Targeting corticostriatal transmission for the treatment of cannabinoid use disorder

It is generally assumed that the rewarding effects of cannabinoids are mediated by cannabinoid CB₁ receptors (CB₁Rs) the activation of which disinhibits dopaminergic neurons in the ventral tegmental area (VTA). However, this mechanism cannot fully explain novel results indicating that dopaminergic neurons also mediate the aversive effects of cannabinoids in rodents, and previous results showing that preferentially presynaptic adenosine A_2A receptor (A_2AR) antagonists counteract self-administration of Δ-9-tetrahydrocannabinol (THC) in nonhuman primates (NHPs). Based on recent experiments in rodents and imaging studies in humans, we propose that the activation of frontal corticostriatal glutamatergic transmission constitutes an additional and necessary mechanism. Here, we review evidence supporting the involvement of cortical astrocytic CB₁Rs in the activation of corticostriatal neurons and that A_2AR receptor heteromers localized in striatal glutamatergic terminals mediate the counteracting effects of the presynaptic A_2AR antagonists, constituting potential targets for the treatment of cannabinoid use disorder (CUD).