The brain's opioid system plays an important role in reward mechanisms and recently it has been targeted in treatment efforts using the opiate antagonist, naltrexone. Our recent findings provide strong evidence for dampened CNS opioid activity in the offspring of alcoholics, an abnormality predating heavy alcohol drinking. However, we know little about the underlying differences in the endogenous opioid system between healthy individuals and the alcohol dependent population. Indeed, little human data exists which address the question ofwhether there are abnormalities in the opioid system in alcohol dependent, individuals and whether such differences are a consequence of genetic determinants, or a consequence of heavy alcohol use or a combination of both. The lack of knowledge of the role of endogenous opioids in alcoholism lias been due primarily to difficulties in making measurements in human subjccis. However, the hypothalamic-pituitary-adrenal (HPA) axis can provide useful measurements of endogenous opioid activity. This is because the HPA axis is modulated by hypothalamic opioid activity. Induction of opioid receptor blockade stimulates the HPA axis allowing a noninvasive, functional assessment of the hypothalamic opioid system . We propose to utilize this neuroendocrine strategy to measure opioid activity in alcohol dependent persons at various stages of their disorder.
In Specific Aim 1, we will measure opioid activity in alcohol dependent individuals in early abstinencemonitored on the CRC and compare to controls. We will determine each subject's sensitivity to naloxone by venerating a dose response curve and then calculating the dose of naloxone required to induce a half-maxima!hormone response (ED50). We will relate this measurement of opioid activityto behavioral and physiologicalmeasures such as alcohol craving, mood and alcohol withdrawal symptoms.Alcoholics and controls will be equally representedby fami.y history positive (FHP) and family history negative (FHN) subjects.
In Specific Aim II , we will measurethe change in ED50 values during eight weeks of supervised abstinenceon the CRC in alcohol dependent subjects compared to the control group.
In Specific Aim 3 we will determine if naloxone sensitivity (ED50) measurementsobtained during controlled abstinence on the CRC predicts the time to relapse after discharge. This study will provide information on the activity of the endogenous opioid system as a function of alcoholism and as a function of family history of alcoholism. These findings will impact our understanding of the neurochemical factors that predispose to- and maintain heavy alcohol drinking. PERFORMANCE S TE($) (organization, city, state} The Johns Hopkins University School of Medicine Baltimore, Maryland KEY PERSONNEL. See inslaiclions on Page 11. Usecontinuation pagesasnccdsd o provide the required informal; Dn inthe format shown below. Name Organization Role on Project Gary Wand, M. D. Mary McCaul, Ph. D. Mark Peyrot, Ph D. Deborah Mangold The Johns Hopkins University Principal Investigator The Johns Hopkins University Co-Investigator Loyola College Statistician, n t Consultant, & Co-Investigator The Johns Hopkins University Post Doctoral Fellow PHS 398(Rev. 5/95) Page2 BB Number pages consecutively at the bottom throughout the application. Do not usesuffixes suchas 3a, 3b. Document 1 CC Prj^A| Investigator/ProgramDirector (Last, first,middle):. Typethe nameofthe principalinvestigator/programdireclorat thetopofeachprinted pageandeachcontinuation page.(Fortype specifications, see instructions onpage 6.) RESEARCH GRANT TABLE OF CONTENTS PageNumbers Face Page 1 Description,

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37AA012303-10
Application #
7474768
Study Section
Special Emphasis Panel (NSS)
Program Officer
Grandison, Lindsey
Project Start
1999-07-01
Project End
2011-07-31
Budget Start
2008-08-01
Budget End
2011-07-31
Support Year
10
Fiscal Year
2008
Total Cost
$415,321
Indirect Cost
Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Zhao, Jichang; Li, Daqing; Sanhedrai, Hillel et al. (2016) Spatio-temporal propagation of cascading overload failures in spatially embedded networks. Nat Commun 7:10094
Weerts, Elise M; Wand, Gary S; Kuwabara, Hiroto et al. (2014) Association of smoking with ?-opioid receptor availability before and during naltrexone blockade in alcohol-dependent subjects. Addict Biol 19:733-42
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
Weerts, Elise M; McCaul, Mary E; Kuwabara, Hiroto et al. (2013) Influence of OPRM1 Asn40Asp variant (A118G) on [11C]carfentanil binding potential: preliminary findings in human subjects. Int J Neuropsychopharmacol 16:47-53
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
Rosenberg, P B; Mielke, M M; Han, D et al. (2012) The association of psychotropic medication use with the cognitive, functional, and neuropsychiatric trajectory of Alzheimer's disease. Int J Geriatr Psychiatry 27:1248-57
Stephens, Mary Ann C; McCaul, Mary E; Weerts, Elise M et al. (2012) Serotonin transporter-linked polymorphic region (5-HTTLPR) genotype is associated with cortisol responsivity to naloxone challenge. Psychopharmacology (Berl) 224:223-30
Stephens, Mary Ann C; Wand, Gary (2012) Stress and the HPA axis: role of glucocorticoids in alcohol dependence. Alcohol Res 34:468-83
Weerts, Elise M; Wand, Gary S; Kuwabara, Hiroto et al. (2011) Positron emission tomography imaging of mu- and delta-opioid receptor binding in alcohol-dependent and healthy control subjects. Alcohol Clin Exp Res 35:2162-73
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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