Desensitization of 5-HT1A receptors by 5-HT2A receptors in neuroendocrine neurons in vivo.
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 microg/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-HT1A receptors. Microinjection of the 5-HT2A receptor antagonist MDL100,907 [(+)-alpha-(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.
Zhang
Yahong
Y
Center for Serotonin Disorders Research and Department of Pharmacology, Loyola University of Chicago, Stritch School of Medicine, Maywood, Illinois 60153, USA.
Gray
Thackery S
TS
D'Souza
Deborah N
DN
Carrasco
Gonzalo A
GA
Damjanoska
Katerina J
KJ
Dudas
Bertalan
B
Garcia
Francisca
F
Zainelli
Gina M
GM
Sullivan Hanley
Nicole R
NR
Battaglia
George
G
Muma
Nancy A
NA
Van de Kar
Louis D
LD
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology; D000324:Adrenocorticotropic Hormone / Q000378:metabolism; D000662:Amphetamines / Q000494:pharmacology; D000818:Animals; D000918:Antibody Specificity; D003346:Corticotropin-Releasing Hormone / Q000378:metabolism; D005464:Fluorobenzenes / Q000494:pharmacology; D008845:Microinjections; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009490:Neurosecretory Systems / Q000166:cytology; D010121:Oxytocin / Q000378:metabolism; D010286:Paraventricular Hypothalamic Nucleus / Q000166:cytology; D010880:Piperidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044282:Receptor, Serotonin, 5-HT1A / Q000276:immunology / Q000378:metabolism*; D044402:Receptor, Serotonin, 5-HT2A / Q000276:immunology / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*
D000662:Amphetamines; D005464:Fluorobenzenes; D010880:Piperidines; D044402:Receptor, Serotonin, 5-HT2A; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D044282:Receptor, Serotonin, 5-HT1A; D010121:Oxytocin; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D000324:Adrenocorticotropic Hormone; D003346:Corticotropin-Releasing Hormone; C079049:volinanserin; C015952:4-iodo-2,5-dimethoxyphenylisopropylamine