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NEUROPHARMACOLOGY

Desensitization of 5-HT_1A Receptors by 5-HT_2A Receptors in Neuroendocrine Neurons in Vivo

Center for Serotonin Disorders Research and Department of Pharmacology (Y.Z., T.S.G., D.N.D., G.A.C., K.J.D., B.D., F.G., G.M.Z., N.R.S.H., G.B., N.A.M., L.D.V.d.K.) and Department of Cell Biology, Neurology, and Anatomy (T.S.G.), Loyola University Chicago, Stritch School of Medicine, Maywood, Illinois

An imbalance between serotonin-2A (5-HT_2A) and 5-HT_1A receptors may underlie several mood disorders. The present studies determined whether 5-HT_2A receptors interact with 5-HT_1A receptors in the rat hypothalamic paraventricular nucleus (PVN). The sensitivity of the hypothalamic 5-HT_1A receptors was measured as oxytocin and adrenocorticotropic hormone (ACTH) responses to the 5-HT_1A receptor agonist (+)-8-hydroxy-2-(di-n-propylamino) tetralin hydrobromide [(+)8-OH-DPAT] (40 µg/kg s.c.). The 5-HT_2A/2C receptor agonist (-)DOI [(-)-1-(2,5-dimethoxy-4-iodophenyl)2-aminopropane HCl] (1 mg/kg s.c.) injected 2 h prior to (+)8-OH-DPAT significantly reduced the oxytocin and ACTH responses to (+)8-OH-DPAT, producing a heterologous desensitization of the 5-HT_1A receptors. Microinjection of the 5-HT_2A receptor antagonist MDL100,907 [(+)--(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidinemethanol; 0, 10, or 20 nmol, 15 min prior to (-)DOI] into the PVN dose-dependently prevented the desensitization of 5-HT_1A receptors induced by the 5-HT_2A receptor agonist (-)DOI. Double-label immunocytochemistry revealed a high degree of colocalization of 5-HT_1A and 5-HT_2A receptors in the oxytocin and corticotropin-releasing factor neurons of the PVN. Thus, activation of 5-HT_2A receptors in the PVN may directly induce a heterologous desensitization of 5-HT_1A receptors within individual neuroendocrine cells. These findings may provide insight into the long-term adaptation of 5-HT_1A receptor signaling after changes in function of 5-HT_2A receptors; for example, during pharmacotherapy of mood disorders.

Address correspondence to: Dr. Louis D. Van de Kar, Department of Pharmacology, Loyola University of Chicago, Stritch School of Medicine, 2160 South First Avenue, Maywood, Illinois 60153. E-mail: lvandek{at}lumc.edu

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