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Nicotine self-administration differentially regulates hypothalamic corticotropin-releasing factor and arginine vasopressin mRNAs and facilitates stress-induced neuronal activation.

ABSTRACT: Acute nicotine is a potent stimulus for activation of the stress-responsive hypothalamic-pituitary-adrenal (HPA) axis, while chronic nicotine self-administration (SA) desensitizes the ACTH response to self-administered nicotine but cross-sensitizes to mild footshock stress (mFSS). To identify underlying mechanisms, we investigated (1) the effects of chronic nicotine SA on the coexpression of corticotropin-releasing factor (CRF) and arginine vasopressin (AVP) mRNAs, the primary hypothalamic neuropeptides regulating ACTH release, in the parvocellular division of paraventricular nucleus (pcPVN), and (2) mFSS-induced activation of these neurons during nicotine SA. Adult male Sprague Dawley rats were given 23 h/d unlimited access to self-administer nicotine (0.03 mg/kg per injection, i.v.) for 19 d. Brains were double labeled with fluorescence in situ hybridization of CRF and AVP mRNAs and triple labeled after mFSS exposure for CRF and AVP mRNAs and c-Fos protein. Chronic nicotine SA significantly increased AVP mRNA signal and the number of pcPVN AVP-positive (AVP(+)) neurons (twofold to threefold), reduced the number of CRF-positive (CRF(+)) neurons by approximately 60%, but increased pcPVN CRF(+)/AVP(+) neuronal number fivefold. Significantly, although chronic nicotine SA did not affect total c-Fos expression induced by mFSS in pcPVN CRF(+) neurons, the majority of the new CRF(+)/AVP(+) population was activated by this heterotypic stressor. These phenotypic neuronal alterations may provide the pivotal mechanism underlying the capacity of chronically self-administered nicotine to cross-sensitize the HPA response to specific stressors, suggesting that nicotine may augment HPA responsiveness to specific stressors in human smokers.

SUBMITTER: Yu G

PROVIDER: S-EPMC6670662 | biostudies-literature | 2008 Mar

REPOSITORIES: biostudies-literature

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Nicotine self-administration differentially regulates hypothalamic corticotropin-releasing factor and arginine vasopressin mRNAs and facilitates stress-induced neuronal activation.

Yu Guoliang G Chen Hao H Zhao Wenyuan W Matta Shannon G SG Sharp Burt M BM

The Journal of neuroscience : the official journal of the Society for Neuroscience 20080301 11

Acute nicotine is a potent stimulus for activation of the stress-responsive hypothalamic-pituitary-adrenal (HPA) axis, while chronic nicotine self-administration (SA) desensitizes the ACTH response to self-administered nicotine but cross-sensitizes to mild footshock stress (mFSS). To identify underlying mechanisms, we investigated (1) the effects of chronic nicotine SA on the coexpression of corticotropin-releasing factor (CRF) and arginine vasopressin (AVP) mRNAs, the primary hypothalamic neuro ...[more]

PMID: 18337407

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Project description:To limit excessive glucocorticoid secretion following hypothalamic-pituitary-adrenal (HPA) axis stimulation, circulating glucocorticoids inhibit corticotropin-releasing hormone (CRH) expression in paraventricular nucleus (PVN) neurons. As HPA function differs between sexes and depends on circulating estradiol (E2) levels in females, we investigated sex/estrous stage-dependent glucocorticoid regulation of PVN Crh. Using NanoString nCounter technology, we first demonstrated that adrenalectomized (ADX'd) diestrous female (low E2), but not male or proestrous female (high E2), mice exhibited a robust decrease in PVN CRH mRNA following 2-day treatment with the glucocorticoid receptor (GR) agonist RU28362. Immunohistochemical analysis of PVN CRH neurons in Crh-IRES-Cre;Ai14 mice, where TdTomato fluorescence permanently tags CRH-expressing neurons, showed similarly abundant co-expression of GR-immunoreactivity in males, diestrous females, and proestrous females. However, we identified sex/estrous stage-related glucocorticoid regulation or expression of GR transcriptional coregulators. Out of 17 coregulator genes examined using nCounter multiplex analysis, mRNAs that were decreased by RU28362 in ADX'd mice in a sex/estrous stage-dependent fashion included: GR (males = diestrous females > proestrous females), signal transducer and activator of transcription 3 (STAT3) (males < diestrous = proestrous), and HDAC1 (males < diestrous > proestrous). Steroid receptor coactivator 3 (SRC-3), nuclear corepressor 1 (NCoR1), heterogeneous nuclear ribonucleoprotein U (hnrnpu), CREB binding protein (CBP) and CREB-regulated transcription coactivator 2 (CRTC2) mRNAs were lower in ADX'd diestrous and proestrous females versus males. Additionally, most PVN CRH neurons co-expressed methylated CpG binding protein 2 (MeCP2)-immunoreactivity in diestrous female and male Crh-IRES-Cre;Ai14 mice. Our findings collectively suggest that GR's sex-dependent regulation of PVN Crh may depend upon differences in the GR transcriptional machinery and an underlying influence of E2 levels in females.

Project description:Numerous studies on humans and animals have indicated that the corticotrophin-releasing hormone (CRH) and arginine vasopressin (AVP) stimulate both individually and synergistically secretion of adrenocorticotropic hormone (ACTH) by corticotropic cells in anterior pituitary. With aim to characterize and better comprehend the mechanisms underlying the effects of AVP on Hypothalamic-Pituitary-Adrenal (HPA) axis ultradian dynamics, AVP is here incorporated into our previously proposed stoichiometric model of HPA axis in humans. This extended nonlinear network reaction model took into account AVP by: reaction steps associated with two separate inflows of AVP into pituitary portal system, that is synthesized and released from hypothalamic parvocellular and magnocellular neuronal populations, as well as summarized reaction steps related to its individual and synergistic action with CRH on corticotropic cells. To explore the properties of extended model and its capacity to emulate the effects of AVP, nonlinear dynamical systems theory and bifurcation analyses based on numerical simulations were utilized to determine the dependence of ultradian oscillations on rate constants of the inflows of CRH and AVP from parvocellular neuronal populations, the conditions under which dynamical transitions occur due to their synergistic action and, moreover, the types of these transitions. The results show that under certain conditions, HPA system could enter into oscillatory dynamic states from stable steady state and vice versa under the influence of synergy reaction rate constant. Transitions between these dynamical states were always through supercritical Andronov-Hopf bifurcation point. Also, results revealed the conditions under which amplitudes of ultradian oscillations could increase several-fold due to CRH and AVP synergistic stimulation of ACTH secretion in accordance with results reported in the literature. Moreover, results showed experimentally observed superiority of CRH as a stimulator of ACTH secretion compared to AVP in humans. The proposed model can be very useful in studies related to the role of AVP and its synergistic action with CRH in life-threatening circumstances such as acute homeostasis dynamic crisis, autoimmune inflammations or severe hypovolemia requiring instant or several-days sustained corticosteroid excess levels. Moreover, the model can be helpful for investigations of indirect AVP-induced HPA activity by exogenously administered AVP used in therapeutic treatment.

Dataset Information

Nicotine self-administration differentially regulates hypothalamic corticotropin-releasing factor and arginine vasopressin mRNAs and facilitates stress-induced neuronal activation.

Publications

Nicotine self-administration differentially regulates hypothalamic corticotropin-releasing factor and arginine vasopressin mRNAs and facilitates stress-induced neuronal activation.

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