Amphetamine-Induced Striatal Dopamine Release Measured With an Agonist Radiotracer in Schizophrenia

BACKGROUND: Receptor imaging studies have reported increased amphetamine-induced dopamine release in subjects with schizophrenia (SCH) relative to healthy control subjects (HCs). A limitation of these studies, performed with D-2/3 antagonist radiotracers, is the failure to provide information about D-2/3 receptors configured in a state of high affinity for the agonists (i.e., D-2/3 receptors coupled to G proteins [D-2/3 (HIGH)]). The endogenous agonist dopamine binds with preference to D-2/3 HIGH receptors relative to D-2/3 LOW receptors, making it critical to understand the status of D-2/3 HIGH receptors in SCH. METHODS: D-2/3 agonist positron emission tomography radiotracer [C-11]N-propyl-norapomorphine ([C-11]NPA) binding potential (BPND) was measured in 14 off-medication subjects with SCH and 14 matched HCs at baseline and after the administration of 0.5 mg kg(-1) oral D-amphetamine. The amphetamine-induced change in BPND (Delta BPND) was calculated as the difference between BPND in the postamphetamine condition and BPND in the baseline condition and was expressed as a percentage of BPND at baseline. RESULTS: A trend-level increase was observed in comparing baseline [C-11]NPA BPND (repeated-measures analysis of variance, F-1,F-26 = 3.34, p = .08) between the SCH and HC groups. Amphetamine administration significantly decreased BPND in all striatal regions across all subjects in both groups. No differences were observed in [C-11]NPA Delta BPND (repeated-measures analysis of variance, F-1,F-26 = 1.9, p = .18) between HCs and subjects with SCH. Amphetamine significantly increased positive symptoms in subjects with SCH (19.5 +/- 5.3 vs. 23.7 +/- 4.1, paired t test, p < 0001); however, no correlations were noted with [C-11]NPA BPND or Delta BPND. CONCLUSIONS: This study provides in vivo indication of a role for postsynaptic factors in amphetamine-induced psychosis in SCH.