The nicotinic α7 receptor agonist GTS-21 improves cognitive performance in ketamine impaired rhesus monkeys.
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'.
Merck Research Laboratories 44E-200, 770 Sumneytown Pike, West Point, PA 19486, USA. christopher_cannon@merck.com
Christopher E
CE
Cannon
Vanita
V
Puri
Jeffrey A
JA
Vivian
Melissa S
MS
Egbertson
Donnie
D
Eddins
Jason M
JM
Uslaner
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001597:Benzylidene Compounds / Q000627:therapeutic use*; D002800:Cholinesterase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use; D003071:Cognition / Q000187:drug effects; D003072:Cognition Disorders / Q000209:etiology / Q000517:prevention & control*; D004195:Disease Models, Animal; D000077265:Donepezil; D004353:Drug Evaluation, Preclinical / Q000379:methods; D018691:Excitatory Amino Acid Antagonists; D007189:Indans / Q000009:adverse effects / Q000627:therapeutic use; D007649:Ketamine; D008253:Macaca mulatta; D008297:Male; D058990:Molecular Targeted Therapy; D018722:Nicotinic Agonists / Q000009:adverse effects / Q000627:therapeutic use*; D018697:Nootropic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D010880:Piperidines / Q000009:adverse effects / Q000627:therapeutic use; D011597:Psychomotor Performance / Q000187:drug effects; D011725:Pyridines / Q000627:therapeutic use*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D011978:Receptors, Nicotinic / Q000737:chemistry / Q000378:metabolism*; D012559:Schizophrenia / Q000188:drug therapy* / Q000503:physiopathology; D064569:alpha7 Nicotinic Acetylcholine Receptor
D001597:Benzylidene Compounds; D002800:Cholinesterase Inhibitors; D018691:Excitatory Amino Acid Antagonists; D007189:Indans; D018722:Nicotinic Agonists; D018697:Nootropic Agents; D010880:Piperidines; D011725:Pyridines; D016194:Receptors, N-Methyl-D-Aspartate; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; D007649:Ketamine; C088936:3-(2,4-dimethoxybenzylidene)anabaseine; D000077265:Donepezil