Effects of Noncompetitive NMDA Receptor Blockade on Anterior Cingulate Cerebral Blood Flow in Volunteers with Schizophrenia

Abstract

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 ¼ 13) and medicated volunteers with schizophrenia (n ¼ 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.

Effects of single-dose ketamine infusion on behavioral parameters and neuronal activation in the medial prefrontal cortex of juvenile rats exposed to prenatal stress

“…[60,61] Likewise, rodent studies showed that ketamine treatment causes rapid increases of glutamate transmission in PFC. [62] It is high likely that ketamine's actions on synapses might reverse the morphological and functional alterations in the medial PFC neurons caused by stress exposure. In a recent study, using optogenetic stimulation of infralimbic PFC, Fuckikami et al [63] showed that rapid and long-lasting antidepressant and anxiolytic effects of systemic ketamine administration is associated with increased number and function of spine synapses of layer V pyramidal neurons of PFC.…”

Does schizophrenia arise from oxidative dysregulation of parvalbumin-interneurons in the developing cortex?

“…This hyper-excitation has been related to an increase in thalamo-cortical glutamatergic excitation of downstream cortical regions such as the anterior cingulate and retrosplenial cortices (Tomitaka et al, 2000;Holcomb et al, 2005). PET scan studies have shown that schizophrenic subjects respond to ketamine with higher hypermetabolism than normal subjects.…”

Differential Effects of Antipsychotic and Glutamatergic Agents on the phMRI Response to Phencyclidine

“…Consistent findings were observed by McKie et al (2007) using BOLD fMRI. Holcomb et al (2005) showed that ketamine increased cerebral blood flow (CBF) in the anterior cingulate and frontal cortices in both healthy volunteers and patients with schizophrenia. Earlier studies also reported that low doses of ketamine affect selectively the areas that are thought to be dysfunctional in schizophrenia such as the limbic cortex and basal ganglia (Morris et al, 2005;Soyka et al, 2005;Tamminga et al, 2003).…”