Blockade of neurotensin binding in the rat hypothalamus and of the central action of neurotensin on the hypothalamic-pituitary-adrenal axis with non-peptide receptor antagonists.
Central administration of neurotensin (NT) has been shown to activate the hypothalamic-pituitary-adrenal axis, an effect which seems dependent upon the release of corticotropin-releasing factor. In this study, we describe the distribution of NT binding sites in the hypothalamus using film and emulsion receptor autoradiography. Among the 125I-NT-labelled hypothalamic nuclei, relatively high densities of neurotensin binding sites were detected over the paraventricular nucleus. Silver grains on emulsion-coated slides overlaid indiscriminately cell bodies and surrounding processes of magnocellular and parvocellular parts of the nucleus. Two newly developed NT receptor antagonists, SR 48692 and its analog SR 48450, competed for 125I-NT binding to hypothalamic tissue sections and membrane preparations with Ki values in the nanomolar range. Moreover, intracerebrally injected SR 48450 was able to block the NT-induced hypothalamic-pituitary-adrenal axis activation in freely moving rats, whereas its administration alone did not significantly affect basal plasma levels of adrenocorticotropin and corticosterone. These data provide anatomical substrate for a potential neurotensin action at the hypothalamus in the hypothalamic-pituitary-adrenal axis activation and highlight the use of new non-peptide NT receptor antagonists to characterize the effects of NT on neuroendrocrine functions.
Nicot
A
A
INSERM U339, Hôpital Saint-Antoine, Paris, France.
Bérod
A
A
Gully
D
D
Rowe
W
W
Quirion
R
R
de Kloet
E R
ER
Rostène
W
W
D000324:Adrenocorticotropic Hormone / Q000097:blood; D000818:Animals; D001345:Autoradiography; D001665:Binding Sites / Q000187:drug effects; D003345:Corticosterone / Q000097:blood; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects* / Q000502:physiology; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D009496:Neurotensin / Q000378:metabolism* / Q000494:pharmacology; D010286:Paraventricular Hypothalamic Nucleus / Q000187:drug effects / Q000378:metabolism; D010913:Pituitary-Adrenal System / Q000187:drug effects* / Q000502:physiology; D011720:Pyrazoles / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D018028:Receptors, Neurotensin / Q000037:antagonists & inhibitors*
D011720:Pyrazoles; D011804:Quinolines; D018028:Receptors, Neurotensin; C089374:SR 48450; C079087:SR 48692; D009496:Neurotensin; D000324:Adrenocorticotropic Hormone; D003345:Corticosterone