Molecular Imaging of Dopaminergic Neurotransmission in Subclinical Paranoia

Elevated dopamine system function in the striatum is a hallmark of psychotic illness. However, the extent to which genetic risk factors contribute to striatal hyperdopaminergia remains largely unexplored. Here, we examined dopaminergic correlates of psychosis risk in those with and without a first-degree relative with psychosis. In the first study, we examined neuromelanin-sensitive magnetic resonance imaging (NM-MRI), which is a proxy of dopamine released over the lifespan and has been shown to be associated with positive symptoms in psychosis. We show that despite lack of a group difference in NM-MRI between those with and without a first-degree relative with psychosis, frequency of subclinical paranoid thought is associated with elevated NM-MRI in the dorsomedial substantia nigra and ventral tegmental area complex. In the second study, we examined task-based dopamine release in the same population using simultaneous [¹¹C]raclopride positron emission tomography (PET) and functional MRI (fMRI) during fear conditioning. First, we confirmed the validity of the PET/fMRI experiment to capture dopamine release during the fear conditioning task. We show that fear conditioning elicits dopamine release in the dorsoposterior striatum of humans, which for the first time, confirms fear-elicited dopamine release in the analogous rodent tail of the striatum. We then compared dopamine release during fear conditioning in those with and without a first-degree relative with psychosis. We report that dopamine release is blunted in the dorsoposterior striatum in those with a first-degree relative. Finally, we report that lack of dopamine release in the dorsoposterior striatum is associated with increased frequency of subclinical paranoid thought. We also show that poor recall of the CS+ is associated with increased frequency of subclinical paranoid thought. For the first time, our findings suggest a lack of adaptive dopamine release is associated with subclinical positive symptomatology. Altogether, these two studies demonstrate that a static measure of dopamine released over the lifespan may be associated with paranoid thought, but that this increased release may not be occurring at relevant times and that a lack of adaptive dopamine release may be also contributing to paranoia, a prominent positive symptom in psychosis.