Selective GABAA α5 positive allosteric modulators improve cognitive function in aged rats with memory impairment

Ming Teng Koh, Sharon Rosenzweig-Lipson, Michela Gallagher

Research output: Contribution to journalArticle

Abstract

A condition of excess activity in the hippocampal formation is observed in the aging brain and in conditions that confer additional risk during aging for Alzheimer's disease. Compounds that act as positive allosteric modulators at GABAA α5 receptors might be useful in targeting this condition because GABAA α5 receptors mediate tonic inhibition of principal neurons in the affected network. While agents to improve cognitive function in the past focused on inverse agonists, which are negative allosteric modulators at GABAA α5 receptors, research supporting that approach used only young animals and predated current evidence for excessive hippocampal activity in age-related conditions of cognitive impairment. Here, we used two compounds, Compound 44 [6,6-dimethyl-3-(3-hydroxypropyl)thio-1- (thiazol-2-yl)-6,7-dihydro-2-benzothiophen-4(5H)-one] and Compound 6 [methyl 3,5-diphenylpyridazine-4-carboxylate], with functional activity as potentiators of γ-aminobutyric acid at GABAA α5 receptors, to test their ability to improve hippocampal-dependent memory in aged rats with identified cognitive impairment. Improvement was obtained in aged rats across protocols differing in motivational and performance demands and across varying retention intervals. Significant memory improvement occurred after either intracereboventricular infusion with Compound 44 (100 μg) in a water maze task or systemic administration with Compound 6 (3 mg/kg) in a radial arm maze task. Furthermore, systemic administration improved behavioral performance at dosing shown to provide drug exposure in the brain and in vivo receptor occupancy in the hippocampus. These data suggest a novel approach to improve neural network function in clinical conditions of excess hippocampal activity. This article is part of a Special Issue entitled 'Cognitive Enhancers'.

Original languageEnglish (US)
Pages (from-to)145-152
Number of pages8
JournalNeuropharmacology
Volume64
DOIs
StatePublished - Jan 2013

Fingerprint

GABA-A Receptors
Cognition
Hippocampus
Nootropic Agents
Aminobutyrates
Aptitude
Brain
Alzheimer Disease
Neurons
Water
Research
Pharmaceutical Preparations
Cognitive Dysfunction

Keywords

  • GABA agonist
  • Inverse agonist
  • Mild cognitive impairment
  • Neural hyperactivity
  • Radial arm maze
  • Water maze

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Pharmacology

Cite this

Selective GABAA α5 positive allosteric modulators improve cognitive function in aged rats with memory impairment. / Koh, Ming Teng; Rosenzweig-Lipson, Sharon; Gallagher, Michela.

In: Neuropharmacology, Vol. 64, 01.2013, p. 145-152.

Research output: Contribution to journalArticle

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