Abstract
Schizophrenia is characterized by increased behavioral and neurochemical responses to dopamine-releasing drugs. 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. 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 D2/3 receptor agonist radioligand [11C]-(+)-PHNO and positron emission tomography. 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. Unmedicated patients with first-episode psychosis (n = 21; 6 female) underwent a single pair of baseline and then post-amphetamine scans. Furthermore, T1 weighted magnetic resonance imaging of the prefrontal cortex was performed. Patients with first-episode psychosis showed larger release of dopamine compared to healthy volunteers. After sensitization of healthy volunteers their dopamine release was significantly amplified and no longer different from that seen in patients. Healthy volunteers showed a negative correlation between prefrontal cortical volume and dopamine release. There was no such relationship after sensitization or in patients. 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.
Highlights
Several lines of evidence demonstrate increased subcortical dopamine (DA) transmission in psychoticThe common mechanism of action of all antipsychotic drugs—reducing DA transmission at postsynaptic D2/3 receptors—confirms the key role of DA signaling in psychosis[7]
Exclusion criteria comprised any intake of drugs of abuse except nicotine, caffeine, and alcohol, five or more stimulant exposures lifetime, psychiatric disorders, having a first-degree relative with schizophrenia or bipolar disorder or having any contraindications against receiving a Positron emission tomography (PET), MRI or damphetamine; in addition, first-episode psychosis (FEP) patients were required to have a minimum Positive and Negative Symptom Scale (PANSS26,27) score of 55 with >3 on at least two PANSS psychosis items or >4 on one psychosis item; no or minimal lifetime exposure to antipsychotics; no lifetime exposure to antipsychotic depot preparations; no antipsychotics within two weeks prior to scanning
DA release in FEP and sensitization The concept of “endogenous sensitization” in psychosis[17] predicts that the difference in AMPH-induced DA release between FEP patients and Healthy volunteers (HV) should disappear or substantially diminish after HV are sensitized to AMPH
Summary
Several lines of evidence demonstrate increased subcortical dopamine (DA) transmission in psychoticThe common mechanism of action of all antipsychotic drugs—reducing DA transmission at postsynaptic D2/3 receptors—confirms the key role of DA signaling in psychosis[7]. Sensitization denotes a process by which repeated exposure to a stimulus induces a progressive increase in responses to the very same stimulus[12,13]. Since psychotic patients show elevated responses to AMPH without any prior drug exposure[1], psychosis has been conceptualized as a state of “endogenous sensitization”[10,17,18]. In order to collect experimental evidence supporting this concept, we used PET and the DA D2/3 receptor agonist radioligand (+)-4-propyl3,4,4a,5,6,10b-hexahydro-2H-naphtho[1,2-b][1,4]oxazin9-ol ([11C]-(+)-PHNO)[24] for measuring AMPH-induced changes in D2/3 receptor binding, semi-quantitative index of DA release, in drug-naïve patients with first-episode psychosis (FEP). In order to identify upstream pathogenic mechanisms of psychotic hyperdopaminergia, we analyzed volumetric parameters in the PFC for their relationship to indices of subcortical DA release
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