In order to explain the induced neurotoxicity of NRHypo, this article suggested that Glu acting through NMDA receptors on noradrenergic, serotonergic and GABAergic neurons inhibits tonic control over many excitatory routes that innervate PC/RS neurons. Administration of one NMDA receptor antagonist would get rid of inhibitory control over various excitatory inputs. This creates disruption for many intracellular messenger system, which leads to derangement of cognitive functions as well as the progressive degeneration of these neurons. The diagram above focuses only on PC/RS neurons. 

Glu activating through NMDA receptors

Classes of drugs that abort the mechanism by which the NRHypo state damages the brain
- GABAa agonists
- muscarinic antagonists
- nonNMDA Glu antagonists
- sigma agents
- a2-adrenergic agonists
- 5HT2a agonists
- novel antipsychotics (such as olanzapine and clozapine)

University of Illinois at Chicago

Many researchers agree that similarities in many major symptom classifications is astounding, and a PCP diagnoses is difficult to separate from schizophrenia. PCP also is known for triggering a prolonged state of acute psychotic symptoms in chronic schizophrenia patients, while other drugs (like LSD) do not cause this scenario. Furthermore, many NMDA antagonists are able to trigger a florrid psychotic reaction similar to PCP psychosis. Since all of these drugs induce an NRHypo state, this article suggests that an NRHypo state (if present in a schizophrenic patient) could explain elements that characterize that illness. 

Evidence supporting hypothesis of NRHypo model

Corso, T. D., & Farber, N. B., et al., (1999, November 29). NMDA receptor hypofunction model of schizophrenia. Journal of Psychiatric Research. https://www.sciencedirect.com/science/article/abs/pii/S0022395699000291#:~:text=When%20the%20NMDA%20receptors%20in,hyperstimulate%20the%20primary%20corticolimbic%20neurons.

NMDA receptor hypofunction model of schizophrenia

As the defect in schizophrenia is developmentally related, this may cause certain treatment approaches to be sabotaged. If this study is correct in its assumption that specific excitatory receptors that lay on the surface of cerebrocortical neurons are being hyperstimulated, then this is a contribution to neurodegenerative or psychotic manifestations of schizophrenia. 

Pharmacological Approaches for this model

The image below displays the distribution of degenerating neurons at eight different levels of an adult rat brain. These results show how the brain looks 4 days following treatment when exposed to a high dosage of an NMDAThis shows which neuronal populations are most at risk of degeneration when the NMDA receptor system is hypofunctional. 

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