Hypothalamic systems known to have a primary role in food intake are also important in controlling the consumption of ethanol. Our previous studies have shown that peptide systems in the hypothalamic paraventricular nucleus (PVN) become engaged in stimulating ethanol intake, which in turn feeds back to further increase the expression of these same peptides. More recently, we have begun to examine the perifornical lateral hypothalamus (PFLH) and have identified marked differences from the PVN in the functioning of the peptides in this area as they relate to ethanol consumption. Building on this information and the extensive preliminary results developed from it, we plan to test in Sprague-Dawley rats the novel idea that hypothalamic peptides expressed in the PFLH, specifically orexin (OX) and melanin-concentrating hormone (MCH), have different functions from those in the PVN, enkephalin (ENK) and galanin (GAL), in enhancing ethanol drinking. Whereas PFLH peptides initiate episodes of ethanol intake, PVN peptides prolong periods of ethanol consumption.
Aim 1 is to examine the behavioral functions of these peptides in the PFLH and PVN, as they trigger or sustain ethanol intake, interact in this process, and respond in turn to the changes in ethanol consumption and corresponding blood ethanol concentrations.
Aim 2 is to determine whether these peptides are disturbed in animals predicted to be at risk for overconsuming ethanol based on different behavioral- and bio-markers. We will test the hypothesis that animals at risk have disturbed expression of peptides in the hypothalamus prior to learning to drink ethanol or before an anticipated, large bout of ethanol consumption.
This aim will also examine ENK in the mesolimbic dopamine (DA) system, which is intimately involved in controlling the ingestion of rewarding substances.
Aim 3 is to determine whether animals at risk for overconsuming ethanol, due to prenatal exposure, exhibit disturbances in in utero development of these peptide systems that cause increased expression of the peptides and long-term overconsumption in the offspring. Lastly, Aim 4 is to investigate the hypothesis that neurochemical feedback signals to the PFLH compared to the PVN, via DA, -aminobutyric acid (GABA), glutamate (GLUT) and ENK inputs, have opposite effects on the local peptide systems that determine how they influence ethanol drinking behavior. As pharmacological therapies used to treat alcoholism act in part through these neurochemical control systems, we will test whether medications more effective in treating relapse in humans, seen as analogous to initiation of drinking, are working through the PFLH peptide systems;in contrast, those therapies more effective in treating ongoing excessive consumption, analogous to prolongation of drinking, are working through the PVN peptide systems. Collectively, these 4 Aims will provide significant, new information regarding the involvement and regulation of two hypothalamic areas and their local peptide systems, as they control patterns of ethanol drinking, contribute to alcohol abuse, and mediate the actions of medications in treating relapse and ongoing drinking in humans.

Public Health Relevance

This project will investigate how brain mechanisms that normally start and maintain eating become dangerously engaged in frequent and prolonged bouts of drinking alcohol. We will identify neuropeptides that start a drinking bout and those that prolong it;characterize disturbances in the brains of animals at risk for excessive alcohol consumption;investigate how prenatal exposure to alcohol programs these systems to increase alcohol intake later in life;and characterize neurotransmitter inputs and medicines that control these peptides. These studies of neural mechanisms in animals will provide useful information on how to predict and prevent overconsumption of alcohol and may help in designing drugs that can be used in the treatment of alcohol-use disorder.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA012882-11
Application #
8374129
Study Section
Neurotoxicology and Alcohol Study Section (NAL)
Program Officer
Grakalic, Ivana
Project Start
2001-07-01
Project End
2015-11-30
Budget Start
2012-12-01
Budget End
2013-11-30
Support Year
11
Fiscal Year
2013
Total Cost
$353,633
Indirect Cost
$144,383
Name
Rockefeller University
Department
Psychiatry
Type
Other Domestic Higher Education
DUNS #
071037113
City
New York
State
NY
Country
United States
Zip Code
10065
Barson, Jessica R; Leibowitz, Sarah F (2016) Hypothalamic neuropeptide signaling in alcohol addiction. Prog Neuropsychopharmacol Biol Psychiatry 65:321-9
Chang, G-Q; Karatayev, O; Lukatskaya, O et al. (2016) Prenatal fat exposure and hypothalamic PPAR β/δ: Possible relationship to increased neurogenesis of orexigenic peptide neurons. Peptides 79:16-26
Poon, Kinning; Barson, Jessica R; Ho, Hui T et al. (2016) Relationship of the Chemokine, CXCL12, to Effects of Dietary Fat on Feeding-Related Behaviors and Hypothalamic Neuropeptide Systems. Front Behav Neurosci 10:51
Sterling, M E; Chang, G-Q; Karatayev, O et al. (2016) Effects of embryonic ethanol exposure at low doses on neuronal development, voluntary ethanol consumption and related behaviors in larval and adult zebrafish: Role of hypothalamic orexigenic peptides. Behav Brain Res 304:125-38
Chang, G-Q; Karatayev, O; Leibowitz, S F (2015) Prenatal exposure to ethanol stimulates hypothalamic CCR2 chemokine receptor system: Possible relation to increased density of orexigenic peptide neurons and ethanol drinking in adolescent offspring. Neuroscience 310:163-75
Barson, Jessica R; Leibowitz, Sarah F (2015) GABA-induced inactivation of dorsal midline thalamic subregions has distinct effects on emotional behaviors. Neurosci Lett 609:92-6
Sterling, M E; Karatayev, O; Chang, G-Q et al. (2015) Model of voluntary ethanol intake in zebrafish: effect on behavior and hypothalamic orexigenic peptides. Behav Brain Res 278:29-39
Barson, Jessica R; Poon, Kinning; Ho, Hui Tin et al. (2015) Substance P in the anterior thalamic paraventricular nucleus: promotion of ethanol drinking in response to orexin from the hypothalamus. Addict Biol :
Karatayev, Olga; Lukatskaya, Olga; Moon, Sang-Ho et al. (2015) Nicotine and ethanol co-use in Long-Evans rats: Stimulatory effects of perinatal exposure to a fat-rich diet. Alcohol 49:479-89
Barson, Jessica R; Ho, Hui Tin; Leibowitz, Sarah F (2015) Anterior thalamic paraventricular nucleus is involved in intermittent access ethanol drinking: role of orexin receptor 2. Addict Biol 20:469-81

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