P.3.021 Biologically active conformation of cholecystokinin-4 retropeptide analogues with anxiolytic activity

Abstract

The effect of cholecystokinin peptides on the release of dynorphin B, aspartate, glutamate, dopamine and GABA in the neostriatum and substantia nigra of the rat was investigated using in vivo microdialysis. Sulphated cholecystokinin-8S in the dialysis perfusate (1–100 μM) induced a concentration-dependent increase in extracellular dynorphin B and aspartate levels, both in the neostriatum and substantia nigra. Striatal dopamine levels were only increased by 100 μM of cholecystokinin-8S, while in the substantia nigra they were increased by 10–100 μM of cholecystokinin-8S. Extracellular GABA and glutamate levels were increased following 100 μM of cholecystokinin-8S only. Striatal cholecystokinin-8S administration also produced a significant increase in nigral dynorphin B levels. Local cholecystokinin-4 (100 μM) produced a moderate, but significant, increase of extracellular dynorphin B and aspartate levels in the neostriatum and substantia nigra. No effect was observed on the other neurotransmitters investigated.A 6-hydroxydopamine lesion of the nigrostriatal dopamine pathway did not affect the increases in dynorphin B and aspartate levels produced by local administration of cholecystokinin-8S. Basal extracellular GABA levels were increased significantly in both the neostriatum and substantia nigra ipsilateral to the lesion. Nigral glutamate and aspartate levels were also increased in the lesioned substantia nigra, but in the lesioned neostriatum aspartate levels were decreased. The cholecystokinin-B antagonist L-365,260 (20 mg/kg, s.c.), but not the cholecystokinin-A antagonist L-364,718 (devazepide; 20 mg/kg, s.c.), significantly inhibited the effect of cholecystokinin-8S on striatal dynorphin B and aspartate levels. In the substantia nigra, however, the effect of cholecystokinin-8S on dynorphin B and aspartate levels was inhibited to a similar extent 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 and 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 via the cholecystokinin-B receptor subtype, while in the substantia nigra, cholecystokinin-8S modulates dynorphin B and aspartate release via both cholecystokinin-A and cholecystokinin-B receptor subtypes. Cholecystokinin-8S modulates dopamine release mainly in the substantia nigra, via the cholecystokinin-A receptor subtype.