Alcoholism is a chronically relapsing psychiatric disorder affecting approximately 10% of the western world population (WHO report on alcohol 2011). However, the majority of people can consume alcohol socially throughout adulthood without developing alcohol abuse disorders, and while many students binge drink during their college years, most of them will not develop alcoholism. This suggests the existence of endogenous homeostatic pathways that counteract neuroadaptations and delay or prevent the development of alcohol addiction. We generated evidence to suggest that BDNF in the dorsal striatum is part of such a protective homeostatic mechanism that gates the level of alcohol (ethanol) intake. We further found that long-term excessive consumption of ethanol in rodents results in a breakdown of this valuable pathway. Here, we plan to test the hypotheses that: (a) epigenetic modifications of the BDNF gene and/or BDNF receptor composition underlie both the positive role of BDNF as well as the cessation of this pathway to function, and (b), that the innate level and/or function of BDNF determines whether or not rodents (and, thus, possibly humans) will transition from moderate (social drinkers) to excessive binge drinkers. To test these hypotheses, we will use in vivo paradigms that mimic human social drinking and excessive binge drinking of alcohol in rodents. We will use state-of-the-art molecular approaches in combination with pharmacological manipulations to determine whether the protective role of BDNF can be restored to prevent or attenuate the escalation of excessive ethanol consumption. Results generated from these studies will expand our knowledge on this highly important signaling pathway. Furthermore, these studies will lead to both the development of new therapeutic approaches as well as the identification of a new biomarker for the identification of humans who are at risk of developing addiction.
This proposal is aimed to study the role of a brain protein (BDNF) in alcohol's actions on the adult brain. Previously we showed that BDNF acts to delay the transition from moderate to excessive consumption of alcohol in rodents. We also found that this protective pathway breaks down in response to long-term excessive alcohol drinking. Here we plan to understand the mechanisms underlying the actions of the valuable action of BDNF as well as the mechanisms that lead to, and result from, it breaking down. We will also test the hypothesis that the level and/or function of BDNF determines whether subjects are at risk to develop alcohol abuse disorders. Results generated from this proposal may open new directions for the development of new therapies, and may identify a new biomarker for the identification of subject at risk to develop alcohol abuse disorder.
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|Darcq, E; Warnault, V; Phamluong, K et al. (2015) MicroRNA-30a-5p in the prefrontal cortex controls the transition from moderate to excessive alcohol consumption. Mol Psychiatry 20:1219-31|
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