Δ9‐Tetrahydrocannabinol self‐administration induces cell type‐specific adaptations in the nucleus accumbens core

Abstract

AbstractDrugs 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).