Alcoholism can be viewed as a motivational disorder that results from alterations in brain systems for ingestive behavior. Evidence supports a strong link between the hypothalamic feeding peptide galanin (GAL) and dietary fat. Our research demonstrated that ethanol increases the expression of GAL and that GAL stimulates ethanol intake. Together, these findings suggest a positive feedback loop between GAL and ethanol, with dietary fat as an initiating factor. The behavioral output of this system releases dopamine (DA) in the nucleus accumbens (NAc). This has led to extensive preliminary studies and the following 5 Aims.
Aim 1 is to test the hypothesis that hypothalamic, fat-stimulated peptides, including GAL, orexins (ORX) and opioids, are enhanced by ethanol consumption. These peptides can be distinguished from others, such as, neuropeptide Y and agouti-related protein, which are related to carbohydrate intake and reduced by ethanol consumption.
Aim 2 is to inject these fat-stimulated peptides into the hypothalamus to reveal a causal role in ethanol intake and ethanol-seeking behavior. We will also expand on new results suggesting that GAL and ORX facilitate opioid gene expression and function.
Aim 3 tests the possibility that dietary fat increases ethanol intake by elevating circulating triglycerides, which in turn enhance expression of fat-stimulated peptides that promote ethanol intake.
Aim 4 investigates mice with targeted disruptions of the GAL gene that may alter their ethanol preference and their responsiveness to the stimulatory effect of fat on ethanol intake Aim 5 suggests that hypothalamic peptides act through the NAc to cause an increase in DA and GABA release, which stimulates ethanol intake. These peptides simultaneously reduce NAc acetylcholine and glutamate thereby disinhibiting ethanol-seeking behavior. In summary, this grant tests the novel hypothesis that ethanol, through its impact on circulating triglycerides, stimulates gene expression of hypothaiamic fat- stimulated peptides that potentiate the intake of more ethanol via the release of DA and GABA in the NAc.
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