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

CB2 receptors (CB2R) are expressed in midbrain neurons. To evidence the control of dopamine release in dorsal striatum by CB2R, we performed experiments of [3H]‐dopamine release in dorsal striatal slices. We found a paradoxical increase in K+‐induced [3H]‐dopamine release by CB2R 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 (CB1R) on GABA release is switched to a stimulatory effect by D2 receptors (D2R). We found that the blockade of D2 autoreceptors with sulpiride prevented the stimulatory effect of CB2R activation; in fact, under this condition, CB2R 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 CB2R effects on release. In addition, D2–CB2R interaction promoted cAMP accumulation, and the increase in [3H]‐dopamine release was prevented by PKA blockade. D2–CB2R coprecipitation and proximity ligation assay studies indicated a close interaction of receptors that could participate in the observed effects. Finally, intrastriatal injection of CB2R 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 CB2R effects on dopamine release, involving the cAMP → PKA pathway in nigrostriatal terminals. Substantia nigra compacta neurons express cannabinoid CB2 receptors. Presynaptic CB2 receptors decrease [3H]‐dopamine release in the rat striatum. When coactivated with D2 autoreceptors, the increase in dopamine release through cAMP and PKA stimulates motor behavior.