANNABINOID SYSTEM IN INCIDENTAL ASSOCIATIONS: FOCUS ON INTERACTIONS WITH DOPAMINE SIGNALING

Reinforced conditioning enables individuals to predict future events, but many everyday behaviors rely on unreinforced associations between low-salience stimuli, known as Incidental Associations (IAs). IAs enhance predictive capacity in unstable environments and are conserved across species. To study them in rodents, sensory preconditioning tasks are used, where two low salience stimuli (S1/S2) are presented together in a preconditioning phase, followed by classical conditioning of S1 with a potent reinforcer. As a result, subjects present a direct response to the S1 stimulus, but also display mediated responses to the S2 stimulus never explicitly reinforced, indicating IA formation. Using a sensory preconditioning task with light (S1) and sound (S2) as sensory cues, we showed that mice exhibit both direct and mediated responses, indicating IA formation. Previous work demonstrated that type-1 cannabinoid receptors (CB1R) are critical for this process. Global CB1R knock-out mice did not show mediated responses while direct response was unaltered. Dopamine signaling has also been implicated in IAs. Consistent with these findings, we found that mice lacking CB1R specifically in D1-receptor–expressing cells (D1R-CB1R-KO) fail to show mediated responses, identifying this CB1R population as essential for IA formation. Furthermore, pharmacological activation of CB1R using THC during short preconditioning facilitated IAs under conditions insufficient for controls. Similar effects were observed by increasing endogenous cannabinoid levels via inhibition of endocannabinoid degradation with JZL195. Notably, THC also induced mediated responses in D1R-CB1R-KO mice, but this effect was blocked by JZL195, indicating that D1R-CB1R cells are required for physiologically but not pharmacologically induced IAs.