D 2 autoreceptor switches CB 2 receptor effects on [ 3 H]‐dopamine release in the striatum

CB 2 receptors (CB 2 R) are expressed in midbrain neurons. To evidence the control of dopamine release in dorsal striatum by CB 2 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 CB 2 R activation with GW 833972A and JWH 133 two selective agonist. To understand the mechanism involved, we tested for a role of the D 2 autoreceptor in this effect; because in pallidal structures, the inhibitory effect of CB 1 receptors (CB 1 R) on GABA release is switched to a stimulatory effect by D 2 receptors (D 2 R). We found that the blockade of D 2 autoreceptors with sulpiride prevented the stimulatory effect of CB 2 R activation; in fact, under this condition, CB 2 R decreased dopamine release, indicating the role of the D 2 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 CB 2 R effects on release. In addition, D 2 –CB 2 R interaction promoted cAMP accumulation, and the increase in [ 3 H]‐dopamine release was prevented by PKA blockade. D 2 –CB 2 R coprecipitation and proximity ligation assay studies indicated a close interaction of receptors that could participate in the observed effects. Finally, intrastriatal injection of CB 2 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 D 2 autoreceptor switches, from inhibitory to stimulatory, the CB 2 R effects on dopamine release, involving the cAMP → PKA pathway in nigrostriatal terminals.