Targeting Cognitive Deficits in Schizophrenia via GABAA Receptors: Focus on α2, α3, and α5 Receptor Subtypes

Uwe Rudolph, H. Möhler

Research output: Chapter in Book/Report/Conference proceedingChapter

Abstract

Deficits in inhibitory GABAergic neurotransmission are likely involved in the pathophysiology of schizophrenia, specifically in cognitive deficits, positive symptoms, and possibly also negative symptoms. GABAA receptors are heteropentamers that are typically classified based on their subunits. Different GABAA receptors have been shown to have distinct physiological and pharmacological functions, and animal models suggest that dysfunction in neuronal circuits containing alpha2-GABAA and possibly α5-GABAA receptors contributes to cognitive deficits and that dysfunction in neuronal circuits containing α3-GABAA or α5-GABAA receptors contribute to increased dopaminergic activity. The α2/α3-selective positive allosteric modulator TPA023 (MK-0777) reduced ketamine-induced memory deficit in primates, and the α5-selective positive allosteric modulator SH-053-2F-R-CH3 reduced hyperactivity of the dopamine system in the rat methylazoxymethanol acetate (MAM) developmental model of schizophrenia. Thus, despite a negative phase II study with TPA023 (MK-0777) in humans, more efficacious subtype-selective GABAA receptor modulators may become useful therapeutic agents targeting cognition and specific pathophysiological deficits in schizophrenia.

Original languageEnglish (US)
Title of host publicationThe Neurobiology of Schizophrenia
PublisherElsevier Inc.
Pages149-164
Number of pages16
ISBN (Electronic)9780128018774
ISBN (Print)9780128018293
DOIs
StatePublished - Jul 26 2016
Externally publishedYes

Keywords

  • Benzodiazepines
  • GABA receptor
  • MK-0777
  • SH-053-2F-R-CH
  • Schizophrenia
  • TPA023

ASJC Scopus subject areas

  • Neuroscience(all)

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