Chronic administration of the antidepressant phenelzine and its N-acetyl analogue: effects on GABAergic function
The MAO inhibitor phenelzine (2-phenylethylhydrazine; PLZ) is used widely in psychiatry for the treatment of depression and panic disorder. Its N-acetyl metabolite, N2-acetylphenelzine (N2AcPLZ) is a reasonably potent nonselective inhibitor of monoamine oxidase (MAO) that causes elevation in brain levels of the biogenic amines. In the studies reported here, PLZ (0.05 mmol/kg/day), N2AcPLZ (0.10 mmol/kg/day) or vehicle were administered to male rats for 28 days s.c. with Alzet minipumps, and their effects on GABAergic function were examined. Whole brain concentrations of γ-aminobutyric acid (GABA) were significantly elevated in the PLZ but not in the N2AcPLZ-treated group. PLZ was found to inhibit the anabolic enzyme glutamic acid decarboxylase (GAD) and, to a greater extent, the catabolic enzyme GABA transaminase (GABA-T). The results of these investigations suggest that the free hydra-zine moiety in PLZ is crucial to producing the elevated levels of GABA, probably through inhibition of GABA-T. Despite the considerable increase in whole brain GABA levels in the PLZ-treated rats, there were no significant differences in GABAA or benzodiazepine receptor binding parameters (KD or Bmax) between the groups as measured using 3H-muscimol and 3H-flunitrazepam in radioligand binding assays.
KeywordsGlutamic Acid Decarboxylase Gaba Level Brain Gaba GABAergic Function Brain Gaba Level
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