REGULATION BY THE NEUROPEPTIDE CHOLECYSTOKININ (CCK-8S) OF PROTEIN-PHOSPHORYLATION IN THE NEOSTRIATUM

Despite physiological evidence that cholecystokinin CCK) is an excitat ory neurotransmitter in the brain, little is known about its mechanism of action. CCK immunoreactivity in the brain, including projections t o the striatum, is primarily attributable to the sulfated octapeptide CCK-8S. We report here that CCK-8S abolishes cAMP-dependent phosphoryl ation of a dopamine- and cAMP-regulated 32-kDa phosphoprotein (DARPP-3 2) in striatal neurons. The effect of CCK-8S is prevented by antagonis ts of CCKB and N-methyl-D-aspartate receptors. Our results support a m odel in which CCK-8S, originating from CCK or CCK/glutamate corticostr iatal neurons, promotes the release of an excitatory neurotransmitter that causes the dephosphorylation and inactivation of DARPP-32, a pote nt protein phosphatase inhibitor, thereby modulating neuronal excitabi lity.