Blunted fear-evoked striatal dopamine release in individuals with a family history of psychosis

While excess tonic dopamine signalling is a hallmark of schizophrenia and psychotic disorders, it has been difficult to reconcile with dopamine-dependent learning deficits seen in schizophrenia. Excess spontaneous activity of tonic dopamine neurons, coupled with reduced coordinated activity of phasic dopamine neurons, may explain the observed discrepancy between increased tonic signalling and impaired learning. Although intriguing, this chaotic dopamine hypothesis lacks empirical support. In the current study, Pavlovian fear conditioning is used to test this hypothesis in healthy individuals with and without a family history of psychosis using simultaneous [11C]raclopride PET/fMRI. In 16 healthy individuals without a family history of psychosis, we first show that fear conditioning releases dopamine and link this release to BOLD responses. We then report that in 12 first-degree relatives of individuals with psychotic disorders, this adaptive dopamine release in the posterior caudate is lacking, despite no differences in behavioural learning. Furthermore, reduced dopamine release is associated with increased self-reported paranoid thinking, but not with anhedonia. These findings provide novel in vivo evidence supporting the chaotic dopamine hypothesis, suggesting that an adaptive, stimulus-driven dopamine release is lacking in psychotic disorders and may contribute to positive symptoms like paranoia.