Phencyclidine-induced cognitive deficits in mice are improved by subsequent subchronic administration of tropisetron: Role of α7 nicotinic receptors
ABSTRACT We examined the effects of tropisetron, a 5-hydroxytryptamine (5-HT(3)) receptor antagonist and alpha7 nicotinic receptor agonist, on cognitive deficits in mice after repeated administration of the NMDA receptor antagonist phencyclidine (PCP). PCP (10 mg/kg/day for 10 days)-induced cognitive deficits were significantly improved by subsequent subchronic (2 weeks) administration of tropisetron, but not ondansetron. Effects of tropisetron were significantly antagonized by co-administration of the alpha7 nicotinic receptor antagonist methyllycaconitine, suggesting the role of alpha7 nicotinic receptors in the active mechanisms of tropisetron. These findings suggest that tropisetron could be a potential therapeutic drug for cognitive deficits in schizophrenic patients.
- SourceAvailable from: Jun Toyohara
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- "Furthermore, we also reported that phencyclidine (PCP)-induced cognitive deficits in mice improve by subsequent subchronic administration of tropisetron, but not ondansetron, and that the improvement was antagonized by co-administration of MLA.40) These preclinical findings suggest that tropisetron could improve abnormal auditory sensory gating and PCP-induced cognitive deficits in mice via α7-nAChRs.39,40) In clinical studies, we reported that a single oral administration of tropisetron (10 mg) improved deficits in P50 suppression in non-smoking patients with schizophrenia.41) "
ABSTRACT: Agonists of α7-nicotinic acetylcholine receptors (nAChRs) have been developed as potential therapeutic drugs for neuropsychiatric diseases such as schizophrenia and Alzheimer's disease. Positron emission tomography (PET) is a noninvasive brain imaging technique to measure receptor occupancy in the living human brain. Although much effort has been expended to create specific PET radioligands for α7-nAChRs in the brain, only 4-[(11)C]methylphenyl-1,4-diazabicyclo[3.2.2.]nonane-4-carboxylate ([(11)C]CHIBA-1001) is currently available for clinical studies. In contrast, two 5-hydroxytryptamine-3 (5-HT(3)) receptor antagonists, tropisetron and ondansetron, have been used to treat patients with chemotherapy-induced or postoperative nausea and vomiting. Furthermore, tropisetron, but not ondansetron, possesses high affinity for α7-nAChRs. In the present study, we evaluated the receptor occupancy in the human brain after a single oral administration of tropisetron and ondansetron using [(11)C]CHIBA-1001 and PET. Two serial dynamic PET scans using [(11)C]CHIBA-1001 in healthy non-smoking male subjects were performed before and after receiving an oral administration of these medications. A single oral administration of tropisetron, but not ondansetron, decreased the total distribution volume of [(11)C]CHIBA-1001 in the human brain. This study shows that tropisetron, but not ondansetron, could bind to α7-nAChRs in the human brain after a single oral administration. Therefore, [(11)C]CHIBA-1001 may be a useful PET radioligand to measure the occupancy of α7-nAChRs in the human brain.Clinical Psychopharmacology and Neuroscience 12/2011; 9(3):111-6. DOI:10.9758/cpn.2011.9.3.111
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- "At present, it is unclear whether improvement of P50 deficits by tropisetron is mediated via direct agonist effects on α7 nAChRs or via direct antagonist effects on 5-HT3 receptors. Previously, we reported that tropisetron, but not the selective 5-HT3 receptor antagonist ondansetron, attenuated PCP-induced cognitive deficits in mice, and that this effect of tropisetron was blocked by coadministration of the selective α7 nAChR antagonist MLA . These results suggest that activation of α7 nicotinic receptors by tropisetron is likely to play a role in the mechanism of action of tropisetron [17,21]. "
ABSTRACT: Cognitive deficits in schizophrenia are associated with psychosocial deficits that are primarily responsible for the poor long-term outcome of this disease. Auditory sensory gating P50 deficits are correlated with neuropsychological deficits in attention, one of the principal cognitive disturbances in schizophrenia. Our studies suggest that the alpha7 nicotinic acetylcholine receptor (alpha7 nAChR) agonist tropisetron might be a potential therapeutic drug for cognitive deficits in schizophrenia. Therefore, it is of particular interest to investigate the effects of tropisetron on the cognitive deficits in patients with schizophrenia. A randomised, placebo-controlled trial of tropisetron in patients with schizophrenia was performed. A total of 40 patients with chronic schizophrenia who had taken risperidone (2 to 6 mg/day) were enrolled. Subjects were randomly assigned to a fixed titration of tropisetron (n = 20, 10 mg/day) or placebo (n = 20) in an 8-week double-blind trial. Auditory sensory gating P50 deficits and Quality of Life Scale (QLS), Cambridge Neuropsychological Test Automated Battery (CANTAB), and Positive and Negative Syndrome Scale (PANSS) scores were measured. In all, 33 patients completed the trial. Tropisetron was well tolerated. Administration of tropisetron, but not placebo, significantly improved auditory sensory gating P50 deficits in non-smoking patients with schizophrenia. The score on the rapid visual information processing (sustained visual attention) task of CANTAB was significantly improved by tropisetron treatment. Total and subscale scores of PANSS were not changed by this trial. QLS scores in the all patients, but not non-smoking patients, were significantly improved by tropisetron trial. This first randomised, double-blind, placebo-controlled trial supports the safety and efficacy of adjunctive tropisetron for treatment of cognitive deficits in schizophrenia.Annals of General Psychiatry 06/2010; 9(1):27. DOI:10.1186/1744-859X-9-27 · 1.40 Impact Factor
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- "We previously reported that repeated administration of PCP (10 mg/kg/day for 10 days) caused long-term cognitive deficits in mice (more than 6 weeks after the final administration of PCP), and that PCP-induced cognitive deficits could be improved by subsequent subchronic (2 weeks) administration of clozapine, but not haloperidol . Therefore, the reversal of PCP-induced cognitive deficits may be a potential animal model of atypical antipsychotic activity, i.e., this model may be beneficial in terms of ameliorating the cognitive deficits in people with schizophrenia [59-67]. Using this model, we reported that treatment with the selective GlyT-1 inhibitor, (R)-(N-[3-(4'-fluorophenyl)-3-(4'-phenylphenoxy)propyl])sarcosine (NFPS, ALX 5407; Fig. 4) [68-71], attenuated PCP-induced cognitive deficits in mice . "
ABSTRACT: Multiple lines of evidence indicate that hypofunction of glutamatergic neurotransmission via N-methyl-D-aspartate (NMDA) receptors might be implicated in the pathophysiology of schizophrenia, suggesting that increasing NMDA receptor function via pharmacological manipulation could provide a new strategy for the management of schizophrenia. Currently, the glycine modulatory sites on NMDA receptors present the most attractive therapeutic targets for the treatment of schizophrenia. One means of enhancing NMDA receptor neurotransmission is to increase the availability of the obligatory co-agonist glycine at modulatory sites on the NMDA receptors through the inhibition of glycine transporter-1 (GlyT-1) on glial cells. Clinical studies have demonstrated that the GlyT-1 inhibitor sarcosine (N-methyl glycine) shows antipsychotic activity in patients with schizophrenia. Accordingly, a number of pharmaceutical companies have developed novel and selective GlyT-1 inhibitors for the treatment of schizophrenia. This paper provides an overview of the various GlyT-1 inhibitors and their therapeutic potential.The Open Medicinal Chemistry Journal 05/2010; 4:10-9. DOI:10.2174/1874104501004010010