Long-Term Antidepressant Treatments Result in a Tonic Activation of Forebrain 5-HT1AReceptors

Abstract

We report here the first direct functional evidence of an increase in the tonic activation of postsynaptic 5-HT_1Areceptors by antidepressant treatments. Because 5-HT_1Areceptor activation hyperpolarizes and inhibits CA₃pyramidal neurons in the dorsal hippocampus, we determined, usingin vivoextracellular recording, whether the selective 5-HT_1Areceptor 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_1Areceptor agonist gepirone or multiple electroconvulsive shock (ECS) administration, WAY 100635 markedly increased (60–200%) the firing activity of CA₃pyramidal neurons. Such a disinhibition was absent in rats treated with the nonantidepressant drug chlorpromazine, in rats receiving only one ECS, or in rats receiving multiple ECSs in combination with an intrahippocampal pertussis toxin treatment to inactivate G_i/o-coupled 5-HT_1Areceptors. 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_1Areceptors.