Effective connectivity of AKT1-mediated dopaminergic working memory networks and pharmacogenetics of anti-dopaminergic treatment

Brain, 05/18/2012

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.

Methods

  • 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.

Results

  • 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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