The general goal of this project is to extend our recent findings of brain abnormalities and neuropsychological deficits in chronic cocaine abusing subjects through the study of putative brain mechanisms of impulsivity in cocaine dependence. As described in the Preliminary Findings section, we observed white matter abnormalities in frontal areas that contain anatomical regions known to be associated with impulse control. We also observed disinhibition on neurocognitive tests including a measure of impulsive decision-making in the cocaine users. Self-reported impulsivity traits, as measured by the Barratt Impulsiveness Scale (BIS), were associated with measures of white matter integrity. In our sample, cocaine users with longer duration of use showed more white matter abnormalities than those with fewer years of use. Together, these data suggest that cocaine abuse may be associated with changes in the brain that result in increased impulsivity. In this project we will build on this preliminary work by collecting more specific assessments of impulsivity and combine this information with neuroimaging measures of white matter integrity using Diffusion Tensor Imaging(DTI) and GABA, the major inhibitory brain neurotransmitter, using Magnetic Resonance Spectroscopy(MRS). Recent findings suggest that impaired prefrontal inhibitory control may not be solely a result of drug use, but may also reflect a preexisting condition that increases the vulnerability to using drugs and becoming addicted. Accordingly, an important goal of this project is to compare cocaine abusers directly with participants in Project 3 (BED), who are not substance abusers yet have an addictive behavior, to determine whether neurobiological findings present in cocaine users are also found in subjects with non-drug addictive behavior. This will allow us to differentiate neurobiological and neurocognitive markers of impulsivity from the neurobiological and neurocognitive effects of drug use. Where possible, we have selected our tasks and measures to overlap with what is being done in the Animal experiments in Project 1, which will allow us address questions difficult to study in humans.The proposed project also promises to generate new findings relating brain GABA levels, white matter microstructure and neurocognitive performance in cocaine abusers. We have three aims: 1) Measure impulsivity in cocaine abusers using behavioral tasks and self-report instruments. 2) Use DTI measures to assess frontal white matter integrity and its relationship to impulsivity measures. 3) Using MRS, determine if cocaine abusers have abnormalities in brain GABA levels.
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