Alcoholism can be viewed as a motivational disorder resulting from alterations in brain systems for ingestive behavior. Preliminary results show that ethanol injected into rats markedly increases the mRNA and production of the feeding-stimulatory peptide, galanin (GAL). This is confirmed with voluntary intake of alcohol, which stimulates GAL message at the same, specific hypothalamic sites. Moreover, GAL mRNA and peptide levels correlate with the initial predisposition to consume alcohol. It is known that GAL injected into the hypothalamus stimulates dopamine (DA) release in the nucleus accumbens (NAc), thereby linking GAL to the addiction process. To counter this process, peptides are needed to oppose GAL. Preliminary results show that cholecystokinin (CCK) has the opposite effect of GAL on accumbens DA, and in addition, CCK- releases accumbens acetylcholine (ACh), which helps to inhibit behavior and can even induce an aversion. The satiety hormone, leptin, is interesting because it inhibits GAL expression in the same nuclei where alcohol acts. Alcohol normally releases DA in the NAc, like GAL. When the animal becomes alcoholic, naloxone induces withdrawal and releases ACh, like CCK, implicating GAL and CCK in opioid-induced reinforcement and withdrawal. Opioids in the NAc control output cells that use the neurotransmitter GABA. A new technique for capillary electrophoresis is being used for repeated measurements of GABA in rats while they drink alcohol. Therefore, the following valuable experiments are proposed: 1) The effect of alcohol injection will be measured and localized for GAL mRNA and immunoreactivity in the hypothalamus and related areas, with neuropeptide Y for comparison. 2) GAL and NPY messages will be related to voluntary intake of alcohol and the stages of addiction. 3) GAL expression will be correlated with the predisposition to drink alcohol. 4) Experiments will explore the impact of GAL injections on animals' manifest desire to drink alcohol. 5) GAL will be tested for its effects on DA and ACh release in the NAc motivational system, in naive and alcohol-treated rats. 6) As a means to inhibit the effects of GAL and alcohol, the satiety peptides, CCK and leptin, will be tested. 7) Parallel studies will test opioid receptor antagonists. 8) Then, GABA release will be measured in 1-min samples from the NAc and hypothalamus while the animals drink. The outcome of these studies will provide a better understanding of hypothalamic peptides in the control of motivation for alcohol and the genesis of alcoholism.
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