Selective GABA(A) α5 positive allosteric modulators improve cognitive function in aged rats with memory impairment

Neuropharmacology. 2013 Jan;64(1):145-52. doi: 10.1016/j.neuropharm.2012.06.023. Epub 2012 Jun 23.


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 GABA(A) α5 receptors might be useful in targeting this condition because GABA(A) 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 GABA(A) 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 GABA(A) 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'.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging*
  • Allosteric Regulation
  • Animals
  • Carboxylic Acids / administration & dosage
  • Carboxylic Acids / therapeutic use
  • Cognition / drug effects*
  • Cognitive Dysfunction / drug therapy*
  • GABA-A Receptor Agonists / administration & dosage
  • GABA-A Receptor Agonists / therapeutic use*
  • Hippocampus / drug effects
  • Hippocampus / growth & development
  • Hippocampus / metabolism
  • Infusions, Intraventricular
  • Injections, Intraperitoneal
  • Male
  • Memory / drug effects
  • Memory Disorders / drug therapy*
  • Molecular Targeted Therapy
  • Neurons / drug effects
  • Neurons / metabolism
  • Nootropic Agents / administration & dosage
  • Nootropic Agents / therapeutic use*
  • Pyridazines / administration & dosage
  • Pyridazines / therapeutic use
  • Rats
  • Rats, Long-Evans
  • Receptors, GABA-A / chemistry
  • Receptors, GABA-A / metabolism*
  • Specific Pathogen-Free Organisms
  • Synaptic Transmission / drug effects
  • Thiazoles / administration & dosage
  • Thiazoles / therapeutic use
  • Thiophenes / administration & dosage
  • Thiophenes / therapeutic use


  • 6,6-dimethyl-3-(3-hydroxypropyl)thio-1-(thiazol-2-y)-6,7-dihydro-2-benzothiophen-4(5H)-one
  • Carboxylic Acids
  • GABA-A Receptor Agonists
  • Gabra5 protein, rat
  • Nootropic Agents
  • Pyridazines
  • Receptors, GABA-A
  • Thiazoles
  • Thiophenes
  • methyl 3,5-diphenylpyridazine-4-carboxylate