Effects of noncompetitive NMDA receptor blockade on anterior cingulate cerebral blood flow in volunteers with schizophrenia.
Schizophrenia may be related to dysfunctional glutamatergic activity, specifically hypofunction of the N-methyl-D-aspartate receptor (NMDAR). In addition, it has been proposed that NMDAR hypofunction may paradoxically cause an increase in glutamate release and hypermetabolism in corticolimbic regions. If a state of partial, chronic NMDAR blockade underlies schizophrenia, then schizophrenic volunteers (SV) may have greater glutamate release and associated elevations in regional cerebral blood flow (rCBF) than normal volunteers (NV), following drug-induced NMDAR antagonism. Therefore, we have given acute ketamine, a noncompetitive NMDAR antagonist, to NV (n=13) and medicated volunteers with schizophrenia (n=10) in conjunction with serial positron emission tomography blood flow studies. Drug administration caused marked rCBF elevations in frontal and cingulate regions in both groups. Contrasts between NV and SV ketamine groups showed that SV had greater relative blood flow increases in the anterior cingulate than NV. Maximum blood flow, and the area under the curve for blood flow in the anterior cingulate cortex, significantly correlated with changes in psychosis ratings in SV and NV (maximum rCBF only). These changes are consistent with a relatively hypoactive thalamic NMDAR and increased cortical glutamate neurotransmission at non-NMDARs in schizophrenia. We hypothesize that ketamine antagonizes an NMDAR-dependent inhibitory system that is partially compromised in subjects with schizophrenia. The ketamine-induced reduction of inhibition leads to a marked increase in glutamate release and hypermetabolism (elevated rCBF) in frontal and cingulate cortical regions. The loss of inhibition and increased glutamate release may cause the distorted thoughts and diminished cognitive abilities elicited by NMDAR blockade.
Holcomb
Henry H
HH
Maryland Psychiatric Research Center, University of Maryland School of Medicine, PO Box 21247, Baltimore, MD 21228, USA. hholcomb@mprc.umaryland.edu
Lahti
Adrienne C
AC
Medoff
Deborah R
DR
Cullen
Tom
T
Tamminga
Carol A
CA
D000328:Adult; D002540:Cerebral Cortex / Q000098:blood supply; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005260:Female; D006179:Gyrus Cinguli / Q000098:blood supply* / Q000000981:diagnostic imaging; D006801:Humans; D007091:Image Processing, Computer-Assisted; D007649:Ketamine / Q000494:pharmacology; D008297:Male; D049268:Positron-Emission Tomography; D011569:Psychiatric Status Rating Scales; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D012559:Schizophrenia / Q000000981:diagnostic imaging / Q000503:physiopathology*
D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D007649:Ketamine