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Tropisetron improves deficits in auditory P50 suppression in schizophrenia

Department of Psychiatry, Chiba University, Tiba, Chiba, Japan
Schizophrenia Research (Impact Factor: 4.43). 08/2005; 76(1):67-72. DOI: 10.1016/j.schres.2004.12.016
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ABSTRACT 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.

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    • "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). "
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    • "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). "
    Dataset: Tropisetron
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    • "It is known that the P50 components have reduction response to the second stimulus (i.e., S2) relative to the response evoked by the first stimulus (i.e., S1) when the interstimulus intervals of 2 stimuli are 500 milliseconds apart. The auditory gating characteristics of P50 are derived from a function of a7-nicotinic cholinergic receptor (Adams et al., 2008; Adler et al., 1998; Koike et al., 2005). A sensory gating function of P50 does not show significant difference between awake, rapid eye movement, and nonerapid eye movement states (Kisley et al., 2001). "
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    ABSTRACT: In general, a prediction of neurologic outcome with respect to the resuscitated cardiac arrest patients has been performed by the auditory brainstem response and somatic evoked potential. The auditory brainstem response and somatic evoked potential are known as the predictors that correspond to neurologically poor outcome. None of the methods have been established to access neurologically good outcome. Because the hippocampal CA3 pyramidal cells have been widely used for pathophysiologic analyses concerning the hypoxic-ischemic encephalopathy and also the source of P50 components of the auditory evoked potential has been considered to be the hippocampal CA3 pyramidal cells, the authors assume that it might be possible that neurologic outcome in resuscitated cardiac arrest patients would be predicted by evaluating the P50 components. The purpose was to examine the P50 as a predictor of neurologic outcome in resuscitated cardiac arrest patients at the early stage from the onset. The P50 components of the auditory evoked potential are recorded in a conditioning-testing paradigm, that is, EEG responses to a pair of auditory stimuli with 500-millisecond interclick interval. In this study, subjects are 10 out-of-hospital cardiac arrest patients, 8 men and 2 women with a mean age of 54.8 years, who were admitted to the intensive care unit after the return of spontaneous circulation, with the presence of both the auditory brainstem response wave V and the somatic evoked potential wave N20 between the period from June 2008 to July 2009. It was found that the presence of the P50 at the early stage from the onset (days 5 ± 1.20) indicates good neurologic outcome, while the absence of the P50 implies poor prognosis. As to the auditory sensory gating of the P50, almost no reduction response to the second stimulus was observed. As a consequence, the evaluation of the P50 in resuscitated cardiac arrest patients would have a possibility to predict neurologically good outcome.
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