DUAL MODULATION OF DOPAMINE RELEASE FROM ANTERIOR NUCLEUS-ACCUMBENS THROUGH CHOLECYSTOKININ-B RECEPTOR SUBSITES

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 19 7 is selective for one subsite, B-1, and that BC 264 has the same affi nity for the two subsites, B-1 and B-2. Therefore, the possible involv ement 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 functiona l response with activation of each subsite. The selective B-1 agonist BC 197 produced a dose-dependent increase of 35 mM K+-stimulated DA re lease. In contrast, al a low concentration (20 nM), BC 264 inhibited t he K+-evoked DA release, whereas at a higher concentration (1 mu M), i t stimulated the DA release. These two opposing effects were suppresse d 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 blocke r. Moreover, BC 264 at 20 nM, in the presence of PD-134,308 at a conce ntration that would block the B, subsites (0.1 nM), increased the evok ed DA release. All together, these results support further the existen ce of distinct CCK-B subsites and suggest that, in the anterior nucleu s accumbens, their stimulation mediates opposite effects on K+-stimula ted DA release via a presynaptic mechanism.