Dual Modulation of Dopamine Release from Anterior Nucleus Accumbens Through Cholecystokinin-B Receptor Subsites

Abstract: Previous binding studies have suggested the existence of two affinity states for cholecystokinin-B (CCK-B) receptor. One study, using BC 197 and BC 264, two highly selective CCK-B agonists, has shown that BC 197 is selective for one subsite, B₁, and that BC 264 has the same affinity for the two subsites, B₁ and B₂. Therefore, the possible involvement of CCK-B subsites in the modulation of endogenous dopamine (DA) release from slices of the anterior part of the nucleus accumbens was investigated with these two agonists in order to associate a functional response with activation of each subsite. The selective B₁ agonist BC 197 produced a dose-dependent increase of 35 m M K⁺-stimulated DA release. In contrast, at a low concentration (20 n M ), BC 264 inhibited the K⁺-evoked DA release, whereas at a higher concentration (1 µ M ), it stimulated the DA release. These two opposing effects were suppressed by the CCK-B antagonist PD-134,308, but not by the CCK-A antagonist L-364,718 and were not prevented by tetrodotoxin, a Na⁺-channel blocker. Moreover, BC 264 at 20 n M , in the presence of PD-134,308 at a concentration that would block the B₂ subsites (0.1 n M ), increased the evoked DA release. All together, these results support further the existence of distinct CCK-B subsites and suggest that, in the anterior nucleus accumbens, their stimulation mediates opposite effects on K⁺-stimulated DA release via a presynaptic mechanism.