A single 20 mg dose of the full D1 dopamine agonist dihydrexidine (DAR-0100) increases prefrontal perfusion in schizophrenia.
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.
Mu
Qiwen
Q
Brain Stimulation Laboratory, Institute of Psychiatry, Medical University of South Carolina, Charleston, SC 29425, USA. muq@musc.edu
Johnson
Kevin
K
Morgan
Paul S
PS
Grenesko
Emily L
EL
Molnar
Christine E
CE
Anderson
Berry
B
Nahas
Ziad
Z
Kozel
F Andrew
FA
Kose
Samet
S
Knable
Michael
M
Fernandes
Prabhavathi
P
Nichols
David E
DE
Mailman
Richard B
RB
George
Mark S
MS
D000328:Adult; D002560:Cerebrovascular Circulation / Q000187:drug effects; D003287:Contrast Media; D018592:Cross-Over Studies; D018491:Dopamine Agonists / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D007839:Functional Laterality / Q000187:drug effects; D006801:Humans; D008279:Magnetic Resonance Imaging; D010617:Phenanthridines / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*; D017397:Prefrontal Cortex / Q000098:blood supply* / Q000187:drug effects* / Q000503:physiopathology; D017447:Receptors, Dopamine D1 / Q000187:drug effects*; D012559:Schizophrenia / Q000188:drug therapy* / Q000378:metabolism* / Q000503:physiopathology; D013997:Time Factors
D003287:Contrast Media; D018491:Dopamine Agonists; D010617:Phenanthridines; D017447:Receptors, Dopamine D1; C061532:dihydrexidine