Stress-Induced Dopamine Response in Subjects at Clinical High Risk for Schizophrenia with and without Concurrent Cannabis Use

Research on the environmental risk factors for schizophrenia has focused on either psychosocial stress or drug exposure, with limited investigation of their interaction. A heightened dopaminergic stress response in patients with schizophrenia and individuals at clinical high risk (CHR) supports the dopaminergic sensitization hypothesis. Cannabis is believed to contribute to the development of schizophrenia, possibly through a cross-sensitization with stress. Twelve CHR and 12 cannabis-using CHR (CHR-CU, 11 dependent) subjects underwent [C-11]-(+)-PHNO positron emission tomography scans, while performing a Sensorimotor Control Task (SMCT) and a stress condition (Montreal Imaging Stress task). The simplified reference tissue model was used to obtain binding potential relative to non-displaceable binding (BPND) in the whole striatum, its functional subdivisions (limbic striatum (LST), associative striatum (AST), and sensorimotor striatum (SMST)), globus pallidus (GP), and substantia nigra (SN). Changes in BPND, reflecting alterations in synaptic dopamine (DA) levels, were tested with analysis of variance. SMCT BPND was not significantly different between groups in any brain region (p>0.21). Although stress elicited a significant reduction in BPND in the CHR group, CHR-CU group exhibited an increase in BPND. Stress-induced changes in regional BPND between CHR-CU and CHR were significantly different in AST (p<0.001), LST (p=0.007), SMST (p=0.002), SN (p=0.021), and whole striatum (p=0.001), with trend level in the GP (p=0.099). All subjects experienced an increase in positive (attenuated) psychotic symptoms (p=0.001) following the stress task Our results suggest altered DA stress reactivity in CHR subjects who concurrently use cannabis, as compared with CHR subjects. Our finding does not support the cross-sensitization hypothesis, which posits greater dopaminergic reactivity to stress in CHR cannabis users, but adds to the growing body of literature showing reduced DA (stress) response in addiction.