MODULATION OF NEUROTRANSMITTER RELEASE BY CHOLECYSTOKININ IN THE NEOSTRIATUM AND SUBSTANTIA-NIGRA OF THE RAT - REGIONAL AND RECEPTOR SPECIFICITY

The effect of cholecystokinin peptides on the release of dynorphin B, aspartate, glutamate, dopamine and GABA in the neostriatum and substan tia nigra of the rat was investigated using in vivo microdialysis. Sul phated cholecystokinin-8S in the dialysis perfusate (1-100 mu M) induc ed a concentration-dependent increase in extracellular dynorphin B and aspartate levels, both in the neostriatum and substantia nigra. Stria tal dopamine levels were only increased by 100 mu M of cholecystokinin -8S, while in the substantia nigra they were increased by 10-100 mu M of cholecystokinin-8S. Extracellular GABA and glutamate levels were in creased following 100 mu M of cholecystokinin-8S only. Striatal cholec ystokinin-8S administration also produced a significant increase in ni gral dynorphin B levels. Local cholecystokinin-4, (100 mu M) produced a moderate. but significant, increase of extracellular dynorphin B and aspartate levels in the neostriatum and substantia nigra. No effect w as observed on the other neurotransmitters investigated. A 6-hydroxydo pamine lesion of the nigrostriatal dopamine pathway did not affect the increases in dynorphin B and aspartate levels produced by local admin istration of cholecystokinin-8S. Basal extracellular GABA levels were increased significantly in both the neostriatum and substantia nigra i psilateral to the lesion. Nigral glutamate and aspartate levels were a lso increased in the lesioned substantia nigra, but in the lesioned ne ostriatum aspartate levels were decreased. The cholecystokinin-B antag onist L-365,260 (20 mg/kg, s.c.), but not the cholecystokinin-A antago nist L-364,718 (devazepide; 20 mg/kg, s.c.), significantly inhibited t he effect of cholecystokinin-8S on striatal dynorphin B and aspartate levels. In the substantia nigra, however, the effect of cholecystokini n-8S on dynorphin B and aspartate levels was inhibited to a similar ex tent by both L-365,260 and L-364,718. Pretreatment with L-364,718, but not with L-365,260, prevented the increase in nigral dopamine levels produced by nigral cholecystokinin-8S administration. Taken together, these results suggest that cholecystokinin-8S modulates dynorphin B an d aspartate release in the neostriatum and substantia nigra of the rat via different receptor mechanisms. In the neostriatum, the effect of cholecystokinin-8S on dynorphin B and aspartate release is mediated vi a the cholecystokinin-B receptor subtype, while in the substantia nigr a, cholecystokinin-8S modulates dynorphin B and aspartate release via both cholecystokinin-A and cholecystokinin-B receptor subtypes. Cholec ystokinin-8S modulates dopamine release mainly in the substantia nigra , via the cholecystokinin-A receptor subtype. Copyright (C) 1996 IBRO.