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"Alterations of Cortical
Synaptic Markers
in Alcohol Dependence"
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Chronic alcoholism is accompanied by functional and structural
changes in the prefrontal cortex of alcohol-dependent subjects. It
is presumed that these changes are associated with changes in the
basic structural unit of information transmission, the synapse,
which includes the neuronal elements of the synapse and the glial
support (namely astrocytes) essential for the homeostasis of the
synapse. However, very little knowledge exists on changes in
synaptic proteins involved in neurotransmitter release and changes
in the glial support of the synapses as a result of chronic
alcoholism. Accordingly, one of the primary goals of this project
is to identify the synaptic and glial changes that occur as a
consequence of chronic alcohol abuse.
Another goal of this project is to
assess the effects of neuroprotective treatments that may alleviate
or prevent the synaptic and glial changes that occur as a result of
chronic alcohol abuse. It is predicted that synaptic and glial
changes in the animal model will be reversed or greatly reduced by
neuroprotective treatments administered to alcohol-dependent
rodents. In the present project, it is hypothesized that
significant synaptic and glial changes will be observed in the
prefrontal cortex of alcohol-dependent human subjects as compared
to non-psychiatric human controls.
If the sites where changes occur in presynaptic proteins are
spatially correlated, this suggests that they form part of a
cascade of events and that they are mechanistically related. It
would then be possible to develop single treatments for the
synaptic pathology of alcoholism.
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If the sites where changes occur in presynaptic proteins are not
spatially correlated, this suggests that different mechanisms are
likely at work and that more than one single therapeutic approach
might be necessary to treat the devastating consequences of
alcoholism. It is further proposed that in a rodent model of
alcohol-dependence with periods of withdrawal and relapse, the
synaptic and glial changes observed will be comparable with those
present in human alcohol-dependent subjects.
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Research Aims:
To begin assessing which therapeutic approaches might provide
protection at the synaptic level against the effects of prolonged
alcohol abuse, the present project proposes to assay in a rodent
model 2 possible neuroprotective agents (BDNF and Vitamin E) that
may produce changes in synaptic and glial proteins through very
different mechanisms. Brain-derived neurotrophic factor (BDNF), a
protein of the family of nerve growth factor, would act directly on
synaptic mechanisms affected by alcoholism. Vitamin E, an
antioxidant agent, would act upstream in the chain of events that
cause synaptic and neuronal pathology.
The hypotheses stated above and the possibility of therapeutic
intervention will be tested as outlined in the specific aims:
Specific Aim 1:
To determine the distribution of synaptic proteins and astroglial
markers in the prefrontal cortex of (i) alcohol-preferring rats
with (a) prolonged alcohol intake, (b) alcohol intake and a period
of withdrawal, (c) prolonged alcohol intake and 3 periods of
withdrawal, (ii) alcohol-preferring rats that are alcohol-dependent
with a prolonged withdrawal period to simulate abstinence, and
(iii) rats never exposed to alcohol.
Specific Aim 2:
To assess the protective effects of treatment with the neurotrophic
factor BDNF and the antioxidant agent Vitamin E on the distribution
of synaptic proteins and astrocytic markers in the animal model
mentioned above.
Specific Aim 3:
To compare the distribution and content of synaptic and astroglial
proteins in three regions of the human prefrontal cortex in a pilot
study with postmortem brains from alcohol-dependent subjects with
remission, alcohol-dependent subjects without remission, and
non-psychiatric controls.
These research findings will determine whether variations in five
presynaptic proteins and the astroglial protein GFAP arise as a
consequence of prolonged alcohol exposure, and whether the sites
where variations occur are spatially correlated or represent
spatially separated phenomena. Accordingly, which type of
therapeutic approach would be more effective in combating synaptic
damage in alcoholism could then begin to be distinguished.
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