Antidepressants and metabolites that block GABAA receptors coupled to 35S-t-butylbicyclophosphorothionate binding sites in rat brain.

Twenty-three clinically effective antidepressants and 9 metabolites of antidepressants (together, about 50% of all antidepressants tested) were found to, fully or partially, reverse the inhibitory action of 1 microM GABA on 35S-TBPS binding. Amoxapine, the most potent of the complete reversers, is a strong convulsant in overdosage while mianserin, the most potent of the partial reversers and a pro-convulsant, almost never produces convulsions in humans, even after massive overdosage. Convulsant side effects, a pervasive property of antidepressants, can probably be attributed to GABA antagonism, perhaps at a subset of GABAA receptors. Further, the structures of the antidepressants, as well as the criteria used to select them for clinical trials, are diverse, raising the possibility that GABA antagonism, perhaps at another subset of GABAA receptors, could be also involved in clinical antidepressant action. We speculate that selective blockade of excessive GABAergic inhibition of reward systems may contribute to the clinical effects of many antidepressants, in some cases via active metabolites.