INIA: Stress, Anxiety of Alcohol Abuse

DESCRIPTION (provided by applicant):
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.