Compulsory drug seeking and consumption is a defining feature of cocaine dependence. Impairment in self control contributes to such compulsory drug using behaviors. Despite abundant behavioral evidence for impaired self control in patients with cocaine dependence (PCD), the neural processes underlying such a deficit remain unclear. In particular, the molecular underpinnings of the impairment in self control in PCD has not been explored. The current proposal fills this important gap by combining functional magnetic resonance imaging (fMRI) during a stop signal task (SST) and positron tomography (PET) imaging of the norepinephrine transporter (NET) to examine the thalamic processes of self control in PCD. Specifically, our previous studies of the SST, which allows trial by trial evaluation of the neural processes of error processing, demonstrates a distinct pattern of error-related cortical and subcortical activities. In particular, error-related thalamic activity is associated with subjective report of difficulty in self control in PCD. Cocaine is known to influence noradernergic neurotransmission, and the thalamus is a key region that receives extensive noradrenergic inputs from the brain stem. A critical question thus is whether prolonged cocaine use has resulted in altered noradernergic neurotransmission in the thalamus and whether such alterations are directly associated with impaired self control and habitual cocaine use in PCD. To address this issue, we take advantage of a specific NET radioligand - (S,S)-[11C]Methylreboxetine (11C-MRB) - to examine the association between error-related thalamic activity evoked during the stop signal task and the NET availability in abstinent PCD. We hypothesize that error-related thalamic activity robustly correlate with NET availability in PCD. These potential results would thus provide important knowledge that complements our understanding of dopaminergic processes of cocaine dependence. This novel study would provide critical data for us to further explore the role of altered noradrenergic neurotransmssion in predicting relapse to cocain use in PCD. This study would also delineate a critical aspect of molecular mechanisms instrumental to the development of novel pharmacotherapy of cocaine dependence.
The current proposal investigates the neural processes of impulse control deficits by combining functional imaging and molecular imaging of the norepinephrine transporter - a key protein that regulates noradrenergic neurotransmission, which is affected by cocaine exposure - in cocaine dependent patients. The potential results would delineate a critical aspect of molecular mechanisms instrumental to the development of novel pharmacotherapy of cocaine dependence.
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