The Administrative Core Component will make sure that all aspects of the INIA consortium work at an optimal level. The core will serve as an identifiable center for entire INIA consortium. This core will be responsible for decisions about research directions, including review of component progress and inclusion and exclusion of investigators. The core will also ensure the proper flow of information between the different consortium components, and flow of information to the larger research community in collaboration with the Bioinformatics Core. The duties of this core will also include organizing and financing all INIA committee meetings, retreats and research presentations. The administrative core will also track the INIA consortium finances and assist in budget planning for the different research components and cores. Stress contributes to excessive drinking and alcoholism, but the molecular and cellular mechanisms that underlie alcohol-stress interactions are not well understood. The brain circuitry involved in coordinating and producing responses to stress is known, and includes the extended amygdala (amygdala, bed nucleus of the stria terminalis and nucleus accumbens (NAc)], the hippocampus (HPC), the prefrontal cortex (PFC) and the hypothalamus. There is also considerable evidence implicating the neurotransmitters glutamate, GABA and serotonin (5-HT) in stress-induced neurophysiological responses in these brain regions. Alcohol effects on synaptic transmission in stress-related brain regions have not been characterized in much detail. Furthermore the role of the aforementioned neurotransmitters in these responses has not been examined. INIA component I will focus on examining synaptic transmission in amygdala, HPC, NAc and PFC in wild-type mice and mice with gene-targeted knockouts of the GABAAbeta3. Delta and gamma2 subunits, the NMDAR2A subunit, theGluRA subunit, the5-HTIA receptor and SERT. Similar experiments will be performed in selected randomly mutagenized mice identified in INIA component 3, and mice from selected BxD recombinant strains identified in INIA component 4. Brain slice preparations and isolated neurons will be examined from all of these groups of mice following chronic alcohol exposure and withdrawal. chronic alcohol self-administration and stress-induced reinstatement of alcohol drinking. Excitatory and inhibitory synaptic transmission will be measured using field potential and intracellular recording in brain slices containing the regions of interest. Synaptic plasticity will also be examined in brain slices. Acutely isolated neurons will be used to examine changes in neurotransmitter receptor function, and single-cell MRNA profiling will be used to identify neuronal subtypes. Serotonin release and reuptake will be examined in brain slices and synaptosomal preparations from the brain regions of interest. These studies will provide crucial information about neuroadaptive changes in synaptic transmission and plasticity induced by ETOH and stress in brain regions implicated in stress responses. We will also gather information about the role of particular neurotransmitter receptors and transporters in these neuroadaptive changes. Findings from this project """""""" Ill be compared to data gathered in INIA components 2, 3 and 4 to generate more integrated information about the neuroadaptive changes related to alcohol-stress interactions. In future studies we will use mice developed by the Knockout Mouse Core and in component 7 in studies such as those proposed at present. Information gained in this component will be compared with that gained in the primate studies proposed in component 5, and will be shared with the larger research community on the INIA web page with the help of the Bioinformatics Core. It is predicted that information from this project will contribute to a better under- standing of the mechanisms underlying stress-alcohol interactions that may lead to better therapies for treating excessive drinking and alcoholism.
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