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Neuropsychopharmacology. 2014 Jun;39(7):1732-42. doi: 10.1038/npp.2014.21. Epub 2014 Jan 29.

Temporal difference error prediction signal dysregulation in cocaine dependence.

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Neuroimaging Research Branch, National Institute on Drug Abuse, Intramural Research Program, NIH, Baltimore, MD, USA.
Maryland Psychiatric Research Center, University of Maryland, School of Medicine, Baltimore, MD, USA.
Department of Psychiatry and Behavioral Sciences, M.I.N.D. Institute, University of California-Davis School of Medicine, Sacramento, CA, USA.
Department of Psychology, Stanford University, Stanford, CA, USA.


Cocaine dependence impacts drug-related, dopamine-dependent reward processing, yet its influence on non-drug reward processing is unclear. Here, we investigated cocaine-mediated effects on reward learning using a natural food reinforcer. Cocaine-dependent subjects (N = 14) and healthy controls (N = 14) learned to associate a visual cue with a juice reward. In subsequent functional imaging sessions they were exposed to trials where juice was received as learned, withheld (negative temporal difference error (NTDE)), or received unexpectedly (positive temporal difference error (PTDE)). Subjects were scanned twice in sessions that were identical, except that cocaine-dependent participants received cocaine or saline 10 min before task onset. In the insula, precentral and postcentral gyri NTDE signals were greater, and PTDE-related function was reduced in cocaine-dependent subjects. Compared with healthy controls, in the cocaine-dependent group PTDE signals were also reduced in medial frontal gyrus and reward-related function, irrespective of predictability, was reduced in the putamen. Group differences in error-related activity were predicted by the time as last self-administered cocaine use, but TDE function was not influenced by acute cocaine. Thus, cocaine dependence seems to engender increased responsiveness to unexpected negative outcomes and reduced sensitivity to positive events in dopaminergic reward regions. Although it remains to be established if these effects are a consequence of or antecedent to cocaine dependence, they likely have implications for the high-cocaine use recidivism rates by contributing to the drive to consume cocaine, perhaps via influence on dopamine-related reward computations. The fact that these effects do not acquiesce to acute cocaine administration might factor in binge-related escalated consumption.

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