Koike, K. et al. Tropisetron improves deficits in auditory P50 suppression in schizophrenia. Schizophr. Res. 76, 67-72

Department of Psychiatry, Chiba University, Tiba, Chiba, Japan
Schizophrenia Research (Impact Factor: 3.92). 08/2005; 76(1):67-72. DOI: 10.1016/j.schres.2004.12.016
Source: PubMed


Physiological deficits in inhibition of the P50 auditory evoked potential in schizophrenia have been related to diminished expression of alpha7 nicotinic acetylcholine receptors. Diminished P50 inhibition is correlated with neuropsychological deficits in attention, one of the principal neurocognitive disturbances in schizophrenia. Nicotine administration improves P50 inhibition, presumably by achieving additional activation of these diminished receptors, but its toxicity and marked tachyphylaxis make it an ineffective therapeutic. Nicotine also has weak positive effects on several neurocognitive deficits in schizophrenia, which raises the possibility that the alpha7 nicotinic receptor is a clinically relevant therapeutic target that should be addressed by less toxic agents. Tropisetron, a drug already approved for clinical use outside the United States as an anti-emetic, is a partial agonist at alpha7 nicotinic receptors and an antagonist at 5-HT(3) receptors. As an initial proof-of-principle study, we determined that a single administration of tropisetron significantly improves P50 inhibition in schizophrenia. These data are consistent with biological activity at a pathophysiological mechanism in schizophrenia and support further trials of this drug as a possible therapeutic for neurocognitive deficits in schizophrenia.

13 Reads
    • "These results suggest that increased release of acetylcholine from the 5HT 3 blockade may be targeting nicotinic receptors. In support of this hypothesis, other 5HT 3 blockers such as olanzapine (Simosky et al., 2003) and tropisetron (Koike et al., 2005; Zhang et al., 2012) also normalize P50 sensory processing. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The human α7 neuronal nicotinic acetylcholine receptor gene (CHRNA7) is ubiquitously expressed in both the central nervous system and in the periphery. CHRNA7 is genetically linked to multiple disorders with cognitive deficits, including schizophrenia, bipolar disorder, ADHD, epilepsy, Alzheimer's disease, and Rett syndrome. The regulation of CHRNA7 is complex; more than a dozen mechanisms are known, one of which is a partial duplication of the parent gene. Exons 5-10 of CHRNA7 on chromosome 15 were duplicated and inserted 1.6 Mb upstream of CHRNA7, interrupting an earlier partial duplication of two other genes. The chimeric CHRFAM7A gene product, dupα7, assembles with α7 subunits, resulting in a dominant negative regulation of function. The duplication is human specific, occurring neither in primates nor in rodents. The duplicated α7 sequence in exons 5-10 of CHRFAM7A is almost identical to CHRNA7, and thus is not completely queried in high throughput genetic studies (GWAS). Further, pre-clinical animal models of the α7nAChR utilized in drug development research do not have CHRFAM7A (dupα7) and cannot fully model human drug responses. The wide expression of CHRNA7, its multiple functions and modes of regulation present challenges for study of this gene in disease. Published by Elsevier Ltd.
    Neuropharmacology 02/2015; 96(Pt B). DOI:10.1016/j.neuropharm.2015.02.006 · 5.11 Impact Factor
  • Source
    • "The mechanism of action of tropisetron in the setting of negative symptoms merits further query and probing. Tropisetron improves the auditory gating deficits in patients with schizophrenia (Hashimoto et al. 2005; Koike et al. 2005; Shiina et al. 2010; Wildeboer et al. 2009). It can be hypothesized that tropisetron exerts this effect through stimulation of acetylcholine release following the inhibition of 5-HT3 receptors (Wildeboer et al. 2009). "

  • Source
    • "The data presented above strongly suggest that patients with schizophrenia manifest typical disturbances of habituation mechanisms linked to information overload, leading to disruption of information processing.90–94 In this context, many studies have shown that the P50 sensory gating ratio in a paired click task is higher in patients with schizophrenia than in healthy controls, indicating more effective sensory gating processes.37,47,61,88,89,95–113 "
    [Show abstract] [Hide abstract]
    ABSTRACT: Sensory gating disturbances in schizophrenia are often described as an inability to filter redundant sensory stimuli that typically manifest as inability to gate neuronal responses related to the P50 wave, characterizing a decreased ability of the brain to inhibit various responses to insignificant stimuli. It implicates various deficits of perceptual and attentional functions, and this inability to inhibit, or "gate", irrelevant sensory inputs leads to sensory and information overload that also may result in neuronal hyperexcitability related to disturbances of habituation mechanisms. These findings seem to be particularly important in the context of modern electrophysiological and neuroimaging data suggesting that the filtering deficits in schizophrenia are likely related to deficits in the integrity of connections between various brain areas. As a consequence, this brain disintegration produces disconnection of information, disrupted binding, and disintegration of consciousness that in terms of modern neuroscience could connect original Bleuler's concept of "split mind" with research of neural information integration.
    Neuropsychiatric Disease and Treatment 07/2014; 10:1309-15. DOI:10.2147/NDT.S64219 · 1.74 Impact Factor
Show more