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The Journal of Neuroscience, December 1, 1998, 18(23):10150-10156

Long-Term Antidepressant Treatments Result in a Tonic Activation of Forebrain 5-HT_1A Receptors

Nasser Haddjeri, Pierre Blier, and Claude de Montigny

Neurobiological Psychiatry Unit, McGill University, Montréal, Québec, Canada H3A 1A1

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 ₂-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 ECS, 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.

Key words: antidepressants; serotonin (5-HT); 5-HT_1A receptors; WAY 100635; disinhibition; dorsal hippocampus

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Copyright © 1998 Society for Neuroscience  0270-6474/98/182310150-07$05.00/0

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