Although much has been learned about molecular sites of action for ethanol, there remains few effective treatments for alcoholism. Naltrexone (NTX) reduces recidivism and ethanol consumption in alcoholics. NTX, an un-selective opioid antagonist, has also been shown to decrease ethanol drinking behavior in animal models, including blocking increased ethanol drinking in a model of relapse drinking, the ethanol deprivation effect (EDE). The molecular mechanism(s) for these responses are not entirely understood. We hypothesize that by studying genome-wide gene expression patterns associated with naltrexone action, EDE and naltrexone effects on EDE, we might gain novel insight into mechanisms relevant to relapse drinking behavior. In this project high-density oligonucleotide arrays will first be used to characterize gene expression patterns evoked by NTX in naive C57BL/6 mice. Ventral tegmental area, nucleus accumbens and medial prefrontal cortex brain regions in C57BL/6 mice will be studied. Expression profiles of NTX will also be compared to those from two other agents that decrease ethanol drinking or the EDE, acamproste and MPEP, an inhibitor of the mGluR5 glutamate receptor.
Aim two will then use arrays to study action of NTX on gene expression patterns evoked by ethanol-deprivation in a 2-bottle choice model of ethanol self administration. Through data mining the combined expression patterns related to NTX action in aims 1-2, we will then characterize particular candidate genes in regard to cellular patterns of their expression changes.
In Aim 3, candidate genes will be evaluated for their role in ethanol drinking or the EDE in a 2-bottle choice model. Pharmacological or genetic (viral vectors, antisense oligonucleotides) means will be used to alter the expression of candidate genes prior to behavioral testing. These studies should provide novel insight into the mechanisms of the EDE and mechanisms of NTX action in altering ethanol drinking behavior. Together, these findings may identify novel targets for therapeutic intervention in alcoholism.
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