The use of brain imaging technology to investigate the effects of PCP provides clues to the acute and chronic regional effects of the drug on brain metabolism. Data from receptor binding studies in animals show that limbic regions (especially the hippocampus) contain high concentrations of NMDA receptors (,). Although it may be supposed that PCP would reduce brain metabolism (especially in frontal brain regions to mimic the hypofrontality seen in schizophrenics) [,], studies in animals administered PCP and PCP-like compounds show that PCP increased regional glucose metabolism, specifically in hippocampal regions (,,,). Ketamine, a PCP-like compound, was similarly shown in five of six studies to increase glucose metabolism in hippocampal regions in animals (,,,,). However, schizophrenia is a chronic illness associated with hypothesized reductions in glutamate activity and hypofrontality (). A chronic PCP study by Gao et al. () in rats showed that glucose metabolism was decreased in limbic regions. Lahti et al. () administered ketamine (0.3 mg/kg, i.v.) to a group of schizophrenics stabilized on haloperidol and measured metabolic activity with HO and PET. In these patients, ketamine increased cerebral blood flow in the anterior cingulate cortex and in an area which extended inferiorly to the medial wall of the prefrontal cortex. In contrast, blood flow to the hippocampus and the primary visual cortex was decreased ().
Specific Aim II tests the hypothesis that the NMDA system plays a role in the discriminative stimulus effects of morphine, enhancing our understanding of NMDA-mediated mechanisms in the subjective effects of morphine.
An NMDA Receptor Mediated Hypothesis - …
As predicted by the Ca2+ recycling hypothesis, blocking the uniporter immediately following challenge with 200 μM NMDA produced a rapid and transient increase in cytosolic Ca2+ without a corresponding increase in matrix Ca2+.
The Pathophysiology of Ischemic Injury
Some evidence from animal studies suggests that specific components of the NMDA receptor unit (e.g., NMDAR2D) may be developmentally regulated (). In one of the first studies of NMDA receptor subunits in schizophrenia, Akbarian et al. () presented data that suggested a regional deficit in NMDA subunit density in brain tissue of schizophrenics. The expression patterns of five NMDA receptor subunits (NMDAR1/NMDAR2 [A-D]) were measured in postmortem prefrontal, parieto-temporal and cerebellar cortical tissue of schizophrenics (N=15) and age-, gender- and autolysis time-matched controls (N=15). A significant 53% proportional increase in NMDAR2D subunit mRNA levels was found in prefrontal areas of schizophrenics, but no significant changes were observed in the expression patterns of the other NMDA receptor subunits. Other brain regions were similar to those in controls, and no medication effects were apparent. Furthermore, some data suggest that NMDAR2D may be necessary for the formation of specific neuronal connections that are, at least in part, mediated by NMDA receptors (). Special kinetic properties of postsynaptic NMDA receptors containing the NR2D polypeptide may effect postsynaptic depolarization when presynaptic activity is reduced (). These data support the hypothesis by Akbarian et al. () that an increase in NMDAR2D subunits could reflect a compensatory response to decreased function (hypofrontality) in prefrontal cortical regions of the schizophrenic brain.
by Mike Darwin, BioPreservation, Inc
Specific Aim 1 tests the hypothesis that disruption of NMDA receptor function alters the antinociceptive effects of morphine after acute and chronic morphine administration in MR1-KD mice, enhancing our understanding of the NMDA- mediated mechanisms in morphine analgesia.