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

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.

D_2/3 agonist positron emission tomography radiotracer [¹¹C]N-propyl-norapomorphine ([¹¹C]NPA) binding potential (BP_ND) 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 BP_ND (ΔBP_ND) was calculated as the difference between BP_ND in the postamphetamine condition and BP_ND in the baseline condition and was expressed as a percentage of BP_ND at baseline.

A trend-level increase was observed in comparing baseline [¹¹C]NPA BP_ND (repeated-measures analysis of variance, F_1,26 = 3.34, p = .08) between the SCH and HC groups. Amphetamine administration significantly decreased BP_ND in all striatal regions across all subjects in both groups. No differences were observed in [¹¹C]NPA ΔBP_ND (repeated-measures analysis of variance, F_1,26 = 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 [¹¹C]NPA BP_ND or ΔBP_ND.

This study provides in vivo indication of a role for postsynaptic factors in amphetamine-induced psychosis in SCH.