Neuroendocrine Therapy of Alcohol Abuse

Summary

Principal Investigator: DENNIS D contact RASMUSSEN
Abstract: We have developed a rat model in which chronic daily ethanol consumption/daily withdrawal induces hypothalamo-pituitary-adrenal (HPA), brain proopiomelanocortin (POMC) opioid, and behavioral (e.g., anxiety) changes persisting at least 4 weeks after stopping ethanol consumption. These interdependent neuronal, neuroendocrine, and behavioral changes have each been suggested to contribute to alcoholism, and together resemble the HPA+opioid+anxiety syndrome exhibited by abstinent alcoholics, so therapy to block or reverse them could contribute significantly to prevention or treatment of alcoholism. Chronic alcohol abuse also suppresses pineal melatonin secretion in both humans and rats, and plasma metatonin levels remain low during subsequent abstinence. Our preliminary studies suggest that restoration of normal plasma melatonin levels and patterns during and/or after chronic ethanol abuse may reverse some or all of the changes in the HPA+opioid+anxiety syndrome. Thus, our specific aims are to answer the following questions: (1) does melatonin therapy block, delay, or counteract effects of chronic daily ethanol consumption on ethanol dependence, the HPA/POMC axis, and interrelated neuroendocrine mechanisms?; (2) can melatonin therapy during and after ethanol withdrawal prevent HPA/POMC and behavioral changes during abstinence?; and (3) can melatonin therapy decrease elective self-administration of ethanol during chronic daily ethanol consumption, abstinence or repeated deprivation? These three specific aims will be addressed in corresponding studies in which nocturnal melatonin versus control treatments will be administered to rats in liquid diet during chronic daily episodes of ethanol consumption and withdrawal (Study 1), in liquid diet during and after withdrawal from chronic ethanol consumption (Study 2), and in water and ethanol solutions during free-choice drinking of ethanol and intervening deprivation periods (Study 3). Melatonin-induced changes will be assessed as behavioral (dependence, self-administration, sucrose preference, locomotor activity in a novel environment, anxiety-like behavior), endocrine (plasma corticosterone and ACTH levels, plasma corticosterone and ACTH responses to CRF and air-puff startle, plasma catecholamine responses to air-puff startle), and gene expression (forebrain and anterior pituitary POMC gene expression) responses characteristic of, consistent with, or contributing to alcohol abuse and/or relapse.
Funding Period: 2003-05-01 - 2009-04-30
more information: NIH RePORT

Top Publications

  1. pmc Prazosin reduces alcohol drinking throughout prolonged treatment and blocks the initiation of drinking in rats selectively bred for high alcohol intake
    Janice C Froehlich
    Indiana University School of Medicine, Indianapolis, Indiana
    Alcohol Clin Exp Res 37:1552-60. 2013
  2. pmc Combining naltrexone and prazosin in a single oral medication decreases alcohol drinking more effectively than does either drug alone
    Janice C Froehlich
    Indiana University School of Medicine, Indianapolis, Indiana
    Alcohol Clin Exp Res 37:1763-70. 2013
  3. ncbi Olanzapine-induced weight gain and increased visceral adiposity is blocked by melatonin replacement therapy in rats
    Murray A Raskind
    VA Puget Sound Health Care System, Mental Illness Research, Education and Clinical Center, Seattle, WA 98108, USA
    Neuropsychopharmacology 32:284-8. 2007
  4. pmc Acoustic startle amplitude predicts vulnerability to develop post-traumatic stress hyper-responsivity and associated plasma corticosterone changes in rats
    Dennis D Rasmussen
    VA Puget Sound Health Care System, Mental Illness Research, Education and Clinical Center, Seattle, WA 98108, USA
    Psychoneuroendocrinology 33:282-91. 2008
  5. pmc The alpha1-adrenergic receptor antagonist, prazosin, reduces alcohol drinking in alcohol-preferring (P) rats
    Dennis D Rasmussen
    VISN 20 Mental Illness Research Education and Clinical Center, Mental Health Service, Department of Veterans Affairs Medical Center and University of Washington, Seattle, Washington, USA
    Alcohol Clin Exp Res 33:264-72. 2009

Scientific Experts

  • DENNIS D contact RASMUSSEN
  • Janice C Froehlich
  • Brett J Hausauer
  • Murray A Raskind
  • David L Federoff
  • Stephen M Fischer
  • Norman J Crites
  • Andre M Tapp
  • Brianna L Burke

Detail Information

Publications5

  1. pmc Prazosin reduces alcohol drinking throughout prolonged treatment and blocks the initiation of drinking in rats selectively bred for high alcohol intake
    Janice C Froehlich
    Indiana University School of Medicine, Indianapolis, Indiana
    Alcohol Clin Exp Res 37:1552-60. 2013
    ....
  2. pmc Combining naltrexone and prazosin in a single oral medication decreases alcohol drinking more effectively than does either drug alone
    Janice C Froehlich
    Indiana University School of Medicine, Indianapolis, Indiana
    Alcohol Clin Exp Res 37:1763-70. 2013
    ....
  3. ncbi Olanzapine-induced weight gain and increased visceral adiposity is blocked by melatonin replacement therapy in rats
    Murray A Raskind
    VA Puget Sound Health Care System, Mental Illness Research, Education and Clinical Center, Seattle, WA 98108, USA
    Neuropsychopharmacology 32:284-8. 2007
    ....
  4. pmc Acoustic startle amplitude predicts vulnerability to develop post-traumatic stress hyper-responsivity and associated plasma corticosterone changes in rats
    Dennis D Rasmussen
    VA Puget Sound Health Care System, Mental Illness Research, Education and Clinical Center, Seattle, WA 98108, USA
    Psychoneuroendocrinology 33:282-91. 2008
    ..These results suggest that initial pre-stress acoustic startle response can identify subgroups of rats which are predisposed to, or resistant to, developing a PTSD-like syndrome following subsequent trauma...
  5. pmc The alpha1-adrenergic receptor antagonist, prazosin, reduces alcohol drinking in alcohol-preferring (P) rats
    Dennis D Rasmussen
    VISN 20 Mental Illness Research Education and Clinical Center, Mental Health Service, Department of Veterans Affairs Medical Center and University of Washington, Seattle, Washington, USA
    Alcohol Clin Exp Res 33:264-72. 2009
    ..Accordingly, we tested the hypothesis that blockade of alpha(1)-adrenergic receptors will suppress alcohol drinking in rats selectively bred for alcohol preference (P line)...