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

• Published in: Neuropharmacology 2013-01, Vol.64, p.191-196
• Main Authors: Cannon, Christopher E., Puri, Vanita, Vivian, Jeffrey A., Egbertson, Melissa S., Eddins, Donnie, Uslaner, Jason M.
• Format: Article
• Language: English
• Subjects: alpha7 Nicotinic Acetylcholine Receptor; Animals; Behavior, Animal - drug effects; Benzylidene Compounds - therapeutic use; Cholinesterase Inhibitors - adverse effects; Cholinesterase Inhibitors - therapeutic use; Cognition; Cognition - drug effects; Cognition Disorders - etiology; Cognition Disorders - prevention & control; Disease Models, Animal; Donepezil; Drug Evaluation, Preclinical - methods; Excitatory Amino Acid Antagonists; GTS-21; Indans - adverse effects; Indans - therapeutic use; Ketamine; Macaca mulatta; Male; Molecular Targeted Therapy; Nicotinic Agonists - adverse effects; Nicotinic Agonists - therapeutic use; Nicotinic α7 receptor; Nootropic Agents - adverse effects; Nootropic Agents - therapeutic use; Piperidines - adverse effects; Piperidines - therapeutic use; Prefrontal cortex; Primate; Psychomotor Performance - drug effects; Pyridines - therapeutic use; Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors; Receptors, Nicotinic - chemistry; Receptors, Nicotinic - metabolism; Schizophrenia; Schizophrenia - drug therapy; Schizophrenia - physiopathology
• ISSN: 0028-3908; 1873-7064
• DOI: 10.1016/j.neuropharm.2012.05.003

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’. ► Preclinical, translatable models of schizophrenia-specific cognition are needed. ► A ketamine-impaired object retrieval assay was developed in the rhesus monkey. ► GTS-21, but not donepezil, reversed the ketamine-induced cognitive impairment. ► This model could provide vital translation between the clinic and preclinic.