Alcohol abuse and dependence are widespread disorders and constitute a significant public health concern. The prevalence of alcohol abuse has increased in the United States from 3.03% in 1992 to 4.65% in 2002. Alcohol use is responsible for 1.5% of all deaths globally and is the third leading preventable cause of death in the United States. In addition, the economic costs associated with alcohol abuse are on the rise in the United States with current estimates at approximately $184 billion. These findings make it clear that a need for treatment strategies aimed at reducing human and financial costs is crucial. Research on the identification of the neurobiological correlates of alcohol abuse and dependence provides a framework as well as specific targets for which to develop pharmacotherapies that can help to achieve this goal. One potential area to focus this targeting is the serotonin system which modulates the reinforcing effects of alcohol. Despite years of research on the interaction between ethanol and the serotonin system, the exact mechanisms of action remain unclear. The 5-HT1A receptor is one of the main cellular constituents controlling extracellular serotonin concentration and also serves to modulate excitatory and inhibitory neurotransmission. In this application, we propose a comprehensive examination of ethanol's effects on the 5-HT1A receptor in a monkey model of chronic ethanol self-administration. We will evaluate the receptor at various levels of analysis: 1) receptor density using in vitro receptor autoradiography, 2) gene transcription using laser capture microdissection and quantitative PCR and 3) Signal transduction and trafficking using an immunoprecipitation protocol followed by multidimensional liquid chromatography and MALDI ToF/ToF mass spectrometry. Using a monkey selfadministration paradigm that very closely models human drinking behavior, these approaches will provide novel findings on ethanol's effects on this receptor system, may help to explain some of the discrepancies reported in the literature and can identify potential pharmacotherapeutic targets. Importantly, the proposed research is also designed to provide me with the training and tools necessary to comprehensively examine similar systems in the future.
Alcohol abuse and dependence are widespread disorders and constitute a significant public health concern. A need for treatment strategies aimed at reducing human and financial costs is evident. The research proposed here on the identification of the neurobiological correlates of alcohol abuse and dependence provides a framework from which to develop targeted pharmacotherapies that can help to achieve this goal.
| Burnett, Elizabeth J; Grant, Kathleen A; Davenport, April T et al. (2014) The effects of chronic ethanol self-administration on hippocampal 5-HT1A receptors in monkeys. Drug Alcohol Depend 136:135-42 |
| Burnett, E J; Davenport, A T; Grant, K A et al. (2012) The effects of chronic ethanol self-administration on hippocampal serotonin transporter density in monkeys. Front Psychiatry 3:38 |
| Daunais, James Bernard; Kraft, Robert Arthur; Davenport, April Teresa et al. (2010) MRI-guided dissection of the nonhuman primate brain: a case study. Methods 50:199-204 |
