The impact of risk factors for psychosis on the dopamine system

Abstract

Risk factors are thought to dysregulate dopamine function leading to the positive psychotic symptoms of schizophrenia. The most common genetic variants affecting the DISC1 gene are associated with schizophrenia, but it is not known if they influence the dopamine system. Evidence indicates that childhood trauma sensitises the dopamine system to increase the effect of later challenges, such as amphetamine. However, it is not known if childhood trauma interacts with amphetamine on dopamine release to induce psychotic symptoms. My first hypothesis was that the DISC1 serine 704 allele (rs821616) was associated with increased dopamine synthesis using [18F]-DOPA PET. Healthy participants DISC1 serine 704 homozygotes exhibited increased striatal dopamine synthesis relative to cysteine 704 carriers, supporting the hypothesis. My second hypothesis was that the DISC1 alleles serine 704 (rs821616), leucine 607 (rs6675281) and arginine 264 (rs3738401) showed increased dopamine receptor levels, using [11C]-(+)-PHNO PET. There was no association between these polymorphisms and striatal dopamine receptor levels in healthy volunteers, refuting the hypothesis. My final hypothesis was that there was an interaction between striatal dopamine release and childhood trauma to increase dexamphetamine-induced psychotic symptoms in healthy participants, using [11C]-(+)-PHNO. Neither childhood trauma nor dopamine release in isolation were predictors of dexamphetamine-induced psychotic symptoms, but a significant interaction was observed between these two variables, supporting the hypothesis. These studies showed 1) that a genetic risk variant is associated with dopamine synthesis but that other variants affecting the gene are not associated with dopamine receptor levels; 2) that induced-psychotic symptoms depend on the interaction between childhood trauma and ventral striatal dopamine release. This is consistent with the theory that a common action of risk factors for schizophrenia is to dysregulate dopamine synthesis and release, but not receptors. Further work is needed to examine how these risk factors affect dopamine function in clinical populations.