Cognitive dysfunction and impaired inhibitory control are hallmarks of addiction. The prefrontal and temporal cortices are essential to effective cognitive performance, and drug abuse is associated with significant structural deficits therein. A crucial unresolved question in clinical studies is whether structural and functional differences in cortex predate, or are consequent to drug use. This application proposes longitudinal structural MR imaging in a monkey model of addiction-related cognitive and inhibitory control deficits to address the role of drug use per se in structural and functional cortical differences seen in cocaine addiction. It also will examine single unit activity to determine what cellular changes could mediate an association of altered structure and function. Animal models are key to addressing questions about the etiology and cellular basis of addiction-related cognitive dysfunction. This is especially so for primate models that share structural and cognitive similarities to humans at the cortical level and that can exploit common methodologies such as brain imaging techniques used clinically. This application will employ a clinically relevant rhesus monkey self- administration model that shows impaired performance virtually identical to that seen clinically on the Stop Task, which is used to measure impaired inhibitory control, and which is supported by a well- defined circuitry identified in clinical and pre-clinical studies. Deficits in stimulus discrimination consistent with clinical reports have also been established. We will employ the monkey model to address these fundamental questions: 1) Do structural alterations in prefrontal and temporal cortex observed in cocaine users result from drug exposure per se, rather than a preexisting condition? 2) Within individuals, does the degree of cognitive impairment correlate with extent of structural change? 3) What are cellular correlates of cognitive dysfunction associated with cocaine use? The integration of a longitudinal application of clinically employed structural and cognitive assessments, along with single unit studies, will help establish the relationship between cocaine use, altered structure, and cellular mechanisms associated with cognitive dysfunction observed clinically. Drug addiction causes extensive human suffering and financial loss to society. Understanding the source and mechanisms of cognitive dysfunction that predicts treatment outcome may help develop therapeutic approaches that lessen harm from addiction.

Public Health Relevance

Drug addiction causes extensive human suffering and financial loss to society. Understanding the source and mechanisms of cognitive dysfunction that predicts treatment outcome may help develop therapeutic approaches that lessen harm from addiction.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA025636-05
Application #
8487378
Study Section
Neurobiology of Motivated Behavior Study Section (NMB)
Program Officer
Volman, Susan
Project Start
2009-09-15
Project End
2014-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
5
Fiscal Year
2013
Total Cost
$295,989
Indirect Cost
$100,617
Name
University of Pittsburgh
Department
Psychiatry
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
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Porter, Jessica N; Minhas, Davneet; Lopresti, Brian J et al. (2014) Altered cerebellar and prefrontal cortex function in rhesus monkeys that previously self-administered cocaine. Psychopharmacology (Berl) 231:4211-8
Porter, Jessica N; Gurnsey, Kate; Jedema, Hank P et al. (2013) Latent vulnerability in cognitive performance following chronic cocaine self-administration in rhesus monkeys. Psychopharmacology (Berl) 226:139-46
Porter, Jessica N; Olsen, Adam S; Gurnsey, Kate et al. (2011) Chronic cocaine self-administration in rhesus monkeys: impact on associative learning, cognitive control, and working memory. J Neurosci 31:4926-34