The nicotinic α7 receptor agonist GTS-21 improves cognitive performance in ketamine impaired rhesus monkeys

Neuropharmacology. 2013 Jan;64:191-6. doi: 10.1016/j.neuropharm.2012.05.003. Epub 2012 May 29.

Abstract

The cognitive deficits associated with schizophrenia are recognized as a core component of the disorder, yet there remain no available therapeutics to treat these symptoms of the disease. As a result, there is a need for establishing predictive preclinical models to identify the therapeutic potential of novel compounds. In the present study, rhesus monkeys were trained in the object retrieval-detour task, which is dependent on the prefrontal cortex, a brain region implicated in the cognitive deficits associated with schizophrenia. The NMDA receptor antagonist ketamine significantly impaired performance without affecting measures of motor or visuospatial abilities. Pre-treatment with the nicotinic α7 agonist GTS-21 (0.03 mg/kg) significantly attenuated the ketamine-induced impairment, consistent with reports from clinical trials suggesting that nicotinic α7 receptor agonism has pro-cognitive potential in clinical populations. In contrast, pretreatment with the acetylcholinesterase inhibitor donepezil failed to reverse the ketamine-induced impairment, consistent with studies showing a lack of pro-cognitive effects in patients with schizophrenia. These data suggest that the ketamine-impaired object retrieval-detour task could provide a model with improved predictive validity for drug development, and confirm the need for additional efforts in back-translation. This article is part of a Special Issue entitled 'Cognitive Enhancers'.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Behavior, Animal / drug effects
  • Benzylidene Compounds / therapeutic use*
  • Cholinesterase Inhibitors / adverse effects
  • Cholinesterase Inhibitors / therapeutic use
  • Cognition / drug effects
  • Cognition Disorders / etiology
  • Cognition Disorders / prevention & control*
  • Disease Models, Animal*
  • Donepezil
  • Drug Evaluation, Preclinical / methods
  • Excitatory Amino Acid Antagonists
  • Indans / adverse effects
  • Indans / therapeutic use
  • Ketamine
  • Macaca mulatta
  • Male
  • Molecular Targeted Therapy
  • Nicotinic Agonists / adverse effects
  • Nicotinic Agonists / therapeutic use*
  • Nootropic Agents / adverse effects
  • Nootropic Agents / therapeutic use*
  • Piperidines / adverse effects
  • Piperidines / therapeutic use
  • Psychomotor Performance / drug effects
  • Pyridines / therapeutic use*
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors
  • Receptors, Nicotinic / chemistry
  • Receptors, Nicotinic / metabolism*
  • Schizophrenia / drug therapy*
  • Schizophrenia / physiopathology
  • alpha7 Nicotinic Acetylcholine Receptor

Substances

  • Benzylidene Compounds
  • Cholinesterase Inhibitors
  • Excitatory Amino Acid Antagonists
  • Indans
  • Nicotinic Agonists
  • Nootropic Agents
  • Piperidines
  • Pyridines
  • Receptors, N-Methyl-D-Aspartate
  • Receptors, Nicotinic
  • alpha7 Nicotinic Acetylcholine Receptor
  • Ketamine
  • 3-(2,4-dimethoxybenzylidene)anabaseine
  • Donepezil