Serotonergic Stimulation of Pituitary-Adrenal Activity in the Mouse

Abstract

Female CF1 mice were given L-5-hydroxytryptophan (5-HTP), quipazine, or 6-methoxy-l,2,3,4-β-carboline (6-MeO-THBC) in conjunction with various serotonergic drugs to determine if the pituitary-adrenal stimulation produced by the former compounds is serotonergically mediated. Corticosterone (CS) responses to 5-HTP were uninfluenced by pretreatment with a tryptophan hydroxylase inhibitor, p-chlorophenylalanine (PCPA), but were significantly potentiated by a serotonin (5-HT) reuptake inhibitor (Lilly 110140), attenuated by two 5-HT receptor blockers, cyproheptadine and methergoline, and almost completely abolished by 2 extracerebral aromatic L-amino acid decarboxylase inhibitors, MK 486 and a low dose of Ro 4–4602. It was also established that L-tryptophan could stimulate pituitary-adrenal activity in animals pretreated with the monoamine oxidase (MAO) inhibitor pargyline. Serotonergic drugs were generally not as effective in modulating the responses to quipazine and 6-MeO-THBC. It is concluded that (1) 5-HTP stimulates pituitary-adrenal activity in mice by being converted to 5-HT and acting on 1 or more groups of serotonergic receptors; (2) these receptors are located either in an area of the brain outside of the blood-brain barrier such as the median eminence or in a peripheral tissue(s); (3) tryptophan-derived 5-HT can stimulate these receptors, but only if allowed to accumulate by inhibiting its catabolism; and (4) it is not yet clear whether pituitary-adrenal responses to quipazine and 6-MeO-THBC are mediated by a serotonergic mechanism.

Lack of Correlation between Hypothalamic Serotonin and the Ether-Induced ACTH Secretion in Adrenalectomized Rats

“…However, the conclusions from studies on the possible role of serotonin in the regulation of HPA activity (circadi an rhythm of corticosterone secretion; feedback sensitivity and stress-responsiveness of the HPA system) are not in agreement. In accordance with clinical findings [15], most of the experimental studies [10,12,16,21,26,31] suggest that serotonin is a stimulatory neurotransmitter. On the oth er hand, the results of several investigations have led to the opposite conclusion [4,25,35,36].…”

“…Table 1 (part 'A') shows that in the case of intact (non adrenalectomized) rats, the previous findings of others [21 ] could be confrmed. since the cyproheptadine treatment resulted in highly elevated ACTH and corticosterone levels.…”

A Role for Serotonin in the Hypothalamic-Pituitary-Adrenal Response to Insulin Stress

“…It is interesting to note that tryptophan also increased serum corticosterone con centrations in the noninsulin injected animals. Once again, this result may be due to the fasted state of the subjects, as we have previously observed no response to tryptophan alone (i.e., in the absence of a monoamine oxidase inhibi tor) in either nonfasted rats [Meyer, Yehuda, unpubl. obser vations] or mice [40].…”

Influence of glucocorticoids on brain serotonin metabolism in rats.

“…Discussion Although brain 5HT has been shown to exist in specific neuronal systems like other biogenic amines in the brain (Dahlstrom and Fuxe, 1964 ;Anden et al, 1966) and has been assumed to have some regulatory relations with various functioning systems including the hypothalamic-pituitary-adrenal axis (Scapagnini and Preziosi, 1972 ;Vermes et al, 1972), reports up to now appear to be in sharp conflict. That is, brain 5HT has been signified as stimulating (Krieger and Lauria, 1976 ;Meyer et al, 1978 ;Fuller, 1981 ;Bruni et al, 1982 ;Holmes et al, 1982), inhibiting (Telegdy and Kardos, 1977 ;Vernicos-Danellis et al, 1977) or to even be unrelated (Smelik, 1967) to the release of CRF, ACTH and corticoids.…”

“…However, the results reported so far appear conflicting mainly because either the static parameter of the tissue amine levels or the known effects of drugs have been employed in the interpretation of data. The brain 5HT has therefore been regarded as stimulating (Scapagnini and Preziosi, 1972 ;Krieger and Lauria, 1976 ;Meyer et al, 1978 ;Fuller, 1981 ;Bruni et al, 1982 ;Holmes et al, 1982), inhibiting (Vermes et al, 1972 ;Telegdy and Kardos, 1977 ;Vernikos-Danellis et al, 1977) or even unrelated to (Smelik , 1967) the release of CRF, ACTH and corticoids.…”