Identification of novel susceptibility pathways and drug targets for psychosis

Niels Speksnijder

Amphetamine use, both acute and chronic, results in symptoms that resemble many aspects of mania and psychosis. Therefore the mechanisms that underlie the response to amphetamine may play a role in a psychosis. In inbred mice we showed that there are large interindividual differences in vulnerability to amphetamine, measured in a locomotor paradigm. Microarray-based expression profiles from selected low and high responders to amphetamine showed large numbers of differentially expressed genes in the NAcc, CA1 and PFC. Real-time quantitative PCR (RT qPCR) and in situ hybridization were used to validate these results. The effects were found to be largest in the CA1 area of the hippocampus.

Pathway analysis of the differentially expressed genes indicated an enrichment of genes involved in glucocorticoid-signaling and/or implicated in epigenetic processes.

Stress is known to be a vulnerability factor for psychosis so we hypothesize that the mechanism underlying the individual differences to amphetamine are glucocorticoid dependent. We will investigate whether the genes differentially expressed between low and high responders are glucocorticoid-responsive and if we can change its expression by siRNA treatment. We also plan to study whether the high responder phenotype can be reversed by targeting one of the differentially expressed genes.

In this way we would like to gain insight in the mechanism behind individual vulnerability to psychosis.