Blockade of alpha 2-adrenoceptors stimulates basal and stress-induced adrenocorticotropin secretion in the developing rat through a central mechanism independent from corticotropin-releasing factor and arginine vasopressin.
In the neonatal rat, the response of the hypothalamo-pituitary-adrenal axis to stressful stimuli is markedly reduced during the first 2 weeks of life [stress-hyporesponsive period (SHRP)]. In this report, we studied the effect of idazoxan (an alpha 2-adrenergic antagonist) on plasma ACTH and corticosterone levels in 8-day-old rats. Indeed, it is known that in the adult rat, blockade of alpha 2-adrenoceptors increases ACTH secretion stimulated by CRF and arginine vasopressin (AVP) injection. Injection of 2.5 micrograms/g idazoxan induced a rapid (within 30 min) increase in basal plasma ACTH and corticosterone levels that lasted for 60 min. Injection of increasing doses of idazoxan led to a dose-dependent stimulation of ACTH and corticosterone levels. Administration of 2.5 micrograms/g idazoxan significantly increased the ACTH response to insulin-induced hypoglycemia, whereas it potentiated and accelerated the ACTH response to ether exposure stress. We next examined ACTH secretion from superfused anterior pituitary glands. Neither the alpha 2-adrenergic agonist clonidine nor idazoxan changed the basal ACTH secretory rate. Idazoxan had no effect on CRF- and AVP-stimulated ACTH secretion. This indicates that in vivo, idazoxan acts at a suprapituitary level. To investigate a possible effect of idazoxan on presynaptic alpha 2-adrenoceptors, we studied the effect of idazoxan on the concentrations of norepinephrine (NE) and L-DOPA in punches of locus coeruleus after dopa-decarboxylase blockade. Idazoxan injection induced a decrease in the NE content, without changing L-DOPA levels, indicating that idazoxan can act at the level of presynaptic alpha 2-adrenoceptors, inducing an increased release and/or degradation of NE without any effect on catecholamines synthesis. Finally, we investigated a possible involvement of CRF and AVP in mediating the effect of alpha 2-adrenoceptor blockade on ACTH secretion. Passive immunization against CRF or AVP did not change the ACTH response to idazoxan administration, whereas idazoxan pretreatment had simply an additive effect on CRF- and lysine vasopressin-stimulated ACTH secretion. In conclusion, our data demonstrate that during the SHRP, blockade of alpha 2-adrenoceptors induces an increase in both basal and stress-induced ACTH secretion. They suggest that a decreased catecholaminergic tone, consecutive to an increased occupation of alpha 2-adrenoceptors, acting through a central mechanism independent from CRF and AVP may be responsible for the SHRP in the developing rat.
Grino
M
M
Laboratoire de Neuroendocrinologie Expérimentale, INSERM U-297, Institut Fédératif Jean Roche, Marseille, France.
Paulmyer-Lacroix
O
O
Faudon
M
M
Renard
M
M
Anglade
G
G
D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000324:Adrenocorticotropic Hormone / Q000097:blood / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn / Q000254:growth & development / Q000378:metabolism*; D001127:Arginine Vasopressin / Q000502:physiology; D001921:Brain / Q000502:physiology*; D002395:Catecholamines / Q000378:metabolism; D003000:Clonidine / Q000494:pharmacology; D003345:Corticosterone / Q000097:blood; D003346:Corticotropin-Releasing Hormone / Q000494:pharmacology / Q000502:physiology; D004146:Dioxanes / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D019329:Idazoxan; D066298:In Vitro Techniques; D008125:Locus Coeruleus / Q000378:metabolism; D008236:Lypressin / Q000494:pharmacology; D010902:Pituitary Gland / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012016:Reference Values; D013312:Stress, Physiological / Q000378:metabolism*
D000317:Adrenergic alpha-Antagonists; D002395:Catecholamines; D004146:Dioxanes; D001127:Arginine Vasopressin; D008236:Lypressin; D000324:Adrenocorticotropic Hormone; D003346:Corticotropin-Releasing Hormone; D003000:Clonidine; D003345:Corticosterone; D019329:Idazoxan