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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. |
