Effective connectivity of AKT1-mediated dopaminergic working memory networks and pharmacogenetics of anti-dopaminergic treatment
Brain, 05/17/2012Tan HY et al.
The authors suggest that genetic modulation of DRD2–AKT1–related prefrontal–subcortical circuits could at least in part influence cognitive dysfunction in psychosis and its treatment.
The authors examined predictions from basic models of dopaminergic signalling in cortical and cortical–subcortical circuitries implicated in dissociable working memory maintenance and manipulation processes.
They also examined pharmacogenetic effects on cognition in the context of anti–dopaminergic drug therapy.
Using dynamic causal models of functional magnetic resonance imaging in normal subjects (n=46), they identified differentiated effects of functional polymorphisms in COMT, DRD2 and AKT1 genes on prefrontal–parietal and prefrontal–striatal circuits engaged during maintenance and manipulation, respectively.
Cortical synaptic dopamine monitored by the COMT Val158Met polymorphism influenced prefrontal control of both parietal processing in working memory maintenance and striatal processing in working memory manipulation.
DRD2 and AKT1 polymorphisms implicated in DRD2 signalling influenced only the prefrontal–striatal network associated with manipulation.
In the context of anti–psychotic drugs, the DRD2 and AKT1 polymorphisms altered dose–response effects of anti–psychotic drugs on cognition in schizophrenia (n=111).
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