Recent evidence suggests that corticotropin releasing factor (CRF) is involved in excessive voluntary ethanol consumption in ethanol dependent animals, as well as stress-induced increases in ethanol consumption in nondependent animals, via CRF1 and CRF2 receptor signaling. Indeed, recent research explores the use of drugs that target CRF as a potential treatment for conditions associated with excessive alcohol consumption. Since CRF signaling appears to underlie neurobiological responses to ethanol involving histories of stress exposure or dependence, it is possible that increased ethanol consumption associated with these responses reflects significant neuroadaptations in common brain regions containing CRF, like the amygdala. Therefore, the guiding hypothesis of this proposal is that increases in ethanol consumption associated with stress and ethanol dependence are mediated by CRF signaling in the amygdala via the CRF1 and CRF2 receptors. To investigate the role of CRF1 and CRF2 signaling in the expression of dependence-induced increases in ethanol consumption in C57BL/6J mice, the CRF1 receptor antagonist CP-154,526 will be administered peripherally and centrally and the CRF2 receptor agonist will be administered centrally following exposure to multiple cycles of ethanol vapor and withdrawal. To investigate the role of amygdalar CRF in the acquisition/expression of dependence-induced increases in ethanol consumption in C57BL/6J mice, site-directed infusions of CRF-SAP will be administered prior to exposure to multiple cycles of ethanol vapor and withdrawal and limited free access to ethanol. To investigate the role of amygdalar CRF in the acquisition/expression of stress-induced increases in ethanol consumption in BALB/cJ mice, site-directed infusions of CRF-SAP will be administered prior to exposure to forced swim stress and continuous free access to ethanol. The role of CRF signaling, via the CRF1 and CRF2 receptors, as well as amygdalar CRF signaling will be further assessed by these experiments. Although there is some evidence to suggest CRF signaling is involved in dependence-induced ethanol consumption in mice, to date there are only a few published reports investigating the role of the CRF1R, and, to the best of our knowledge, no published reports investigating the role of the CRF2R in mice with a history of ethanol dependence. Additionally, to date, the role of amygdalar CRF in stress-induced ethanol consumption has not been investigated. Therefore, these experiments will extend the current literature on the role of CRF in ethanol-related phenotypes to mice and thereby aid in the development of clinical and pharmacological treatments for disorders characterized by excessive ethanol consumption. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
1F31AA017803-01A1
Application #
7613627
Study Section
Special Emphasis Panel (ZAA1-CC (12))
Program Officer
Grandison, Lindsey
Project Start
2008-09-01
Project End
2011-08-31
Budget Start
2008-09-01
Budget End
2009-08-31
Support Year
1
Fiscal Year
2008
Total Cost
$29,635
Indirect Cost
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
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
Lowery-Gionta, Emily G; Navarro, Montserrat; Li, Chia et al. (2012) Corticotropin releasing factor signaling in the central amygdala is recruited during binge-like ethanol consumption in C57BL/6J mice. J Neurosci 32:3405-13
Thiele, Todd E (2012) Commentary: studies on binge-like ethanol drinking may help to identify the neurobiological mechanisms underlying the transition to dependence. Alcohol Clin Exp Res 36:193-6
Sparrow, Angela M; Lowery-Gionta, Emily G; Pleil, Kristen E et al. (2012) Central neuropeptide Y modulates binge-like ethanol drinking in C57BL/6J mice via Y1 and Y2 receptors. Neuropsychopharmacology 37:1409-21
Ryabinin, Andrey E; Tsoory, Michael M; Kozicz, Tamas et al. (2012) Urocortins: CRF's siblings and their potential role in anxiety, depression and alcohol drinking behavior. Alcohol 46:349-57
Sprow, Gretchen M; Thiele, Todd E (2012) The neurobiology of binge-like ethanol drinking: evidence from rodent models. Physiol Behav 106:325-31
Navarro, Montserrat; Lerma-Cabrera, Jose M; Carvajal, Francisca et al. (2011) Assessment of voluntary ethanol consumption and the effects of a melanocortin (MC) receptor agonist on ethanol intake in mutant C57BL/6J mice lacking the MC-4 receptor. Alcohol Clin Exp Res 35:1058-66
Lowery, Emily G; Spanos, Marina; Navarro, Montserrat et al. (2010) CRF-1 antagonist and CRF-2 agonist decrease binge-like ethanol drinking in C57BL/6J mice independent of the HPA axis. Neuropsychopharmacology 35:1241-52
Lowery, Emily G; Thiele, Todd E (2010) Pre-clinical evidence that corticotropin-releasing factor (CRF) receptor antagonists are promising targets for pharmacological treatment of alcoholism. CNS Neurol Disord Drug Targets 9:77-86
Lowery, Emily G; Thiele, Todd E (2009) Pre-Clinical Evidence that Corticotropin-Releasing Factor (CRF) Receptor Antagonists are Promising Targets for Pharmacological Treatment of Alcoholism. CNS Neurol Disord Drug Targets :