Drugs of abuse induce cell type‐specific adaptations in D1‐ and D2‐medium spiny neurons (MSNs) in the nucleus accumbens core (NAcore) that can bias signalling towards D1‐MSNs and enhance relapse vulnerability. Whether Δ9‐tetrahydrocannabinol (THC) use initiates similar neuroadaptations is unknown. D1‐ and D2‐Cre transgenic rats were transfected with Cre‐dependent reporters and trained to self‐administer THC + cannabidiol (THC + CBD). After extinction training spine morphology, glutamate transmission, CB1R function and cFOS expression were quantified. We found that extinction from THC + CBD induced a loss of large spine heads in D1‐ but not D2‐MSNs and commensurate reductions in glutamate synaptic transmission. Also, presynaptic CB1R function was impaired selectively at glutamatergic synapses on D1‐MSNs, which augmented the capacity to potentiate glutamate transmission. Using cFOS expression as an activity marker, we found no change after extinction but increased cFOS expression in D1‐MSNs after cue‐induced drug seeking. Contrasting D1‐MSNs, CB1R function and glutamate synaptic transmission on D2‐MSN synapses were unaffected by THC + CBD use. However, cFOS expression was decreased in D2‐MSNs of THC + CBD‐extinguished rats and was restored after drug seeking. Thus, CB1R adaptations in D1‐MSNs partially predicted neuronal activity changes, posing pathway specific modulation of eCB signalling in D1‐MSNs as a potential treatment avenue for cannabis use disorder (CUD).

Given that 30% of chronic cannabis users develop cannabis use disorder (CUD), it is critical to identify neuroadaptations that contribute to this disease. The nucleus accumbens core (NAcore) is important for drug seeking and ~ 90% of all NAcore neurons are divided into D1- and D2-medium spiny neurons (MSNs) that serve opposing roles in drug seeking. Drugs of abuse induce D1- and D2-MSN specific adaptations but whether ∆9-tetrahydrocannabinol (THC) use initiates similar neuroadaptations is unknown. D1- and D2-Cre transgenic rats were transfected with Cre-dependent reporters and trained to self-administer THC + cannabidiol (THC + CBD). After extinction training dendritic spine morphology, glutamate transmission, CB1R function and cFOS expression were quantified. We found that extinction from THC + CBD induced a loss of large spine heads in D1- but not D2-MSNs and a commensurate reduction in glutamate synaptic transmission. Also, CB1R function was impaired on glutamatergic synapses onto D1-MSNs and this was paralleled by an augmented capacity to potentiate glutamate transmission in D1-MSNs. CB1R function and glutamate synaptic transmission on D2-MSN synapses were unaffected by THC + CBD use. Using cFOS expression as an activity marker, we found that D1-MSNs activity remained unchanged after extinction from THC + CBD but significantly increased after 60 minutes cue-induced drug seeking. Surprisingly, the percentage of D2-MSNs expressing cFOS decreased after extinction from THC + CBD and this decrease was restored by drug cues. Thus, glutamatergic adaptations in D1-MSNs partially predict activity changes and pose modulating CB1R function that is down-regulated selectively at D1-MSN synapses as a potential treatment strategy for CUD.