Desensitization of 5-HT1A Receptors by 5-HT2A Receptors in Neuroendocrine Neurons in Vivo

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 310; no. 1; pp. 59 - 66
• Main Authors: Zhang, Yahong, Gray, Thackery S., D’Souza, Deborah N., Carrasco, Gonzalo A., Damjanoska, Katerina J., Dudas, Bertalan, Garcia, Francisca, Zainelli, Gina M., Sullivan Hanley, Nicole R., Battaglia, George, Muma, Nancy A., Van de Kar, Louis D.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.07.2004; American Society for Pharmacology and Experimental Therapeutics
• Subjects: 8-Hydroxy-2-(di-n-propylamino)tetralin - pharmacology; Adrenocorticotropic Hormone - metabolism; Amphetamines - pharmacology; Animals; Antibody Specificity; Corticotropin-Releasing Hormone - metabolism; Fluorobenzenes - pharmacology; Microinjections; Neurons - drug effects; Neurons - metabolism; Neurosecretory Systems - cytology; Oxytocin - metabolism; Paraventricular Hypothalamic Nucleus - cytology; Piperidines - pharmacology; Rats; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT1A - immunology; Receptor, Serotonin, 5-HT1A - metabolism; Receptor, Serotonin, 5-HT2A - immunology; Receptor, Serotonin, 5-HT2A - metabolism; Serotonin Antagonists - pharmacology; Serotonin Receptor Agonists - pharmacology
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.103.062224

An imbalance between serotonin-2A (5-HT2A) and 5-HT1A receptors may underlie several mood disorders. The present studies determined whether 5-HT2A receptors interact with 5-HT1A receptors in the rat hypothalamic paraventricular nucleus (PVN). The sensitivity of the hypothalamic 5-HT1A receptors was measured as oxytocin and adrenocorticotropic hormone (ACTH) responses to the 5-HT1A receptor agonist (+)-8-hydroxy-2-(di-n-propylamino) tetralin hydrobromide [(+)8-OH-DPAT] (40 μg/kg s.c.). The 5-HT2A/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-HT1A receptors. Microinjection of the 5-HT2A receptor antagonist MDL100,907 [(+)-α-(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-HT1A receptors induced by the 5-HT2A receptor agonist (-)DOI. Double-label immunocytochemistry revealed a high degree of colocalization of 5-HT1A and 5-HT2A receptors in the oxytocin and corticotropin-releasing factor neurons of the PVN. Thus, activation of 5-HT2A receptors in the PVN may directly induce a heterologous desensitization of 5-HT1A receptors within individual neuroendocrine cells. These findings may provide insight into the long-term adaptation of 5-HT1A receptor signaling after changes in function of 5-HT2A receptors; for example, during pharmacotherapy of mood disorders.