Striatal dopamine release in schizophrenia comorbid with substance dependence

Abstract

Dopamine plays a role in the pathophysiology of schizophrenia and addiction. Imaging studies have indicated that striatal dopamine release is increased in schizophrenia, predominantly in the precommissural caudate (preDCA), and blunted in addiction, mostly in the ventral striatum (VST). Therefore we aimed to measure striatal dopamine release in patients with comorbid schizophrenia and substance dependence. We used [11C]raclopride PET and an amphetamine challenge to measure baseline dopamine D2-receptor availability (BPND) and its percent change post-amphetamine (∆BPND, to index amphetamine-induced dopamine release) in striatal subregions in 11 unmedicated, drug-free patients with both schizophrenia and substance dependence and 15 healthy controls. There were no significant group differences in baseline BPND. Linear mixed modeling using ∆BPND as the dependent variable and striatal ROI as a repeated measure indicated a significant main effect of diagnosis, F(1, 24)=8.38, p=.008, with significantly smaller ∆BPND in patients in all striatal subregions (all ps≤.04) except VST. Among patients, change in positive symptoms after amphetamine was significantly associated with ∆BPND in the preDCA (rs=.69, p=.03) and VST (rs=.64, p=.05). In conclusion, patients with comorbid schizophrenia and substance dependence showed significant blunting of striatal dopamine release, in contrast to what has been found in schizophrenia without substance dependence. Despite this blunting, dopamine release was associated with the transient amphetamine-induced positive-symptom change, as observed in schizophrenia. This is the first description of a group of patients with schizophrenia who display low presynaptic dopamine release, yet show a psychotic reaction to increases in D2 stimulation, suggesting abnormal post-synaptic D2 function.