Targeting corticostriatal transmission for the treatment of cannabinoid use disorder

Abstract

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).

Keywords: adenosine; cannabinoids; dopamine; glutamate; receptor heteromers; striatum.

Figure 1.. Cellular elements of the VTA, prefrontal cortex and NAc that mediate the dopamine-releasing effects of THC.

The classical VTA mechanism involves CB₁Rs localized in terminals of GABAergic neurons from the rostromedial tegmental nucleus (RMTgN) and terminals of GABAergic efferent neurons from the NAc, promoting activation of dopamine (DA) neurons by disinhibition. The corticostriatal mechanism results from activation of the pyramidal cells of the prefrontal cortex (PFC) induced by, first, DA release from the disinhibited VTA DA neurons; second, activation of CB₁Rs localized in the terminals of GABAergic interneurons; and third, by CB₁Rs localized in astrocytes, which produces astrocytic glutamate (glu) release by a G_q/G_i/odependent increase in calcium transients. THC-induced increase in the activity of PFC-NAc neurons leads to glu release in the NAc, which promotes DA release by the intermediate activation of ACh interneurons. CB₁Rs are also localized in corticostriatal terminals, but their potential inhibition of glu release is counteracted by the concomitant increase in synaptic adenosine generated by ATP released upon the strong corticostriatal input (see text and Fig. 2).

Figure 2.. Schematic representation of corticostriatal glutamatergic terminals and their modulatory A₁R-A_2AR and A_2AR-CB₁R heteromers.

Glutamate (glu) release by the terminals of corticostriatal pyramidal neurons depends on the firing rate of the pyramidal neuron and on the local levels of adenosine (Ado) and endocannabinoids, mainly 2-arachidonoylglycerol (2AG). A fine-tune modulation is mediated by A₁R-A_2AR and A_2AR-CB₁R heteromers. With a low firing rate (A), local Ado originates mostly from astrocytic ATP and binds with more affinity to the A₁R than to the A_2AR in the A₁R-A_2AR heteromer, where a type II allosteric mechanism blunts the constitutive activity of the A_2AR; on the other hand, the A_2AR in the A_2AR-CB₁R heteromer shows significant constitutive activity, which is negatively modulated by activation of the CB₁R by a type III allosteric interaction. With a high firing rate (B), including that induced by THC, a higher synaptic concentration of Ado is produced upon ATP co-released with glu and metabolized by synaptic ectonucleotidase CD73; increased levels of Ado lead to activation of A_2ARs, which counteract A₁R and CB₁R signaling in the A₁R-A_2AR and A_2AR-CB₁R heteromers by type I allosteric interactions.