Mechanisms of Serotonin Receptor Agonist-Induced Activation of the Hypothalamic-Pituitary-Adrenal Axis in the Rat

Abstract

A substantial body of experimental evidence indicates that serotonin (5-HT) and several synthetic 5-HT receptor agonists activate the hypothalamic-pituitary-adrenal (HPA) axis. To explore the mechanism(s) by which 5-HT or 5-HT agonists enhance the activity of the HPA axis in vitro, we examined the stimulatory effects of the 5-HT1a agonist 8-hydroxy-2(di-n-propylamino)tetralin (8-OH-DPAT), THE 5-HT1c/5-HT1b against m-chlorophenylpiperazine (m-CPP), and the 5-HT2/5-HT1c agonist 1-(2,5-dimethoxy-4-iodophenyl)2-amino-propane (DOI) on plasma ACTH and corticosterone secretion in the rat. To test whether 8-OH-DPAT, m-CPP, or DOI increase plasma ACTH levels by stimulating the release of endogenous CRH, catheterized conscious male Sprague-Dawley rats were pretreated with hyperimmune CRH rabbit serum (TS-6) or normal rabbit serum and subsequently challenged with a maximally stimulatory dose of the above 5-HT agonists. Pretreatment with TS-6 completely suppressed the ACTH response to m-CPP and significantly blunted the responses to 8-OH-DPAT or DOI. To examine whether the remaining ACTH response to 8-OH-DPAT or DOI was also mediated by a pituitary site of action, we administered each of these agents to pituitary stalk-transected or sham-operated rats. The ACTH responses to 8-OH-DPAT and DOI in stalk-transected rats were preserved, although significantly blunted, compared to those in sham-operated rats. This suggested that both of these 5-HT agonists may also act at the pituitary level to stimulate ACTH release in vivo. Although the ACTH responses to 8-OH-DPAT, m-CPP, and DOI were blunted after both TS-6 pretreatment and pituitary stalk transection, corticosterone responses were only slightly affected, suggesting that some of these compounds may cause corticosterone release in the rat through another mechanism. To evaluate this hypothesis, ACTH and corticosterone responses to 8-OH-DPAT, m-CPP, and DOI were examined in rats whose HPA axis had been suppressed by a single high dose injection of dexamethasone. The corticosterone responses to 8 OH-DPAT and DOI were blunted compared to those of saline-pretreated rats, but were inappropriately high compared to the ACTH responses observed in these rats. On the other hand, both ACTH and corticosterone responses to m-CPP were completely abolished by dexamethasone. In conclusion, the present findings suggest that the 5-HT1a receptor agonist 8-OH-DPAT and the 5-HT2/5-HT1c receptor agonist DOI may cause ACTH release in vivo by stimulating both hypothalamic CRH and pituitary ACTH secretion, whereas the ACTH response to the 5-HT1c/5-HT1b receptor agonist m-CPP appears to be primarily CRH dependent. It appears that both 8-OH-DPAT and DOI may be capable of stimulating corticosterone secretion through an ACTH-independent mechanism.