The role of α5 GABAA receptor agonists in the treatment of cognitive deficits in schizophrenia

Curr Pharm Des. 2014;20(31):5069-76. doi: 10.2174/1381612819666131216114612.

Abstract

Currently available pharmacotherapies for the treatment of schizophrenia are ineffective in restoring the disrupted cognitive function associated with this disorder. As such, there is a continued search for more viable novel drug targets. Engaging in cognitive behaviors is associated with distinct coordinated oscillatory activity across brain regions, in particular the hippocampus and prefrontal cortex. In schizophrenia patients, pathological alterations in the functionality of GABAergic interneurons in the PFC and HPC responsible for generating network oscillations are thought to contribute to impaired cognition. Destabilized GABAergic interneuron activity in the HPC is further associated with aberrant increases in HPC output and enhanced dopamine neuron activity. Consequently, drugs directed at restoring HPC function could impact both oscillatory activity along with dopamine tone. There is compelling evidence from animal models of schizophrenia that allosteric modulation of the α5 subunit of the GABA<sub>A</sub> receptor is a viable means of resolving aberrant dopamine system activity through indirect alteration of HPC output. Consequently, these compounds are promising for their potential in also ameliorating cognitive deficits attributed to dysfunction in HPC network activity.

Publication types

  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • Animals
  • Cognition Disorders / complications
  • Cognition Disorders / drug therapy*
  • Cognition Disorders / physiopathology
  • Dopamine / physiology
  • GABA-A Receptor Agonists / pharmacology*
  • GABA-A Receptor Agonists / therapeutic use*
  • Hippocampus / drug effects
  • Hippocampus / physiology
  • Humans
  • Models, Neurological
  • Neural Pathways / drug effects
  • Neural Pathways / physiopathology
  • Nootropic Agents / pharmacology
  • Nootropic Agents / therapeutic use
  • Prefrontal Cortex / drug effects
  • Prefrontal Cortex / physiology
  • Schizophrenia / complications
  • Schizophrenia / drug therapy*
  • Schizophrenia / physiopathology
  • Schizophrenic Psychology*

Substances

  • GABA-A Receptor Agonists
  • Nootropic Agents
  • Dopamine