title: Nicotine stimulates secretion of corticosterone via both CRH and AVP receptors.
abstract: Corticosterone-releasing hormone (CRH) and arginine vasopressin (AVP) are crucial components of the hypothalamic-pituitary-adrenal axis that stimulates the release of adrenocorticotropic hormone from the pituitary and mediate the stress response. CRH binds to two subtypes of CRH receptors (CRH-R1 and CRH-R2) that are present in both central and peripheral tissues. We used the CRH-R1-specific antagonist, antalarmin (ANT), the CRH-R1 and CRH-R2 peptide antagonist, astressin (AST), and the CRH-R2-specific peptide antagonist, astressin2b (AST2b), to determine which CRH receptor is involved in the nicotine-stimulated secretion of corticosterone. Male C57BL/6 mice were administered ANT (20 mg/kg, i.p.), AST (0.3 mg/kg, i.p.), AST2b (0.3 mg/kg, i.p.) or vehicle prior to administration of nicotine (1.0 mg/kg, s.c.), CRH (10 μg/kg, s.c.), AVP (10 μg/kg, s.c.) or saline (s.c.), killed 15 min later and trunk blood collected and assayed for corticosterone plasma levels. We found that CRH enhanced corticosterone release, and this response was blocked by both AST and ANT. Nicotine also increased corticosterone secretion, but this effect persisted in the presence of either CRH antagonist. Furthermore, AST but not ANT or AST2b decreased corticosterone levels associated with stress of handling and injection. We also assessed the role of AVP V(1b) -specific receptor antagonist, SSR149415 alone and in combination with AST and AST2b. Although the AVP antagonist did not alter basal or nicotine-stimulated corticosterone secretion, it attenuated the AVP-induced stimulation of corticosterone and its combination with AST but not AST2b completely abolished nicotine-mediated stimulation of corticosterone secretion. Our results demonstrate that the nicotine-induced stimulation of the hypothalamic-pituitary-adrenal axis is mediated by both the CRH-R and the AVP V(1b) receptor and when the CRH receptor is blocked, nicotine may utilize the AVP V(1b) receptor to mediate secretion of corticosterone. These results argue in favor of the development of specific antagonists that block both AVP and CRH receptors to decrease the pleasurable component of nicotine, which may be mediated by corticosterone.
authors.affiliation: Division of Endocrinology, Molecular Medicine and Metabolism, Department of Internal Medicine, Charles R. Drew University of Medicine & Sciences-David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
authors.forename: Kabirullah
authors.initials: K
authors.lastname: Lutfy
authors.forename: Otaren
authors.initials: O
authors.lastname: Aimiuwu
authors.forename: Michael
authors.initials: M
authors.lastname: Mangubat
authors.forename: Chang-Sung
authors.initials: CS
authors.lastname: Shin
authors.forename: Namiko
authors.initials: N
authors.lastname: Nerio
authors.forename: Richard
authors.initials: R
authors.lastname: Gomez
authors.forename: Yanjun
authors.initials: Y
authors.lastname: Liu
authors.forename: Theodore C
authors.initials: TC
authors.lastname: Friedman
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D065092:Antidiuretic Hormone Receptor Antagonists; D001127:Arginine Vasopressin / Q000494:pharmacology; D003345:Corticosterone / Q000097:blood*; D003346:Corticotropin-Releasing Hormone / Q000494:pharmacology; D004347:Drug Interactions; D007211:Indoles / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009538:Nicotine / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000494:pharmacology*; D010446:Peptide Fragments / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017483:Receptors, Vasopressin / Q000378:metabolism*
chemical_list: C456029:1-(5-chloro-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl)-4-hydroxy-N,N-dimethyl-2-pyrrolidinecarboxamide; D065092:Antidiuretic Hormone Receptor Antagonists; D007211:Indoles; D018722:Nicotinic Agonists; D010446:Peptide Fragments; D011743:Pyrimidines; D011758:Pyrroles; D011759:Pyrrolidines; D018019:Receptors, Corticotropin-Releasing Hormone; D017483:Receptors, Vasopressin; C103016:antalarmin; D001127:Arginine Vasopressin; C104416:astressin; D009538:Nicotine; D003346:Corticotropin-Releasing Hormone; D003345:Corticosterone