∆9-tetrahydrocannabinol self-administration induces cell-type specific adaptations in the nucleus accumbens core

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 signaling towards D1-MSNs and enhance relapse vulnerability. 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 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 signaling in D1-MSNs as a potential treatment avenue for cannabis use disorder (CUD).