Patients who have a phenotype of psychosis that is responsive to dopamine-blocking medication may have dysregulated striatal hyperdopaminergia related to circuit abnormalities within the fronto-striatal complex of the mesolimbic dopaminergic pathway. Glutamatergic projections from the PFC to the ventral tegmental area (VTA) normally regulate dopamine release in the nucleus accumbens. Within this circuit phenotype, hypofunctioning NMDA glutamate receptors on cortical parvalbumin+ GABAergic interneurons will cause an excessive release of glutamate within the VTA. Hyperglutamatergia then leads to overstimulation (on circuit phenotype) of dopaminergic neurons within the mesolimbic dopamine pathway and excessive release of dopamine within limbic structures, such as the nucleus accumbens, amygdala and hippocampus (130, 131). Hyperdopaminergia within the fronto-striatal circuit underlies the beneficial positive symptom domain response that treatment-responsive patients achieve with D2-blocking medications.