Effects of cholecystokinin peptides and GV 150013, a selective cholecystokinin(B) receptor antagonist, on electrically evoked endogenous GABA releasefrom rat cortical slices

The effects of cholecystokinin (CCK) agonists and antagonists on spontaneou s and electrically evoked endogenous GABA release from rat cerebral cortex slices were evaluated. Neither the nonselective and CCKB-selective receptor agonists CCK-8S (3-1,000 nM) and CCK-4 (3-1,000 nM), respectively, nor the selective CCKB and CCKA receptor antagonists GV 150013 (3-30 nM) and L-364 ,718 (10-100 nM), respectively, significantly affected spontaneous GABA rel ease. CCK-8S (1-1,000 nM) and CCK-4 (1-1,000 nM) increased the electrically (5 and 10 Hz)-evoked GABA release. On the contrary, GV 150013 (10 and 30 n M) significantly decreased the electrically evoked GABA release only when t he slices were stimulated at the higher 10 Hz frequency. The CCK-8S- and CC K-4-induced increases in electrically evoked GABA release were counteracted by GV 150013, but not by L-364,718. Furthermore, GV 150013 at 3 nM shifted to the right the CCK-4 concentration-response curve, whereas at the higher 10 nM concentration it dramatically flattened the curve. Finally, in corti cal slices obtained from rats chronically treated with GV 150013, the conce ntration-response curve of CCK-4 was shifted to the left and the peak effec t of the peptide was significantly higher than that observed in naive anima ls. These results suggest that CCK increases electrically evoked, but not s pontaneous, endogenous GABA release from rat cortical slices, possibly by a ctivating local CCKB receptors. In addition, chronic treatment with the nov el CCKB receptor antagonist GV 150013 leads to an enhanced responsiveness o f cortical slices to CCK-4 application.