Estrogen desensitizes 5-HT(1A) receptors and reduces levels of G(z), G(i1) and G(i3) proteins in the hypothalamus.
The present study investigated whether estrogen would desensitize hypothalamic serotonin(1A) (5-HT(1A)) receptors by examining the neuroendocrine response to 8-OH-DPAT, a 5-HT(1A) agonist. Rats were ovariectomized, allowed to recover for 5 days, then given 2 daily injections of estradiol benzoate or vehicle (10 microg/day, s.c.). Twenty-four hours after the second injection, rats were challenged with a sub-maximal dose of 8-OH-DPAT (50 microg/kg, sc) or saline 15 min prior to sacrifice. 8-OH-DPAT produced a significant increase in plasma oxytocin, ACTH and corticosterone levels in ovariectomized rats. While estrogen treatment for 2 days did not alter basal hormone levels, it did significantly reduce the magnitude of oxytocin, ACTH and corticosterone responses to 8-OH-DPAT. The reduction in hormone responses was accompanied by a significant reduction in hypothalamic levels of G(z), G(i1) and G(i3) proteins (by 50%, 30% and 50%, respectively). These findings suggest that a reduction in these G proteins may contribute to the mechanisms underlying estrogen-induced desensitization of 5-HT(1A) receptors. The desensitization of 5-HT(1A) receptors has been suggested to underlie the therapeutic effects of antidepressant 5-HT uptake inhibitors (SSRIs). Thus, the present results suggest that estrogen or estrogen-like substances in combination with SSRIs may prove effective in developing novel therapeutic strategies for neuropsychiatric disorders in women.
Raap
D K
DK
Department of Pharmacology, Stritch School of Medicine, Loyola University Chicago, 2160 S. First Avenue, IL 60153, Maywood, USA.
DonCarlos
L
L
Garcia
F
F
Muma
N A
NA
Wolf
W A
WA
Battaglia
G
G
Van de Kar
L D
LD
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology; D000324:Adrenocorticotropic Hormone / Q000097:blood / Q000187:drug effects; D000818:Animals; D003345:Corticosterone / Q000097:blood; D004967:Estrogens / Q000494:pharmacology*; D005260:Female; D044385:GTP-Binding Protein alpha Subunits; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism*; D020962:Heterotrimeric GTP-Binding Proteins / Q000378:metabolism*; D007031:Hypothalamus / Q000187:drug effects* / Q000378:metabolism; D010052:Ovariectomy; D010121:Oxytocin / Q000097:blood / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000378:metabolism; D044263:Receptors, Serotonin, 5-HT1
D004967:Estrogens; D044385:GTP-Binding Protein alpha Subunits; C490963:Gnaz protein, rat; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D010121:Oxytocin; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D000324:Adrenocorticotropic Hormone; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D020962:Heterotrimeric GTP-Binding Proteins; D003345:Corticosterone