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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]

Abstract: Aims: Even though the presence of α7 nicotinic receptor (nAChR) in lymphocytes has been demonstrated, its functional role still remains elusive. The aim of our study was to characterize α7 nAChRs in human lymphocytes upon phytohemagglutinin (PHA) stimulation. Main methods: Lymphocytes were activated with the mitogen PHA. α7 nAChRs were studied by reverse transcription-polymerase chain reaction (RT-PCR), real time PCR, flow cytometry and confocal laser scanning microscopy. The effects of nicotinic drugs on PHA-induced proliferation was evaluated by the [3H]-thymidine incorporation assay. Key findings: We show that the expression of functional α7 receptors increases after PHA stimulation. The activation of peripheral lymphocytes by PHA increases 2.2-fold the α7 subunit mRNA expression and 4-fold the binding of the antagonist α-bungarotoxin (α-BTX) with respect to non activated lymphocytes. By measuring the increase of intracellular calcium in response to nicotine we determine that α7 receptors in lymphocytes are functional. Nicotinic drugs differentially modulate T cell activation. While nicotine tends to inhibit proliferative responses, specific α7 antagonists, such as α-BTX and methyllycaconitine, enhance cell division. Significance: This study reveals that the α7 receptor modulates lymphocyte activation and contributes to clarifying the role of the non neuronal cholinergic system in the immune response. [Copyright &y& Elsevier]