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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21DA026998-01
Application #
7706430
Study Section
Neural Basis of Psychopathology, Addictions and Sleep Disorders Study Section (NPAS)
Program Officer
Bjork, James M
Project Start
2009-08-01
Project End
2011-05-31
Budget Start
2009-08-01
Budget End
2010-05-31
Support Year
1
Fiscal Year
2009
Total Cost
$211,005
Indirect Cost
Name
Yale University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Manza, Peter; Hu, Sien; Ide, Jaime S et al. (2016) The effects of methylphenidate on cerebral responses to conflict anticipation and unsigned prediction error in a stop-signal task. J Psychopharmacol 30:283-93
Ide, Jaime S; Hu, Sien; Zhang, Sheng et al. (2015) Impaired Bayesian learning for cognitive control in cocaine dependence. Drug Alcohol Depend 151:220-7
Li, Chiang-shan R; Potenza, Marc N; Lee, Dianne E et al. (2014) Decreased norepinephrine transporter availability in obesity: Positron Emission Tomography imaging with (S,S)-[(11)C]O-methylreboxetine. Neuroimage 86:306-10
Farr, Olivia M; Zhang, Sheng; Hu, Sien et al. (2014) The effects of methylphenidate on resting-state striatal, thalamic and global functional connectivity in healthy adults. Int J Neuropsychopharmacol 17:1177-91
Zhang, Sheng; Hu, Sien; Bednarski, Sarah R et al. (2014) Error-related functional connectivity of the thalamus in cocaine dependence. Neuroimage Clin 4:585-92
Farr, Olivia M; Hu, Sien; Matuskey, David et al. (2014) The effects of methylphenidate on cerebral activations to salient stimuli in healthy adults. Exp Clin Psychopharmacol 22:154-65
Zhang, Sheng; Hu, Sien; Chao, Herta H et al. (2014) Ventromedial prefrontal cortex and the regulation of physiological arousal. Soc Cogn Affect Neurosci 9:900-8
Matuskey, David; Luo, Xi; Zhang, Sheng et al. (2013) Methylphenidate remediates error-preceding activation of the default mode brain regions in cocaine-addicted individuals. Psychiatry Res 214:116-21
Ide, Jaime S; Shenoy, Pradeep; Yu, Angela J et al. (2013) Bayesian prediction and evaluation in the anterior cingulate cortex. J Neurosci 33:2039-47
Zhang, Sheng; Ide, Jaime S; Li, Chiang-shan R (2012) Resting-state functional connectivity of the medial superior frontal cortex. Cereb Cortex 22:99-111

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