Mechanisms of 5-hydroxy-L-tryptophan-induced adrenocorticotropin release: a major role for central noradrenergic drive.
The serotonin (5-hydroxytryptamine, 5-HT) precursor 5-hydroxy-L-tryptophan (5-HTP) and 5-HT antagonists, respectively, are able to stimulate and block pituitary adrenocorticotropin (ACTH) release. However, our previous data do not support a role of central serotoninergic systems in the neural control of ACTH release. We thus examined the hypothesis that 5-HTP given either alone or with uptake-blocking drugs such as fluoxetine caused stimulation of ACTH through activation of central noradrenergic neuronal activity (NNA). The hypothesis was tested in normal adult male rats by correlating medial basal hypothalamic NNA and serotoninergic neuronal activity (SNA) with serum ACTH following administration of 5-HTP (20 and 100 mg/kg, i.p.) in the presence or absence of fluoxetine (10 mg/kg, i.p.) or cyproheptadine (10 mg/kg, i.p.). The alpha 2-adrenergic agonist clonidine (150 micrograms/kg, i.p.) was used to inhibit central NNA and to examine the role of alpha 2-adrenoceptors in the actions of serotoninergic drugs. Computerized mass spectrometry was employed to specifically and precisely assay hypothalamic norepinephrine (NE), 3,4-dihydroxyphenylethyleneglycol (DHPG), 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) to obtain indices of hypothalamic NNA (DHPG/NE) and SNA (5-HIAA/5-HT). The administration of fluoxetine/5-HTP stimulated (p less than 0.01) both hypothalamic NNA and ACTH release.(ABSTRACT TRUNCATED AT 250 WORDS)
Smythe
G A
GA
Garvan Institute of Medical Research, St. Vincent's Hospital, Sydney, Australia.
Gleeson
R M
RM
Stead
B M
BM
D006916:5-Hydroxytryptophan / Q000494:pharmacology*; D000324:Adrenocorticotropic Hormone / Q000378:metabolism*; D000818:Animals; D003000:Clonidine / Q000494:pharmacology; D005473:Fluoxetine / Q000494:pharmacology; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009638:Norepinephrine / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains
D005473:Fluoxetine; D000324:Adrenocorticotropic Hormone; D006916:5-Hydroxytryptophan; D003000:Clonidine; D009638:Norepinephrine