The circuit diagram in the previous node displays various transmitter receptors as components of the NRHypo system, with individual receptor systems showing either an inhibitory or excitatory  influence (this contributes to the dynamic system equilibrium). This article explains that there is no evidence of D2 receptors functioning within the network, but they may be essential extrinsic regulatory substances. 

Role of dopamine in the Glu model

Glu functions as a major regulatory of inhibitory tone and an excitatory agent in the brain. To achieve this, Glu activates NMDA recepotors on GABAergic, noradrenergic, and serotonergic neurons, which causes them to inhibit major excitatory pathways that innervate cerebrocortical and limbic brain neurons. Glu is then used as a transmitter and fire a recurrent inhibitory collateral to an NMDA receptor on a GABAergic neuron. If an excitatory input to the primary neurons is strong and persistent enough, it will slowly kill these neurons and prevent them from firing on other neurons. This may describe the clinical deterioration seen in some patients (manifestation of enduring symptoms, positive symptom burnout an cognitive loss)

Disinhibition as the core principle of Glu

A primary disturbance in the DA system causes it to hyperinhibit the release or Glu at receptors for NMDA. This causes the NMDA receptor system to become hypofunctional. NRHypo equivalent conditions could also produce the network disruption, like GABAergic disturbances that prevent Glu from moving through NMDA receptors (causing regulated inhibition). 

Genetic Mechanisms that may contribute to an NRHypo state

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. 

University of Illinois at Chicago

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)

Complex polysynaptic network disturbance is the pathophysiological mechanism

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.

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