The Glutamate Hypothesis of Schizophrenia

THE GLUTAMATE HYPOTHESIS OF SCHIZOPHRENIA

Glutamate is the major excitatory neurotransmitter in the brain . Phencyclidine and ketamine are noncompetitive inhibitors of the NMDA receptor that exacerbate both cogni-tive impairment and psychosis in patients with schizophrenia. PCP and a related drug, MK-801, increase locomotor activity and, acutely or chronically, a variety of cognitive impairments in rodents and primates. These effects are widely employed as a means to develop novel antipsychotic and cognitive-enhancing drugs. Selective 5-HT_2A antagonists, as well as atypical antipsy-chotic drugs, are much more potent than D₂ antagonists in blocking these effects of PCP and MK-801. This was the starting point for the hypothesis that hypofunction of NMDA receptors, located on GABAergic interneurons, leading to diminished inhibitory influences on neuronal function, contributed to schizophrenia. The diminished GABAergic activity can induce disinhibition of downstream glutamatergic activity, which can lead to hyperstimulation of cortical neurons through non-NMDA receptors. Preliminary evidence suggests that LY2140023, a drug that acts as an agonist of the metabotropic 2/3 glutamate receptor (mGLuR2/3), may be effective in schizophrenia.

The NMDA receptor, an ion channel, requires glycine for full activation. It has been suggested that in patients with schizophre-nia, the glycine site of the NMDA receptor is not fully saturated. There have been several trials of high doses of glycine to promote glutamatergic activity, but the results are far from convincing. Currently, glycine transport inhibitors are in development as pos-sible antipsychotic agents.

Ampakines are drugs that potentiate currents mediated by AMPA-type glutamate receptors. In behavioral tests, ampakines are effective in correcting behaviors in various animal models of schizophrenia and depression. They protect neurons against neu-rotoxic insults, in part by mobilizing growth factors such as brain-derived neurotrophic factor.