When repeatedly administered, d-amphetamine (AMPH) induces behavioral sensitization and a progressive amplification in AMPH-induced DA release 14, 15, 16. Sensitization denotes a process by which repeated exposure to a stimulus induces a progressive increase in responses to the very same stimulus 12, 13. While the pathophysiological basis of DA dysfunction in SCZ remains unknown, current versions of the DA theory of SCZ 8 posit that upstream pathogenic factors converge on subcortical DA pathways to mediate the expression and intensity of psychotic symptoms 9, 10, 11. The common mechanism of action of all antipsychotic drugs-reducing DA transmission at postsynaptic D 2/3 receptors-confirms the key role of DA signaling in psychosis 7. Positron emission tomography (PET) studies show increased dopamine synthesis capacity and heightened behavioral and neurochemical responses towards DA-releasing compounds 1, 2, 3, 4, 5, 6. Several lines of evidence demonstrate increased subcortical dopamine (DA) transmission in psychotic patients with schizophrenia (SCZ). Our data in patients with untreated first-episode psychosis confirm the “endogenous sensitization” hypothesis and support the notion of impaired prefrontal control of the dopamine system in schizophrenia. There was no such relationship after sensitization or in patients. Healthy volunteers showed a negative correlation between prefrontal cortical volume and dopamine release. After sensitization of healthy volunteers their dopamine release was significantly amplified and no longer different from that seen in patients. Patients with first-episode psychosis showed larger release of dopamine compared to healthy volunteers. Furthermore, T1 weighted magnetic resonance imaging of the prefrontal cortex was performed. Unmedicated patients with first-episode psychosis ( n = 21 6 female) underwent a single pair of baseline and then post-amphetamine scans. Healthy volunteers ( n = 28, 14 female) underwent a baseline and then a post-amphetamine scan before and after a mildly sensitizing regimen of repeated oral amphetamine. To show that patients with first-episode psychosis release more dopamine upon amphetamine-stimulation than healthy volunteers, and to reveal for the first time that prospective sensitization induced by repeated amphetamine exposure increases dopamine-release in stimulant-naïve healthy volunteers to levels observed in patients, we collected data on amphetamine-induced dopamine release using the dopamine D 2/3 receptor agonist radioligand -(+)-PHNO and positron emission tomography. This prompted the hypothesis of psychosis as a state of “endogenous” sensitization of the dopamine system although the exact basis of dopaminergic disturbances and the possible role of prefrontal cortical regulation have remained uncertain. Schizophrenia is characterized by increased behavioral and neurochemical responses to dopamine-releasing drugs. Translational Psychiatry volume 10, Article number: 2 ( 2020) On the relationship of first-episode psychosis to the amphetamine-sensitized state: a dopamine D 2/3 receptor agonist radioligand study
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