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NIDA Proteomics Center
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Investigators
> Jane R. Taylor
Proteomic Analysis of Cellular
Alterations Associated with Cocaine-Induced Impairments in
Incentive-Motivational Processes and Cognitive/Inhibitory Function in Non-Human
Primates
Jane R. Taylor, Department of Psychiatry,
Yale University Over the
last few years we have extensively used the proteomics approaches provided by
the Center to identify alterations in synaptic protein expression in monkeys and
rodents chronically exposed to cocaine. Extensive behavioral testing had been
conducted on these same animals thereby allowing for the integration of
behavioral with biochemical findings. We propose to continue to use these
sophisticated proteomics techniques to identify novel proteins involved in
dysfunction of cortico-limbic-striatal circuits that may subserve addictive
behavior in monkeys and rodents.
To date our behavioral and
biochemical evidence suggest that dysfunction in the frontal cortex may be
concomitant with the progressive augmentation of limbic-striatal transmission
induced by chronic drug exposure. Our data demonstrate that persistent
drug-induced enhancement in incentive motivation are associated with, and can be
mimicked by, increases in limbic-striatal dopamine/PKA/BDNF/CREB activity. In
monkeys we have also found long-lasting deficits in PFC-dependent inhibitory
control functions after repeated cocaine exposure and the orbitofrontal cortex (OFC)
appears to be particularly sensitive to the effects of cocaine. These deficits
in OFC-dependent cognitive performance were associated with decreases in
dopamine D2 receptor expression and proteins involved in glucose/energy
metabolism.
We will continue to examine the
effects of long-term cocaine exposures in primate brain by focusing on
additional cellular fractions (i.e., nuclear, mitochondrial and intracellular)
and additional techniques (i.e., antibody arrays and lipidomics). Animals will
be exposed to cocaine as adolescents but analyzed as adults and will be
behaviorally characterized using sophisticated tests of cognitive and
motivational functions. Such studies are difficult to perform in rodents given
the relatively brief adolescence period. These studies will allow us to
characterize the underlying molecular adaptations and correlate these
alterations with behavior and with changes in gene expression. The contribution
of selected targets identified using proteomics to addictive behavior will be
determined using intra-cerebral infusions of viral-vectors to alter the levels
of proteins of interest in combination with sophisticated behavioral assessment
methods. These ongoing studies in rats, mice and monkeys are part of several
funded NIDA/NIAAA projects.
RELEVANCE:
Drug-induced neuroadaptations are considered essential for the development of
addiction in humans. The proposed studies will continue to identify
cocaine-induced alterations in monkeys and rodents using chronic cocaine
exposure or self-administration paradigms that are known to induce behavioral
changes associated with cortico-limbic-striatal dysfunction. The results will
provide new insights into the molecular mechanisms underlying such behavioral
changes and thus increase our understanding of the neurobiology of addiction. |
