Inhibition of [3H]D-aspartate release by deramciclane.
The effects of the 5-HT2C receptor inverse agonist deramciclane on the gamma-aminobutyric acid (GABA) uptake and excitatory amino acid release processes were compared in rat cerebrocortical homogenates containing resealed plasmalemma fragments and nerve endings. Deramciclane non-competitively inhibited the uptake of [3H]GABA with a Ki value of 13.7 +/- 0.5 microM and partially displaced specifically bound [3H](R,S)-N-[4,4-bis(3-methyl-2-thienyl)-3-butenyl]nipecotic acid ([3H]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 the release of [3H]D-aspartate. Deramciclane (10 microM) partially (approximately 50%) inhibited the release of [3H]D-aspartate without affecting [3H]D-aspartate uptake. These results suggest a role for presynaptic inhibition of excitatory amino acid release and GABA uptake in the anxiolytic properties of deramciclane.
Kovács
I
I
Department of Neurochemistry, Chemical Institute, Chemical Research Center, Hungarian Academy of Sciences, Budapest. ilkovacs@cric.chemres.hu
Skuban
N
N
Nyitrai
G
G
Kardos
J
J
D015761:4-Aminopyridine / Q000494:pharmacology; D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D001224:Aspartic Acid / Q000378:metabolism*; D001892:Camphanes / Q000494:pharmacology*; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D003864:Depression, Chemical; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology; D008297:Male; D009411:Nerve Endings / Q000187:drug effects / Q000378:metabolism; D014179:Neurotransmitter Uptake Inhibitors / Q000494:pharmacology; D009557:Nipecotic Acids / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000187:drug effects; D000078308:Tiagabine; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D014151:Anti-Anxiety Agents; D001892:Camphanes; D018690:Excitatory Amino Acid Agonists; D018756:GABA Antagonists; D014179:Neurotransmitter Uptake Inhibitors; D009557:Nipecotic Acids; D011963:Receptors, GABA-A; D001224:Aspartic Acid; D005680:gamma-Aminobutyric Acid; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D015761:4-Aminopyridine; C060555:deramciclane; D000078308:Tiagabine