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.
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.