ANXIOLYTIC ACTIVITY OF GLYCINE-B ANTAGONISTS AND PARTIAL AGONISTS - NO RELATION TO INTRINSIC ACTIVITY IN THE PATCH-CLAMP

On the basis of animal models, anxiety was one of the first suggested clinical applications of partial agonists of the glycine(B) site coupl ed to the NMDA receptor. It is not certain, however, whether these fin dings can be extended to full glycine(B) antagonists and what is the r elation between intrinsic activity (degree of NMDA receptor antagonism ) and anxiolytic effect. In the present study several NMDA receptor an tagonists, including several glycine(B) antagonists/partial agonists, were tested for anxiolytic activity in the Vogel conflict test and the elevated plus-maze. Additionally, the intrinsic activities of the gly cine(B) partial agonists used [ACPC, (R,+)-HA-966 and D-cycloserine] w ere compared in patch-clamp experiments in cultured neurones. In the p lus-maze the most striking increase in the time spent in open arms (in dex of anxiolytic effect) was seen after diazepam and D-cycloserine (a t doses that did not change locomotion). Also reliable (dose-dependent ), although weaker, anxiolytic activity was produced by the uncompetit ive NMDA receptor antagonist (+)MK-801 and the competitive antagonist CGP 39551. Modest anxiolytic-like effect in the plus-maze was also obs erved after the glycine(B) antagonist L-701,324 and the partial agonis t (+,R)-HA-966. Uncompetitive antagonists memantine and amantadine, th e glycine(B) partial agonist ACPC (up to 600 mg/kg) or the full antago nists MRZ 2/570, MRZ 2/571 and MRZ 2/576 had no effect. In the Vogel c onflict test neither memantine, nor any of the full glycinea antagonis ts tested (L-701,324 and MRZ 2/576), showed anxiolytic activity. Patch -clamp studies revealed that the intrinsic activity of (+,R)-HA-966, D -cycloserine and ACPC was 13, 57 and 92%, respectively, as compared to that of glycine itself (100%). In conclusion, for the agents tested t here is no clear relation between the levels of intrinsic activity, i. e. degree of NMDA receptor inhibition, and anxiolytic activity. Moreov er, L-701,324 and MRZ-type glycine(B) full antagonists do not exchibit anxiolytic activity in the elevated plus-maze and Vogel conflict test . (C) 1997 Published by Elsevier Science Ltd.