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To explore the involvement of 5-hydroxytryptamine-1A (5-HT1A) receptors in hypothalamic-pituitary-adrenal (HPA) axis regulation, various doses of ipsapirone (IPS), a centrally acting pyrimidinylpiperazine with considerable affinity and selectivity for 5-HT1A recognition sites, were administered to normal subjects. IPS dose-dependently increased plasma ACTH concentrations from −78 ± 63 to 614 ± 250 pmol·min/ L (P < 0.01) and plasma cortisol concentrations from −10.8 ± 2.9 × 103 to 21.3 ± 8.2 × 103 nmol·min/L (P / 0.01) at a dose of 0.3 mg/kg in six men. The nonselective 5-HT receptor antagonist metergoline which acts at both 5-HT1 and 5-HT2 receptors partially blocked the HPA response to IPS in six women and three men. The mean maximal integrated ACTH response decreased from 746 ± 297 to 40 ± 146 pmol/min·L (P < 0.05), and the increase in cortisol was attenuated from 22.9 ± 9.9 × 103 to 11.9 ± 6.3 × 103 nmol·min/L (P < 0.05).

The nonselective β-adrenergic and selective 5-HT1A/1B receptor antagonist (±)pindolol was without effect on basal HPA activity, but completely antagonized the IPS-induced plasma ACTH and cortisol responses. The mean maximal integrated ACTH response decreased to 8.0 ± 78 pmol·min/L (P < 0.05), and the cortisol response was reduced to −2.3 ± 6.5 × 103 nmol·min/L (P < 0.05). The selective β1-adrenoceptor antagonist betaxolol did not significantly alter the IPS-induced HPA response. It is concluded that activation of the 5-HT1A receptor subtype results in ACTH and cortisol secretions in humans, thus further emphasizing the role of the central serotonergic system in the regulation of HPA axis function at the hypothalamic level.

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Copyright © 1990 by The Endocrine Society
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