Experimental basis for the antidepressant action of the GABA receptor agonist progabide

gamma-Aminobutyric acid (GABA) receptor agonists (e.g. progabide) are effective in behavioral tests predictive of antidepressant drug action. Also, these compounds, by changing the firing rate of the corresponding neurons, accelerate norepinephrine turnover (without changes in postsynaptic receptor density) and decrease 5-hydroxytryptamine (5-HT) liberation (with up-regulation of 5-HT2 receptors). At variance, tricyclic antidepressants block monoamine reuptake and cause down-regulation of beta-adrenergic and 5-HT2 receptors. Progabide exerts an antidepressant action which is indistinguishable from that of imipramine. The different modes of action of GABA receptor agonists and tricyclics, as well as alterations of GABA-related parameters by tricyclics, challenge the classical monoaminergic hypothesis of depression and suggest that GABA-mediated mechanisms play a role in this disorder.