Amphetamine sensitization impairs cognition and reduces dopamine turnover in primate prefrontal cortex.
BACKGROUND
Amphetamine (AMPH) sensitization in monkeys produces long-lasting behavioral changes that model positive (hallucinatory-like behaviors) and negative (psychomotor depression) symptoms of schizophrenia. The extent to which this model produces the core deficit in schizophrenia--working memory impairment--is unknown.


METHODS
Two groups of rhesus monkeys were sensitized to AMPH over 6 weeks. In one group, acquisition of cognitive tasks (delayed response, visual discrimination, delayed nonmatch-to-sample) was examined beginning 6+ months postsensitization. The second group was pretrained to stability on delayed response before sensitization. Regional postmortem concentrations of dopamine and its metabolites were examined in tissue from age-matched AMPH-naive and AMPH-sensitized monkeys using high-performance liquid chromatography with electrochemical detection (HPLC-ECD).


RESULTS
The AMPH-sensitized monkeys were profoundly impaired in their ability to acquire cognitive tasks compared with AMPH-naïve monkeys. Pretrained monkeys showed impaired delayed response performance for several months following sensitization. Analysis by HPLC revealed that AMPH sensitization significantly reduced dopamine turnover in prefrontal cortex and striatum.


CONCLUSIONS
Impairments in the acquisition and performance of spatial delayed response in association with reduced dopamine turnover in prefrontal cortex following AMPH sensitization provide further support for the relevance of this model to both the etiology and the treatment of cognitive dysfunction in schizophrenia.
Castner
Stacy A
SA
Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut 06519, USA. stacy.castner@yale.edu
Vosler
Peter S
PS
Goldman-Rakic
Patricia S
PS
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000661:Amphetamine / Q000009:adverse effects / Q000494:pharmacology*; D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D000697:Central Nervous System Stimulants / Q000009:adverse effects / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D003072:Cognition Disorders / Q000139:chemically induced* / Q000503:physiopathology; D003342:Corpus Striatum / Q000378:metabolism; D004193:Discrimination Learning / Q000187:drug effects; D004298:Dopamine / Q000378:metabolism*; D004563:Electrochemistry / Q000379:methods; D005260:Female; D006719:Homovanillic Acid / Q000378:metabolism; D008253:Macaca mulatta; D008297:Male; D009483:Neuropsychological Tests / Q000706:statistics & numerical data; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D011930:Reaction Time / Q000187:drug effects; D012201:Reward; D013997:Time Factors; D014796:Visual Perception / Q000187:drug effects
D000697:Central Nervous System Stimulants; D015102:3,4-Dihydroxyphenylacetic Acid; D000661:Amphetamine; D004298:Dopamine; D006719:Homovanillic Acid