Effects of NMDA-Receptor Antagonist Treatment on c-fos Expression in Rat Brain Areas Implicated in Schizophrenia

Abstract

1. The noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonists produce behavioral responses that closely resemble both positive and negative symptoms of schizophrenia. These drugs also induce excitatory and neurotoxic effects in limbic cortical areas. 2. We have here mapped the brain areas which show increased activity in response to noncompetitive NMDA-receptor antagonist administration concentrating especially to those brain areas that have been suggested to be relevant in the pathophysiology of schizophrenia. 3. Rats were treated intraperitoneally with a NMDA-receptor antagonist MK801 and activation of brain areas was detected by monitoring the expression of c-fos mRNA by using in situ hybridization. 4. MK801 induced c-fos mRNA expression of in the retrosplenial, entorhinal, and prefrontal cortices. Lower c-fos expression was observed in the layer IV of the parietal and frontal cortex. In the thalamus, c-fos mRNA expression was detected in the midline nuclei and in the reticular nucleus but not in the dorsomedial nucleus. In addition, c-fos mRNA was expressed in the anterior olfactory nucleus, the ventral tegmental area, and in cerebellar granule neurons. 5. NMDA-receptor antagonist ketamine increased dopamine release in the parietal cortex, in the region where NMDA-receptor antagonist increased c-fos mRNA expression. 6. Thus, the psychotropic NMDA-receptor antagonist induced c-fos mRNA expression in most, but not all, brain areas implicated in the pathophysiology of schizophrenia. The high spatial resolution of in situ hybridization may help to define regions of interest for human imaging studies.

Acute phencyclidine administration induces c-Fos-immunoreactivity in interneurons in cortical and subcortical regions

“…This is supported by previous studies (Habara et al 2001), but this finding is not consistent across all studies using NMDA antagonists (Gao et al 1998 (NAc overall); De Leonibus et al 2002 (NAc core)). We also find that PCP induces c-Fos-IR in the CA1, which has not previously been found in studies with similar or lower PCP doses (Näkki et al 1996;Gotoh et al 2002Santana et al 2011, but is in line with previous studies using stronger PCP doses or other NMDA antagonists (Näkki et al 1996;Väisänen et al 2004;Imre et al 2006) supporting this region to be involved in mechanisms underlying NMDA hypofunction.…”

Region-Specific Reduction in Entorhinal Gamma Oscillations and Parvalbumin-Immunoreactive Neurons in Animal Models of Psychiatric Illness

“…Noncompetitive NMDA receptor antagonists generate psychomotor-gating deficits and other behavioral responses closely associated with schizophrenia (Ellison, 1995) and selectively enhance c-fos expression in entorhinal and prefrontal areas (Vaisanen et al, 2004). Parvalbumin-immunopositive basket cells in LII entorhinal cortex are activated strongly by NMDA receptor agonists (Jones and Buhl, 1993), and these cells possess a marked tonic excitatory component to their drive during gamma oscillations (Cunningham et al, 2003).…”

Circuit-based framework for understanding neurotransmitter and risk gene interactions in schizophrenia

“…[74]). Other work has pointed to the thalamus as a region particularly sensitive to antagonist [61,70]. The basis of this regional variability remains to be determined.…”

“…This has been observed in rodents by electrophysiological methods [60], metabolic imaging methods [61,62] and measurements of glutamate release [63]. The prolonged overactivity of pyramidal cells could have deleterious consequences; indeed, this is the likely explanation of the fact that prolonged inhibition of NMDARs produces swelling of pyramidal cells and other signs of cellular stress [64].…”