EFFECT OF A PROLYL ENDOPEPTIDASE INHIBITOR, JTP-4819, ON RADIAL MAZE PERFORMANCE IN HIPPOCAMPAL-LESIONED RATS

The effect of a novel prolyl endopeptidase (PEP) inhibitor, arbonyl]-N -(phenylmethyl)-1-pyrrolidinecarboxamide (JTP-4819), on spatial learni ng deficits in rats with dorsal hippocampal (DH) lesions was examined using an eight-arm radial maze. The correct performance remained at ch ance levels even after 18 acquisition trials in rats with DH lesions. JTP-4819 (3.0 mg/kg, p.o.) significantly ameliorated this learning imp airment after 34-41 days of treatment. When DH lesions were created in rats after achievement of learning, postoperative performance deterio rated prominently, but gradually recovered with the repetition of tria ls. JTP-4819 (3.0 mg/kg, p.o.) significantly de creased the number of trials needed to reattain learning criterion. After the behavioral exp eriment, the choline acetyltransferase (ChAT) activity and [H-3]-piren zepine binding (K-d, B-max) in the residual hippocampus and cerebral c ortex were analyzed. Neither parameter was significantly affected by J TP-4819. In conclusion JTP-4819 can improve both learning and relearni ng deficits of spatial memory in DH-lesioned rats, postulating that en hancement of neuropeptide activity via PEP inhibition may be involved in the mechanism of action of JTP-4819. (C) 1998 Elsevier Science Inc.