Central 5-HT1A receptors inhibit adrenocortical secretion.
Serotonin (5-HT) is generally considered to serve a facilitatory role in the regulation of adrenocortical secretion. Numerous studies have shown that administration of 5-HT1A receptor agonists increases plasma corticosterone (CS) concentrations in rats; however, the mechanism has not been established. Rats were prepared with a cannula implanted above the lateral cerebral ventricle, or bilateral cannulae above the hypothalamic paraventricular nuclei (PVN), the site of the perikarya of corticotropin-releasing factor (CRF)-secreting neurons regulating adrenocortical secretion. In sodium pentobarbital-anesthetized rats, intracerebroventricular and intra-PVN administration of 5-HT resulted in a multi-component dose-response curve in plasma CS, whereas administration of 5-HT in conscious animals resulted in low-dose inhibition and higher dose elevation of plasma CS levels. Under pentobarbital anesthesia, central administration of the selective 5-HT1A agonists, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and ipsapirone decreased plasma CS levels, relative to saline-treated control rats, at all doses tested (0.001-20 nmol). In conscious rats, administration of 8-OH-DPAT decreased adrenocortical secretion at lower doses and significantly increased plasma CS concentrations at higher doses. Ipsapirone produced similar but less pronounced effects. In contrast, intraperitoneal injection of 8-OH-DPAT (2 mumol/kg) increased plasma CS concentrations, but this was not prevented by prior intracerebroventricular administration of the 5-HT1A antagonist, NAN-190 (5 nmol). Pentobarbital anesthesia completely blocked the plasma CS response to peripheral administration of 8-OH-DPAT. In view of the adrenocortical activating effects of hypotensive stimuli, we speculate that the well-documented hemodynamic changes following 5-HT1A receptor stimulation may be responsible for the adrenocortical responses observed. Our data demonstrate that low doses of 5-HT1A agonists delivered directly into the CNS decrease adrenocortical secretion. Since intra-PVN injections of 8-OH-DPAT to pentobarbital-anesthetized rats also decreased hypothalamo-pituitary-adrenocortical activity, it appears that a component of the inhibitory effect of 5-HT1A receptor activation is mediated by a direct effect at the level of the PVN, and presumably involves CRF-secreting neurons.
Department of Pharmacology and Therapeutics, Louisiana State University Medical Center, Shreveport, LA 71130-3932.
J E
JE
Welch
G E
GE
Farrar
A J
AJ
Dunn
D
D
Saphier
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000008:administration & dosage / Q000494:pharmacology; D000302:Adrenal Cortex / Q000378:metabolism*; D000758:Anesthesia; D000818:Animals; D003345:Corticosterone / Q000378:metabolism*; D007276:Injections, Intraventricular; D008297:Male; D010286:Paraventricular Hypothalamic Nucleus / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000502:physiology*; D012701:Serotonin / Q000008:administration & dosage / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000494:pharmacology
D010879:Piperazines; D011743:Pyrimidines; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; C058895:1-(2-methoxyphenyl)-4-(4-(2-phthalimido)butyl)piperazine; D012701:Serotonin; C043077:ipsapirone; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D003345:Corticosterone