LONG-TERM ANTIDEPRESSANT TREATMENTS RESULT IN A TONIC ACTIVATION OF FOREBRAIN 5-HT1A RECEPTORS

We report here the first direct functional evidence of an increase in the tonic activation of postsynaptic 5-HT1A receptors by antidepressan t treatments. Because 5-HT1A receptor activation hyperpolarizes and in hibits CA, pyramidal neurons in the dorsal hippocampus, we determined, using in vivo extracellular recording, whether the selective 5-HT1A r eceptor antagonist WAY 100635 could disinhibit these neurons. Unexpect edly, no disinhibition could be detected in controls. However, after l ong-term treatment with the tricyclic antidepressant imipramine, the s elective 5-HT reuptake inhibitor paroxetine, the reversible monoamine oxidase-A inhibitor befloxatone, the alpha(2)-adrenergic antagonist mi rtazapine, or the 5-HT1A receptor agonist gepirone or multiple electro convulsive shock (ECS) administration, WAY 100635 markedly increased ( 60-200%) the firing activity of CA, pyramidal neurons. Such a disinhib ition was absent in rats treated with the nonantidepressant drug chlor promazine, in rats receiving only one ECS, or in rats receiving multip le ECSs in combination with an intrahippocampal pertussis toxin treatm ent to inactivate G(i/o)-coupled 5-HT1A receptors. These data indicate that such antidepressant treatments, acting on entirely different pri mary targets, might alleviate depression by enhancing the tonic activa tion of forebrain postsynaptic 5-HT1A receptors.