Inhibition of [H-3]D-aspartate release by deramciclane

The effects of the 5-HT2C receptor inverse agonist deramciclane on the gamm a-aminobutyric acid (GABA) uptake and excitatory amino acid release process es were compared in rat cerebrocortical homogenates containing resealed pla smalemma fragments and nerve endings. Deramciclane non-competitively inhibi ted the uptake of [H-3]GABA with a K-i value of 13.7 +/- 0.5 mu M and parti ally displaced specifically bound [H-3]( R,S)-N-[4,4-bis(3-methyl-2-thienyl )-3-butenyl]nipecotic acid ([H-3]NNC-328) with high affinity (IC50 = 2.0 +/ - 0.7 nM). Depolarization by 4-aminopyridine or by 4-aminopyridine with (S) -alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate [(S)-AMPA] induced t he release of [H-3]D-aspartate. Deramciclane (10 mu M) partially (similar t o 50%) inhibited the release of [H-3]D-aspartate without affecting [H-3]D-a spartate uptake. These results suggest a role for presynaptic inhibition of excitatory amino acid release and GABA uptake in the anxiolytic properties of deramciclane. (C) 1999 Elsevier Science B.V. All rights reserved.