Brain CCK-B receptors mediate the suppression of dopamine release by cholecystokinin

The sulfated octapeptide of cholecystokinin (CCK-8S) and CCK fragments were administered to mice to determine the subtype and central versus peripheral location of the CCK receptor that modulates dopamine release in the neostriatum. Dopamine release was decreased when unsulfated CCK (CCK-8U) or the butoxycarbonyl tetrapeptide of CCK (t-boc-CCK-4) was infused into the brain ventricles but not when injected subcutaneously. These CCK fragments bind to the brain-type (CCK-B) but not alimentary-type (CCK-A) receptor. Centrally or peripherally administered CCK-8S also lowered dopamine release and this action was not blocked by the selective CCK-A receptor antagonist, L 364,718. The increase in dopamine release following amphetamine administration was attenuated by central injections of t-boc-CCK-4, CCK-8U, or CCK-8S, and this action of CCK-8S was not prevented by L 364,718. These data are the first to demonstrate that CCK-B receptors in brain mediate the suppression of dopamine release by cholecystokinin, especially when release is augmented. CCK-B receptor agonists should be useful for the treatment of psychiatric conditions that result from hyperactive dopamine neurons.