63 In contrast to the equivocal and hard-to-interpret data concerning dopamine receptors in schizophrenia, there is emerging good evidence for alterations in dopamine neurons. Several PET and single photon emission computed tomography (SPECT) studies have shown elevated striatal dopamine release in response

to amphetamine in untreated, acutely psychotic patients, implying a dysregulation and hyperresponsiveness of dopamine neurons.65 There is also recent evidence that D2 receptor occupancy is higher in schizophrenia, implying an increased synaptic dopamine concentration; interestingly, the magnitude of the elevation Inhibitors,research,lifescience,medical predicts response to antipsychotic medication.66 Although the state -dependent nature of the changes mandates in vivo rather than postmortem studies, the latter can provide independent and corroborative support; for example, an altered dopaminergic innervation in schizophrenia may be an anatomical correlate.67 Serotonin Inhibitors,research,lifescience,medical (5-HT) There are two well-replicated postmortem findings concerning the 5-HT system in schizophrenia: a loss of the serotonin 5-HT2A receptor expression from the frontal cortex; Inhibitors,research,lifescience,medical and an increased density of 5-HT1A receptors.63 Changes in the 5-HT transporter have also been reported. Both of the receptor alterations have been found in medication-free patients and are not reproduced in rats by antipsychotics, suggesting that,

unlike the dopamine receptor findings, they are not primarily caused by drug treatment. The 5-HT2A receptor data Inhibitors,research,lifescience,medical illustrate how postmortem studies suggest targets for in vivo ligand-based imaging, since the data have led to three PET studies of younger and unmedicated subjects, and also how postmortem data can clarify their interpretation. Only one of the three imaging studies has replicated the decrease in 5-HT2A receptors in the frontal cortex,68 but this Inhibitors,research,lifescience,medical may reflect methodological problems. That is, the cerebellum is used as the reference region for the PET analysis, which presupposes an absence of cerebellar 5-HT2A receptors, but

this may not be the case.69 Hypotheses to explain the role of 5-HT in schizophrenia include the trophic functions of the 5-HT system in neurodevelopment, interactions between 5-HT and dopamine, impaired 5-HT2A receptor-mediated activation of prefrontal cortex, and 5HT2A receptors as candidate genes.70-72 Glutamate The observation that phencyclidine and other noncompetitive first antagonists of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor produce a psychosis resembling schizophrenia has driven hypotheses of glutamatergic dysfunction in the disorder.73 There are now some postmortem data in schizophrenia to support this proposal. For example, in the temporal lobe, glutamatergic markers are decreased,74 with reduced expression of non-NMDA glutamate receptors.75 In the prefrontal cortex, the alterations Pexidartinib chemical structure affect.