A single 20 mg dose of the full D1 dopamine agonist dihydrexidine (DAR-0100) increases prefrontal perfusion in schizophrenia

Qiwen Mu, Kevin Johnson, Paul S. Morgan, Emily L. Grenesko, Christine E. Molnar, Berry Anderson, Ziad Nahas, F. Andrew Kozel, Samet Kose, Michael Knable, Prabhavathi Fernandes, David E. Nichols, Richard B. Mailman, Mark S. George

Research output: Contribution to journalArticlepeer-review

71 Scopus citations

Abstract

Dopamine D1 receptors play an important role in memory and cognition in non-human primates. Dopamine D1 agonists have been shown to reverse performance deficits in both aged non-human primates and in primates with lesions to dopamine systems. This study explored whether a single dose of the first full D1 agonist dihydrexidine (DAR-0100) would cause changes in brain activity (perfusion) in dopamine-rich brain regions. We used a new gadolinium-contrast magnetic resonance perfusion scanning technique to measure brain activity. A within-subject cross-over double-blind randomized design was used in 20 adults with SCID-diagnosed schizophrenia. Each morning at 0800 h, they were scanned on a 3.0 T MRI scanner for perfusion. They then received either 20 mg of dihydrexidine, or placebo, subcutaneously over 15 min. Over the next 45 min, they had intermittent MRI scans. Two days later, they had a repeat of the Day 1 schedule, but received the opposite treatment from that given on the first day. Within-day, as well as between-day, comparisons were made to test for perfusion effects of dihydrexidine. Analysis revealed that dihydrexidine induced a significant increase in both prefrontal and non-prefrontal perfusion compared to placebo. The greatest increases occurred approximately 20 min after dihydrexidine infusion, consistent with the short pharmacokinetic half-life of dihydrexidine. These data are consistent with the hypothesis formulated from studies of non-human primates that dihydrexidine and other D1 agonists may be able to modulate prefrontal dopaminergic function.

Original languageEnglish (US)
Pages (from-to)332-341
Number of pages10
JournalSchizophrenia Research
Volume94
Issue number1-3
DOIs
StatePublished - Aug 2007

Bibliographical note

Funding Information:
This study was funded by the Stanley Medical Research Institute.

Funding Information:
This study was funded by the Stanley Medical Research Institute. The authors would like to thank Crisis Ministries Homeless Shelter and the Charleston County Community Mental Health Center. Ms. Minnie Dobbins provided invaluable administrative help, Debra Axness for informatics support, and Kimberley Gatgounis of MUSC Pharmacy Services. Portions of this work were presented at the 2006 Annual Meeting of the American College of Neuropharmacology.

Keywords

  • D dopamine receptor agonist
  • Dopamine
  • Magnetic resonance imaging
  • Perfusion
  • Prefrontal cortex
  • Schizophrenia

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