Amphetamine sensitization impairs cognition and reduces dopamine turnover in primate prefrontal cortex

Stacy A. Castner, Peter S. Vosler, Patricia S. Goldman-Rakic

Research output: Contribution to journalArticle

Abstract

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-naïve 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.

Original languageEnglish (US)
Pages (from-to)743-751
Number of pages9
JournalBiological psychiatry
Volume57
Issue number7
DOIs
StatePublished - Mar 15 2005

Keywords

  • Behavioral sensitization
  • Dopamine transmission
  • Dorsolateral prefrontal cortex
  • Nonhuman primate
  • Schizophrenia
  • Spatial working memory

ASJC Scopus subject areas

  • Biological Psychiatry

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