Prefrontal dopamine D1 receptors and working memory in schizophrenia.
Studies in nonhuman primates documented that appropriate stimulation of dopamine (DA) D1 receptors in the dorsolateral prefrontal cortex (DLPFC) is critical for working memory processing. The defective ability of patients with schizophrenia at working memory tasks is a core feature of this illness. It has been postulated that this impairment relates to a deficiency in mesocortical DA function. In this study, D1 receptor availability was measured with positron emission tomography and the selective D1 receptor antagonist [11C]NNC 112 in 16 patients with schizophrenia (seven drug-naive and nine drug-free patients) and 16 matched healthy controls. [11C]NNC 112 binding potential (BP) was significantly elevated in the DLPFC of patients with schizophrenia (1.63 +/- 0.39 ml/gm) compared with control subjects (1.27 +/- 0.44 ml/gm; p = 0.02). In patients with schizophrenia, increased DLPFC [11C]NNC 112 BP was a strong predictor of poor performance at the n-back task, a test of working memory. These findings confirm that alteration of DLPFC D1 receptor transmission is involved in working memory deficits presented by patients with schizophrenia. Increased D1 receptor availability observed in patients with schizophrenia might represent a compensatory (but ineffective) upregulation secondary to sustained deficiency in mesocortical DA function.
Abi-Dargham
Anissa
A
Department of Psychiatry, Columbia University College of Physicians and Surgeons and New York State Psychiatric Institute, New York, New York 10032, USA. aa324@columbia.edu
Mawlawi
Osama
O
Lombardo
Ilise
I
Gil
Roberto
R
Martinez
Diana
D
Huang
Yiyun
Y
Hwang
Dah-Ren
DR
Keilp
John
J
Kochan
Lisa
L
Van Heertum
Ronald
R
Gorman
Jack M
JM
Laruelle
Marc
M
D000328:Adult; D000367:Age Factors; D001552:Benzazepines / Q000493:pharmacokinetics; D001572:Benzofurans / Q000493:pharmacokinetics; D001667:Binding, Competitive; D002250:Carbon Radioisotopes; D018492:Dopamine Antagonists / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008569:Memory Disorders / Q000150:complications / Q000175:diagnosis / Q000503:physiopathology*; D008570:Memory, Short-Term; D009483:Neuropsychological Tests; D011237:Predictive Value of Tests; D017397:Prefrontal Cortex / Q000000981:diagnostic imaging / Q000378:metabolism*; D025341:Principal Component Analysis; D017447:Receptors, Dopamine D1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012559:Schizophrenia / Q000150:complications / Q000175:diagnosis / Q000000981:diagnostic imaging / Q000503:physiopathology*; D014055:Tomography, Emission-Computed
D001552:Benzazepines; D001572:Benzofurans; D002250:Carbon Radioisotopes; D018492:Dopamine Antagonists; D017447:Receptors, Dopamine D1; C077123:NNC 112