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 A2A receptor (A2AR) antagonists counteract self-administration of & UDelta;-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 A2AR receptor heteromers localized in striatal glutamatergic terminals mediate the counteracting effects of the pre synaptic A2AR antagonists, constituting potential targets for the treatment of cannabinoid use disorder (CUD).

Automated summary

The rewarding effects of cannabinoids are believed to be mediated by CB1 receptors, but recent results suggest that dopaminergic neurons also play a role in the aversive effects of cannabinoids. Additionally, A2AR antagonists have been shown to counteract the self-administration of THC, suggesting a potential treatment for cannabinoid use disorder. Recent experiments in rodents and imaging studies in humans support the involvement of cortical astrocytic CB1 receptors and A2AR receptor heteromers in this process.