It has been proposed that the nigrostriatal dopaminergic abnormalities arise secondary to dysfunction in cortical circuits; this proposes that lower cortical glutamate and NMDA receptor levels lead to reduced activation of cortical GABA interneurons regulating glutamatergic projection neurons into the striatum, as shown in the figure.1,2
Imaging studies indicate higher striatal dopamine, which has been linked to psychotic symptoms.2
Lower cortical levels of glutamate and GABA underpin an excitation/inhibition imbalance, which has been linked to both cognitive deficits and negative symptoms.2
This helps explain why dopamine-targeting treatments improve psychosis but often have limited effects on negative symptoms and cognition, as these are likely reflecting upstream cortical glutamatergic, and GABAergic dysfunction.2
GABA=gamma-aminobutyric acid; NDMA=N-methyl-D-aspartate
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