This Competitive Revision Application is submitted in response to NOT-OD-09-058, """"""""NIH Announces the Availability of Recovery Act Funds for Competitive Revision Applications"""""""". The parent funded grant is 1R01AA016157, entitled """"""""Brain Biomarkers of Alcoholism and Abstinence"""""""". Alcoholism is one of the most overwhelming problems facing society today. Alcoholism has been defined as the compulsive, uncontrolled use of ethanol regardless of the physical or social consequences, as well as a strong tendency to relapse when abstinent. The cost to society, in terms of both health and social disruption is enormous. While significant advances in our understanding of alcoholism have been made, our knowledge is far from complete. Much further research is needed to elucidate the mechanisms responsible. Thus, an experimental focus on blocking the expression of behaviors motivated by the overwhelming need to use drugs and the intense craving for drugs in their absence would have a more immediate and dramatic impact on the damage to health and society caused by addictive drugs. The goals of the parent grant are: 1) to delineate brain biomarkers that indicate the neurobiological mechanisms responsible for increased alcohol intake;and 2) to define brain biomarkers associated with relapse. The hypotheses being tested are: 1) Sufficient exposure to alcohol leads to changes in specific elements of the extended amygdala that produce elevations in the hedonic set point. In turn, this leads to progressive elevation in ethanol intake and a propensity to relapse during abstinence;and 2) Self-administration of ethanol coupled with passive administration causes changes in protein expression levels and function more characteristic of the addictive process than passive administration alone.
The Specific Aims designed to test these hypotheses are: 1) To examine the effects of ethanol dependence on protein expression and modification with a focus on changes associated with ethanol reinforcement;and 2) To determine long-lasting changes in protein expression and modification associated with vulnerability to relapse upon re-exposure to ethanol. This competitive revision will expand the scope and objectives of our grant by investigating and validating a particularly promising biomarker, platelet-derived growth factor receptor-beta (PDGFR2). We will test a completely new hypothesis, that PDGFR2 antagonism can reverse the neuroplasticity that drives alcoholism. This hypothesis will be tested by accomplishing the following Specific Aim: Determining the effect of PDGFR2 antagonism on the escalation of ethanol self- administration after previous drug exposure using a cutting-edge rat model of alcoholism and relapse. This set of experiments will take our grant to the next level, rapidly transforming it from a """"""""discovery"""""""" project into a focused, hypothesis-testing proposal. This was our long-term objective when writing the parent grant. This revision would enable us to markedly accelerate our progress toward this objective, as well as creating new jobs and permitting job retention. We also hope that this unique and innovative proposal will ultimately have a major impact on the problem of alcoholism and result in major benefits for health and society.
Alcoholism is one of the most devastating diseases in the world. This project consists of the behavioral and biochemical validation of a completely new and very promising biomarker of alcoholism, the platelet-derived growth factor receptor-beta. We will determine the effect of antagonizing this receptor on alcohol drinking behavior in rats. We hope that this unique and innovative proposal will ultimately lead to new and more effective treatment strategies for alcoholism.
