Z-321, a prolyl endopeptidase inhibitor, augments the potentiation of synaptic transmission in rat hippocampal slices

The present study investigated the effects of arginine-vasopressin (AVP) and (1-[3-(2-indanylacetyl)-L-thioprolyl]pyrrolidine (Z-321), an inhibitor of prolyl endopeptidase (PEP; (EC 3.4.21.26)) which degrades AVP in vitro, on the short-lasting potentiation of the field excitatory postsynaptic potentials (EPSP) coupled with a weak tetanus. The EPSP, after the electrical stimulation of the Schaffer collateral/commissural pathway, were recorded in the CA1 region of rat hippocampal slices. AVP at 10^-8 M and Z-321 at 10^-4 M augmented the potentiation induced by the weak tetanus; the magnitude of the post-tetanic potentiation of the EPSP was enhanced and the potentiation lasted for 60 min. In contrast, the racemic D-thioprolyl compound of Z-321, which virtually lacks any inhibitory effects on PEP, failed to affect the potentiation at 10^-4 M. The facilitatory effect of Z-321 was reversed by the application of [d(CH₂)₅,Tyr(Me)²]AVP (10^-8 M), an antagonist of the AVP V₁ receptors, indicating that the effect of Z-321 was mediated through the V₁ receptors. These findings suggest that Z-321 augmented the potentiation due to its inhibitory influence on the AVP degradation by PEP.