CHRONIC ADMINISTRATION OF THE ANTIDEPRESSANT PHENELZINE AND ITS N-ACETYL ANALOG - EFFECTS ON GABAERGIC FUNCTION

The MAO inhibitor phenelzine (2-phenylethylhydrazine; PLZ) is used wid ely in psychiatry for the treatment of depression and panic disorder. Its N-acetyl metabolite, N-2-acetylphenelzine (N(2)AcPLZ) is a reasona bly potent nonselective inhibitor of monoamine oxidase (MAO) that caus es elevation in brain levels of the biogenic amines. In the studies re ported here, PLZ (0.05 mmol/kg/day), N(2)AcPLZ (0.10 mmol/kg/day) or v ehicle were administered to male rats for 28 days s.c. with Alzet mini pumps, and their effects on GABAergic function were examined. Whole br ain concentrations of gamma-aminobutyric acid (GABA) were significantl y elevated in the PLZ but not in the N(2)AcPLZ-treated group. PLZ was found to inhibit the anabolic enzyme glutamic acid decarboxylase (GAD) and, to a greater extent, the catabolic enzyme GABA transaminase (GAB A-T). The results of these investigations suggest that the free hydraz ine moiety in PLZ is crucial to producing the elevated levels of GABA, probably through inhibition of GABA-T. Despite the considerable incre ase in whole brain GABA levels in the PLZ-treated rats, there were no significant differences in GABAA or benzodiazepine receptor binding pa rameters (K-D or B-max) between the groups as measured using H-3-musci mol and H-3-flunitrazepam in radioligand binding assays.