Serotonin 2A receptors modulate tail-skin temperature in two rodent models of estrogen deficiency-related thermoregulatory dysfunction.
Menopause-associated thermoregulatory dysfunction, including hot flushes and night sweats, is effectively treated by hormonal therapies that include estrogens. Evidence suggests that estrogen regulates serotonin 2A (5-HT(2A)) receptor expression and that 5-HT(2A) receptors are involved in thermoregulation. Therefore, the role of 5-HT(2A) receptors in thermoregulation was assessed in two rat models of ovariectomy-induced thermoregulatory dysfunction. The first model is based on measurement of the tail-skin temperature (TST) increase following naloxone-induced withdrawal in morphine-dependent ovariectomized (OVX) rats (MD model), while the second model relies on telemetric assessment of diurnal TST changes in ovariectomized rats (telemetry model). Treatment with a 5-HT(2A/2C) receptor agonist, (-)-2,5-dimethoxy-4-iodoamphetamine hydrochloride (DOI), prevented the naloxone-induced TST increase in the MD model and restored normal active-phase TST in the telemetry model. The selective 5-HT(2A) receptor antagonist, MDL-100907, had no effect on the naloxone-induced flush when administered alone in the MD model, but it decreased DOI's ability to abate the flush. In the telemetry model, MDL-100907 attenuated the DOI-induced decrease in active-phase TST. Interestingly, MDL-100907 increased TST in both models when given alone, with the TST increase occurring prior to the naloxone-induced flush in the MD model. To evaluate the role of central nervous system (CNS) 5-HT(2A) receptors in TST regulation, DOI was administered in combination with a known peripheral 5-HT(2A/2C) receptor antagonist, xylamidine, in the MD model. Xylamidine had no effect on DOI's ability to abate the naloxone-induced flush. These results indicate that activation of central 5-HT(2A) receptors restores temperature regulation in two rodent models of ovariectomy-induced thermoregulatory dysfunction.
Sipe
Kimberly
K
Women's Health Research Institute, Wyeth Research N3151A, 500 Arcola Rd., Collegeville, PA 19426, USA.
Leventhal
Liza
L
Burroughs
Kevin
K
Cosmi
Scott
S
Johnston
Grace H
GH
Deecher
Darlene C
DC
D000578:Amidines / Q000494:pharmacology; D000662:Amphetamines / Q000494:pharmacology; D000818:Animals; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004700:Endocrine System Diseases / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology*; D004958:Estradiol / Q000494:pharmacology; D004967:Estrogens / Q000172:deficiency*; D005260:Female; D005464:Fluorobenzenes / Q000494:pharmacology; D009270:Naloxone / Q000009:adverse effects; D010052:Ovariectomy / Q000379:methods; D010880:Piperidines / Q000494:pharmacology; D051381:Rats; D011930:Reaction Time / Q000187:drug effects; D044402:Receptor, Serotonin, 5-HT2A / Q000502:physiology*; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D012881:Skin Temperature / Q000187:drug effects / Q000502:physiology*; D013375:Substance Withdrawal Syndrome / Q000150:complications / Q000378:metabolism / Q000503:physiopathology; D013686:Telemetry / Q000379:methods; D013997:Time Factors
D000578:Amidines; D000662:Amphetamines; D004967:Estrogens; D005464:Fluorobenzenes; D010880:Piperidines; D044402:Receptor, Serotonin, 5-HT2A; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D009270:Naloxone; D004958:Estradiol; C079049:volinanserin; C005894:xylamidine; C015952:4-iodo-2,5-dimethoxyphenylisopropylamine