THE ANTIDEPRESSANT DRUG PHENELZINE PRODUCES ANTIANXIETY EFFECTS IN THE PLUS-MAZE AND INCREASES IN RAT-BRAIN GABA

Research on the effects of antidepressant/antipanic drugs in animal mo dels of anxiety has yielded equivocal results, even after chronic drug regimens. In contrast, we found that the antidepressant/antipanic dru g phenelzine,given acutely, produced a clear anxiolytic effect in the elevated plus-maze, a widely-used animal model of ''anxiety'' that is primarily sensitive to benzodiazepine-type anxiolytics (e.g., diazepam ). Furthermore, the effective dose of phenelzine (15 mg/kg) administer ed to rats was associated with more than a 2- fold increase in whole b rain levels of gamma-aminobutyric acid (GABA), whereas an ineffective dose of phenelzine (5.1 mg/kg) did not significantly change GABA level s. The N-acetylated metabolite of phenelzine, N-2-acetylphenelzine, pr oduced neither an anxiolytic effect in the elevated plus-maze nor a si gnificant change in whole-brain levels of GABA. However, both phenelzi ne and N-2-acetylphenelzine potently inhibited monoamine oxidase, a me chanism commonly thought to be involved in the therapeutic effects of monoamine oxidase inhibitors such as phenelzine in the treatment of de pression in humans. These results suggest that the mechanism whereby p henelzine produces anxiolytic effects in the plus-maze model is unique to a facilitatory action on brain levels of GABA, in contrast to clas sical benzodiazepines, which produce anxiolytic effects by enhancing t he affinity of the GABA(A)-receptor for GABA.