PMID- 16034443
OWN - NLM
STAT- MEDLINE
DCOM- 20060124
LR  - 20161124
IS  - 0893-133X (Print)
IS  - 0893-133X (Linking)
VI  - 30
IP  - 12
DP  - 2005 Dec
TI  - Effects of noncompetitive NMDA receptor blockade on anterior cingulate cerebral 
      blood flow in volunteers with schizophrenia.
PG  - 2275-82
AB  - 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.
FAU - Holcomb, Henry H
AU  - Holcomb HH
AD  - Maryland Psychiatric Research Center, University of Maryland School of Medicine, 
      PO Box 21247, Baltimore, MD 21228, USA. hholcomb@mprc.umaryland.edu
FAU - Lahti, Adrienne C
AU  - Lahti AC
FAU - Medoff, Deborah R
AU  - Medoff DR
FAU - Cullen, Tom
AU  - Cullen T
FAU - Tamminga, Carol A
AU  - Tamminga CA
LA  - eng
GR  - R01 DA 09483-01/DA/NIDA NIH HHS/United States
PT  - Clinical Trial
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Neuropsychopharmacology
JT  - Neuropsychopharmacology : official publication of the American College of 
      Neuropsychopharmacology
JID - 8904907
RN  - 0 (Excitatory Amino Acid Antagonists)
RN  - 0 (Receptors, N-Methyl-D-Aspartate)
RN  - 690G0D6V8H (Ketamine)
SB  - IM
MH  - Adult
MH  - Cerebral Cortex/blood supply
MH  - Cerebrovascular Circulation/*drug effects
MH  - Excitatory Amino Acid Antagonists/*pharmacology
MH  - Female
MH  - Gyrus Cinguli/*blood supply/diagnostic imaging
MH  - Humans
MH  - Image Processing, Computer-Assisted
MH  - Ketamine/pharmacology
MH  - Male
MH  - Positron-Emission Tomography
MH  - Psychiatric Status Rating Scales
MH  - Receptors, N-Methyl-D-Aspartate/*antagonists & inhibitors
MH  - Schizophrenia/diagnostic imaging/*physiopathology
EDAT- 2005/07/22 09:00
MHDA- 2006/01/25 09:00
CRDT- 2005/07/22 09:00
PHST- 2005/07/22 09:00 [pubmed]
PHST- 2006/01/25 09:00 [medline]
PHST- 2005/07/22 09:00 [entrez]
AID - 1300824 [pii]
AID - 10.1038/sj.npp.1300824 [doi]
PST - ppublish
SO  - Neuropsychopharmacology. 2005 Dec;30(12):2275-82. doi: 10.1038/sj.npp.1300824.