D₂ autoreceptor switches CB₂ receptor effects on [³ H]-dopamine release in the striatum

CB₂ receptors (CB₂ R) are expressed in midbrain neurons. To evidence the control of dopamine release in dorsal striatum by CB₂ R, we performed experiments of [³ H]-dopamine release in dorsal striatal slices. We found a paradoxical increase in K⁺ -induced [³ H]-dopamine release by CB₂ R activation with GW 833972A and JWH 133 two selective agonist. To understand the mechanism involved, we tested for a role of the D₂ autoreceptor in this effect; because in pallidal structures, the inhibitory effect of CB₁ receptors (CB₁ R) on GABA release is switched to a stimulatory effect by D₂ receptors (D₂ R). We found that the blockade of D₂ autoreceptors with sulpiride prevented the stimulatory effect of CB₂ R activation; in fact, under this condition, CB₂ R decreased dopamine release, indicating the role of the D₂ autoreceptor in the paradoxical increase. We also found that the effect occurs in nigrostriatal terminals, since lesions with 6-OH dopamine in the middle forebrain bundle prevented CB₂ R effects on release. In addition, D₂ -CB₂ R interaction promoted cAMP accumulation, and the increase in [³ H]-dopamine release was prevented by PKA blockade. D₂ -CB₂ R coprecipitation and proximity ligation assay studies indicated a close interaction of receptors that could participate in the observed effects. Finally, intrastriatal injection of CB₂ R agonist induced contralateral turning in amphetamine-treated rats, which was prevented by sulpiride, indicating the role of the interaction in motor behavior. Thus, these data indicate that the D₂ autoreceptor switches, from inhibitory to stimulatory, the CB₂ R effects on dopamine release, involving the cAMP → PKA pathway in nigrostriatal terminals.