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Rationale: Disturbances in information processing and cognitive function are key features of schizophrenia. Nicotinic α7 acetylcholine receptors (α7-nAChR) are involved in sensory gating and cognition, thereby representing a viable therapeutic strategy. Objectives and methods: We investigated the effects of GTS-21, an α7-nAChR partial agonist, on prepulse inhibition (PPI) of acoustic startle in two pharmacologic impairment models in Wistar male rats: NMDA-glutamate receptor antagonism by MK-801 and dopamine receptor agonism by apomorphine. The cognitive effects of GTS-21 were assessed using the object recognition task (ORT) at short (3 h) and long (48 h) delays in Sprague-Dawley male rats. Pharmacological specificity was assessed by methyllycaconitine (MLA) coadministration with GTS-21. Results: In the PPI task, GTS-21 (1-10 mg/kg) alone did not alter the PPI response or startle amplitude. Coadministration of GTS-21 with MK-801 (0.1 mg/kg) or apomorphine (0.5 mg/kg) abolished the pharmacologic-induced PPI impairment as did the antipsychotics clozapine (5.0 mg/kg) and haloperidol (0.3 mg/kg). MK-801 alone increased startle amplitude which was blocked by GTS-21. In the ORT, GTS-21 (0.1-10 mg/kg) reversed the MK-801 (0.08 mg/kg)-induced memory deficit at the 3 h delay and enhanced memory at the 48 h delay, an effect abolished by MLA (0.313-5 mg/kg). Conclusions: The results extend our preclinical pharmacological understanding of GTS-21 to include the ability of GTS-21 to modulate NMDA-glutamate receptor function, in vivo. Given the role of NMDA-glutamate receptor involvement in schizophrenia, α7-nAChR agonists may represent a novel treatment strategy for the pathophysiological deficits of schizophrenia and other psychiatric disorders. [ABSTRACT FROM AUTHOR]

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’. [Copyright &y& Elsevier]