Abstract

Endogenous opioid peptides, including proopiomelanocortin (POMC)-derived beta-endorphin, modulate neurobiological responses to ethanol and administration of ethanol alters the expression of POMC and beta- endorphin. Given that ethanol has direct effects on POMC activity, it is possible that the other POMC-derived peptides, namely the melanocortins (MCs), are also involved with neurobiological responses to ethanol. MC peptides include alpha-melanocyte stimulating hormone (alpha-MSH), which is synthesized in the arcuate nucleus of the hypothalamus, the nucleus of the solitary tract, and the medulla, regions that project to many brain regions of known relevance to alcoholism. Pre-treatment with MC receptor (MCR) agonists reduce heroin self-administration and chronic administration of morphine or cocaine increases MC-4 receptor (MC4R) levels in striatum rats. Interestingly, rats selectively bred for high ethanol consumption have abnormal levels of MC-3 receptor (MC3R) and MC4R in the nucleus accumbens (NAc) and hypothalamus, and we have provided preliminary findings indicating that intracerebroventricular (i.c.v.) infusion of a selective MC4R agonist reduces, while i.c.v. infusion of a non-selective MCR antagonist increases, ethanol drinking by C57BL/6J mice. Hence, the specific aims proposed below will test the guiding hypothesis that MCR signaling modulates ethanol consumption and neurobiological responses to ethanol. Specifically, we will determine if MC3R and/or MC4R signaling limits self-administration of ethanol by mice (Specific Aim 1), if the endogenous MCR antagonist, agouti-related protein (AgRP), promotes ethanol self-administration by mice (Specific Aim 2), if MCR agonists and antagonists influence ethanol consumption by acting on the MC3R and/or MC4R (Specific Aim 3), and if administration of ethanol will increase alpha-MSH and MC3R/MC4R levels while at the same time decrease AgRP levels, a response that could theoretically protect against uncontrolled ethanol drinking (Specific Aim 4).

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
1R01AA015148-01A1
Application #
6985128
Study Section
Neurotoxicology and Alcohol Study Section (NAL)
Program Officer
Grandison, Lindsey
Project Start
2005-08-01
Project End
2009-06-30
Budget Start
2005-08-01
Budget End
2006-06-30
Support Year
1
Fiscal Year
2005
Total Cost
$263,234
Indirect Cost

  Institution

Name
University of North Carolina Chapel Hill
Department
Psychology
Type
Schools of Arts and Sciences
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599

  Publications

Olney, Jeffrey J; Marshall, S Alex; Thiele, Todd E (2018) Assessment of depression-like behavior and anhedonia after repeated cycles of binge-like ethanol drinking in male C57BL/6J mice. Pharmacol Biochem Behav 168:1-7
Companion, Michel A; Thiele, Todd E (2018) Assessment of ventral tegmental area-projecting GABAergic neurons from the bed nucleus of the stria terminalis in modulating binge-like ethanol intake. Eur J Neurosci 48:3335-3343
Burnham, Nathan W; Thiele, Todd E (2017) Voluntary Binge-like Ethanol Consumption Site-specifically Increases c-Fos Immunoexpression in Male C57BL6/J Mice. Neuroscience 367:159-168
Carvajal, Francisca; Lerma-Cabrera, José M; Alcaraz-Iborra, Manuel et al. (2017) Nucleus Accumbens MC4-R Stimulation Reduces Food and Ethanol Intake in Adult Rats Regardless of Binge-Like Ethanol Exposure during Adolescence. Front Behav Neurosci 11:167
Olney, Jeffrey J; Navarro, Montserrat; Thiele, Todd E (2017) The Role of Orexin Signaling in the Ventral Tegmental Area and Central Amygdala in Modulating Binge-Like Ethanol Drinking Behavior. Alcohol Clin Exp Res 41:551-561
Marshall, S Alex; McKnight, Kyle H; Blose, Allyson K et al. (2017) Modulation of Binge-like Ethanol Consumption by IL-10 Signaling in the Basolateral Amygdala. J Neuroimmune Pharmacol 12:249-259
Rinker, Jennifer A; Marshall, S Alex; Mazzone, Christopher M et al. (2017) Extended Amygdala to Ventral Tegmental Area Corticotropin-Releasing Factor Circuit Controls Binge Ethanol Intake. Biol Psychiatry 81:930-940
Sprow, Gretchen M; Rinker, Jennifer A; Lowery-Gointa, Emily G et al. (2016) Lateral hypothalamic melanocortin receptor signaling modulates binge-like ethanol drinking in C57BL/6J mice. Addict Biol 21:835-46
Marshall, S Alex; Casachahua, John D; Rinker, Jennifer A et al. (2016) IL-1 receptor signaling in the basolateral amygdala modulates binge-like ethanol consumption in male C57BL/6J mice. Brain Behav Immun 51:258-67
Navarro, Montserrat; Olney, Jeffrey J; Burnham, Nathan W et al. (2016) Lateral Hypothalamus GABAergic Neurons Modulate Consummatory Behaviors Regardless of the Caloric Content or Biological Relevance of the Consumed Stimuli. Neuropsychopharmacology 41:1505-12

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