GABA-elevating effects of the antidepressant/antipanic drug phenelzine in brain: effects of pretreatment with tranylcypromine, (-)-deprenyl and clorgyline.
The antidepressant/antipanic drug phenelzine (PLZ) is both an inhibitor of, and a substrate for, monoamine oxidase (MAO). PLZ also causes an elevation of brain levels of the amino acid neurotransmitter gamma-aminobutyric acid (GABA); this action can be reversed by pretreatment with the MAO inhibitor tranylcypromine (TCP), suggesting that the GABA-elevating effect is largely the result of a metabolite of PLZ formed by MAO. In the present report, rats were pretreated with the nonselective MAO inhibitor TCP, the MAO-A inhibitor clorgyline and the MAO-B inhibitor (-)-deprenyl: at the doses used, clorgyline and (-)-deprenyl caused selective inhibition of MAO-A and MAO-B, respectively. Both TCP and (-)-deprenyl caused a greater reduction in the GABA-elevating action of PLZ than did clorgyline, suggesting that MAO-B is more important than MAO-A in the formation of the active metabolite of PLZ. The results also suggest that an effect other than, or in addition to, inhibition of GABA transaminase by the metabolite may be important in the GABA-elevating action.
Todd
K G
KG
Department of Psychiatry, University of Alberta, Mackenzie Health Sciences Centre, Edmonton, Canada.
Baker
G B
GB
D000612:4-Aminobutyrate Transaminase / Q000037:antagonists & inhibitors; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects* / Q000201:enzymology; D003010:Clorgyline / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D008297:Male; D008995:Monoamine Oxidase / Q000378:metabolism; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology*; D010624:Phenelzine / Q000494:pharmacology*; D011292:Premedication; D051381:Rats; D017207:Rats, Sprague-Dawley; D012642:Selegiline / Q000494:pharmacology*; D014191:Tranylcypromine / Q000494:pharmacology*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D000928:Antidepressive Agents; D007527:Isoenzymes; D008996:Monoamine Oxidase Inhibitors; D012642:Selegiline; D014191:Tranylcypromine; D005680:gamma-Aminobutyric Acid; D008995:Monoamine Oxidase; D000612:4-Aminobutyrate Transaminase; D003010:Clorgyline; D010624:Phenelzine