Long-term antidepressant treatments result in a tonic activation of forebrain 5-HT(1A) receptors

Abstract

We report here the first direct functional evidence of an increase in the tonic activation of postsynaptic 5-HT(1A) receptors by antidepressant treatments. Because 5-HT(1A) receptor activation hyperpolarizes and inhibits CA3 pyramidal neurons in the dorsal hippocampus, we determined, using in vivo extracellular recording, whether the selective 5-HT(1A) receptor antagonist WAY 100635 could disinhibit these neurons. Unexpectedly, no disinhibition could be detected in controls. However, after long-term treatment with the tricyclic antidepressant imipramine, the selective 5-HT reuptake inhibitor paroxetine, the reversible monoamine oxidase-A inhibitor befloxatone, the α2-adrenergic antagonist mirtazapine, or the 5-HT(1A) receptor agonist gepirone or multiple electroconvulsive shock (ECS) administration, WAY 100635 markedly increased (60-200%) the firing activity of CA3 pyramidal neurons. Such a disinhibition was absent in rats treated with the nonantidepressant drug chlorpromazine, in rats receiving only one FCS or in rats receiving multiple ECSs in combination with an intrahippocampal pertussis toxin treatment to inactivate G(i/o)-coupled 5- HT(1A) receptors. These data indicate that such antidepressant treatments, acting on entirely different primary targets, might alleviate depression by enhancing the tonic activation of forebrain postsynaptic 5-HT(1A) receptors.