Functional subsensitivity of 5-hydroxytryptamine1C or alpha 2 adrenergic heteroreceptors mediating clonidine-induced growth hormone release in the Fawn-Hooded rat strain relative to the Wistar rat strain.
Administration of various doses of clonidine increased plasma growth hormone levels. Pretreatment with the alpha 2 adrenergic antagonists, yohimbine and 1-(2-pyrimidyl)piperazine, completely blocked clonidine's effect on growth hormone levels. Pretreatment with the 5-hydroxytryptamine3 (5-HT3) receptor antagonist, MDL-72222, the 5-HT1A/5-HT2 antagonist, spiperone, and the mixed beta adrenergic/5-HT1B antagonists, l-propranolol and CGP361A, did not attenuate clonidine-induced increases in growth hormone levels. In contrast, pretreatment with the non-selective 5-HT1/2 antagonist, metergoline, and the 5-HT1C/5-HT2-selective antagonist, mesulergine, reduced clonidine-induced increases in growth hormone levels 81 to 87% without affecting clonidine-induced decreases in locomotor activity. Two other 5-HT1C/5-HT2 antagonists, ritanserin and mianserin, also attenuated (47%) clonidine-induced increases in growth hormone levels. Pretreatment with the noradrenergic neurotoxin, DSP4, did not block clonidine's effect on growth hormone levels. Clonidine administration decreased locomotor activity in both the Fawn-Hooded and the Wistar rat strains to the same extent. On the other hand, clonidine administration failed to increase growth hormone levels in the Fawn-Hooded rat strain. These findings suggest that clonidine stimulates growth hormone secretion by activation of alpha 2 adrenergic heteroreceptors present on 5-HT nerve terminals which, in turn, enhance 5-HT activity via stimulation of postsynaptic 5-HT1C receptors to promote growth hormone releasing factor. Furthermore, either 5-HT1C receptors or alpha 2 adrenergic heteroreceptors or both are functionally sub-sensitive in the Fawn-Hooded rat strain relative to the Wistar rat strain.
Aulakh
C S
CS
Laboratory of Clinical Science, National Institute of Mental Health, Bethesda, Maryland.
Hill
J L
JL
Lesch
K P
KP
Murphy
D L
DL
D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D003000:Clonidine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D013006:Growth Hormone / Q000097:blood / Q000378:metabolism*; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains; D011985:Receptors, Serotonin / Q000187:drug effects; D012702:Serotonin Antagonists / Q000494:pharmacology*; D013045:Species Specificity
D000317:Adrenergic alpha-Antagonists; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D013006:Growth Hormone; D003000:Clonidine