Vulnerability to alcoholism is influenced by genetic as well as environmental determinants. This important finding has stimulated a search for biochemical, hormonal, physiological, and genetic markers to identify nonalcoholic individuals at increased risk of developing alcoholism. The hypothalamic-pituitary-adrenal (HPA) axis is altered by ethanol exposure. Furthermore, evidence is mounting which shows that the dynamics of the HPA axis may differ markedly in high-risk compared to low-risk nonalcoholic individuals. However, studies of this problem have not been comprehensive nor conclusive. High risk subjects are defined as persons with a history of alcoholism in the biological father and are referred to as family history positive (FHP). Low-risk subjects are defined as persons with no history of alcoholism in first- or second- degree biological relatives and are referred to as family history negative (FHN). In the present proposal, we shall compare dynamics of the HPA axis in FHP and FHN nonalcoholic subjects. First, we will identify potential differences in the pulsatile mode of ACTH and cortisol release. This will be accomplished by measuring hormone concentrations in blood samples collected at 10-min intervals over a 24-h period. We will apply deconvolution analysis to the 24-h time series to specifically define the individual secretion and clearance rates of ACTH and cortisol in both groups. Regulation of the hypothalamus, pituitary and adrenal glands will be studied after administration of CRH, Cortrosyn, naloxone and placebo in order to test: i) the pituitary corticotropic response to exogenously- administered CRH; ii) the adrenal gland's response to endogenously- generated and exogenously-administered ACTH; iii) and the magnitude of centrally activating the HPA stress response following opiate blockade with naloxone. It is important to determine if the HPA axis can serve as a marker to identify nonalcoholic individuals at increased risk for the future development of alcoholism. Markers for a genetic vulnerability toward alcoholism could be used to select high-risk individuals for primary prevention and allow investigations of environmental factors or pharmacological agents that may prevent expression of alcoholism. Markers may be used in longitudinal studies to determine whether the markers are primary (causally related) or secondary (genetically linked to causal factors). The resultant knowledge will aid in the diagnosis, evaluation, management and prognosis of alcoholism.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA010158-05
Application #
2894069
Study Section
Clinical and Treatment Subcommittee (ALCP)
Project Start
1995-08-01
Project End
2000-07-31
Budget Start
1999-08-01
Budget End
2000-07-31
Support Year
5
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Alvanzo, Anika A H; Wand, Gary S; Kuwabara, Hiroto et al. (2017) Family history of alcoholism is related to increased D2/D3receptor binding potential: a marker of resilience or risk? Addict Biol 22:218-228
Weerts, Elise M; Wand, Gary S; Maher, Brion et al. (2017) Independent and Interactive Effects of OPRM1 and DAT1 Polymorphisms on Alcohol Consumption and Subjective Responses in Social Drinkers. Alcohol Clin Exp Res 41:1093-1104
Crum, Rosa M; La Flair, Lareina; Storr, Carla L et al. (2013) Reports of drinking to self-medicate anxiety symptoms: longitudinal assessment for subgroups of individuals with alcohol dependence. Depress Anxiety 30:174-83
Mahon, Pamela Belmonte; Zandi, Peter P; Potash, James B et al. (2013) Genetic association of FKBP5 and CRHR1 with cortisol response to acute psychosocial stress in healthy adults. Psychopharmacology (Berl) 227:231-41
Wand, Gary S; Weerts, Elise M; Kuwabara, Hiroto et al. (2013) The relationship between naloxone-induced cortisol and delta opioid receptor availability in mesolimbic structures is disrupted in alcohol-dependent subjects. Addict Biol 18:181-92
Kuwabara, Hiroto; McCaul, Mary E; Wand, Gary S et al. (2012) Dissociative changes in the Bmax and KD of dopamine D2/D3 receptors with aging observed in functional subdivisions of the striatum: a revisit with an improved data analysis method. J Nucl Med 53:805-12
Wand, Gary S; Weerts, Elise M; Kuwabara, Hiroto et al. (2012) The relationship between naloxone-induced cortisol and mu opioid receptor availability in mesolimbic structures is disrupted in alcohol dependent subjects. Alcohol 46:511-7
Yang, Xiaoju; Ewald, Erin R; Huo, Yuqing et al. (2012) Glucocorticoid-induced loss of DNA methylation in non-neuronal cells and potential involvement of DNMT1 in epigenetic regulation of Fkbp5. Biochem Biophys Res Commun 420:570-5
Stephens, Mary Ann C; Wand, Gary (2012) Stress and the HPA axis: role of glucocorticoids in alcohol dependence. Alcohol Res 34:468-83
Wand, Gary S; Weerts, Elise M; Kuwabara, Hiroto et al. (2011) Naloxone-induced cortisol predicts mu opioid receptor binding potential in specific brain regions of healthy subjects. Psychoneuroendocrinology 36:1453-9

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