Abstract

The purpose of this proposal is to explore the relationship between stress response, alcohol drinking and neuroactive steroid levels in primate plasma. A large body of evidence in rodent models suggests that GABAergic neuroactive steroids contribute to ethanol sensitivity, tolerance, protection against dependence and reduces excessive alcohol consumption. Primates synthesize different steroid precursors and exhibit 5preductase activity that necessitates the development of a highly sensitive GCMS assay to measure both 3 The first aim will develop a highly sensitive GCMS assay to measure both 3a5a- and 3a5[3- reduced metabolites of progesterone, deoxycorticosterone and cortisol in primate plasma.
The second aim will determine if HPA axis stimulation at the level of the hypothalamus (naloxone administration), pituitary (oCRF infusion) or adrenal gland (ACTH infusion after dexamethasone pretreatment) and systemic ethanol administration alters the levels of GAB A receptor neuroactive steroids in plasma of monkeys.
The third aim will investigate the effect of schedule-induced drinking and ad lib ethanol consumption for one year on both the precursor steroids and neuroactive steroid levels following HPA axis stimulation using the same challenge procedure.
The fourth aim will provide a service core to other INIA investigators exploring the effects of chronic ethanol exposure on neurosteroid levels in mice, macaque monkeys and alcoholic humans. Each investigator will explore if neuroactive steroid responses to ethanol or HPA axis stimulation are altered by chronic ethanol history or predictive of voluntary alcohol consumption levels. ? ? ?

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01AA016672-02
Application #
7350262
Study Section
Special Emphasis Panel (ZAA1-DD (71))
Program Officer
Greenwell, Thomas
Project Start
2007-02-05
Project End
2012-01-31
Budget Start
2008-02-01
Budget End
2009-01-31
Support Year
2
Fiscal Year
2008
Total Cost
$259,446
Indirect Cost

  Institution

Name
University of North Carolina Chapel Hill
Department
Psychiatry
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599

  Publications

Hasirci, Ahmet Sait; Maldonado-Devincci, Antoniette M; Beattie, Matthew C et al. (2017) Cellular GABAergic Neuroactive Steroid (3?,5?)-3-Hydroxy-Pregnan-20-One (3?,5?-THP) Immunostaining Levels Are Increased in the Ventral Tegmental Area of Human Alcohol Use Disorder Patients: A Postmortem Study. Alcohol Clin Exp Res 41:299-311
Maldonado-Devincci, Antoniette M; Cook, Jason B; O'Buckley, Todd K et al. (2014) Chronic intermittent ethanol exposure and withdrawal alters (3?,5?)-3-hydroxy-pregnan-20-one immunostaining in cortical and limbic brain regions of C57BL/6J mice. Alcohol Clin Exp Res 38:2561-71
Cook, Jason B; Nelli, Stephanie M; Neighbors, Mackenzie R et al. (2014) Ethanol alters local cellular levels of (3?,5?)-3-hydroxypregnan-20-one (3?,5?-THP) independent of the adrenals in subcortical brain regions. Neuropsychopharmacology 39:1978-87
Cook, Jason B; Werner, David F; Maldonado-Devincci, Antoniette M et al. (2014) Overexpression of the steroidogenic enzyme cytochrome P450 side chain cleavage in the ventral tegmental area increases 3?,5?-THP and reduces long-term operant ethanol self-administration. J Neurosci 34:5824-34
Porcu, Patrizia; Morrow, A Leslie (2014) Divergent neuroactive steroid responses to stress and ethanol in rat and mouse strains: relevance for human studies. Psychopharmacology (Berl) 231:3257-72
Cook, Jason B; Dumitru, Ana Maria G; O'Buckley, Todd K et al. (2014) Ethanol administration produces divergent changes in GABAergic neuroactive steroid immunohistochemistry in the rat brain. Alcohol Clin Exp Res 38:90-9
Fish, Eric W; Whitman, Buddy J; DiBerto, Jeff F et al. (2014) Effects of the neuroactive steroid allopregnanolone on intracranial self-stimulation in C57BL/6J mice. Psychopharmacology (Berl) 231:3415-3423
Porcu, Patrizia; O'Buckley, Todd K; Song, Soomin C et al. (2011) Genetic analysis of the neurosteroid deoxycorticosterone and its relation to alcohol phenotypes: identification of QTLs and downstream gene regulation. PLoS One 6:e18405
Porcu, Patrizia; O'Buckley, Todd K; Alward, Sarah E et al. (2010) Differential effects of ethanol on serum GABAergic 3alpha,5alpha/3alpha,5beta neuroactive steroids in mice, rats, cynomolgus monkeys, and humans. Alcohol Clin Exp Res 34:432-42
Morrow, A Leslie; Biggio, Giovanni; Serra, Mariangela et al. (2009) The role of neuroactive steroids in ethanol/stress interactions: proceedings of symposium VII at the Volterra conference on alcohol and stress, May 2008. Alcohol 43:521-30

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