In vivo screening method of therapeutic agent for memory/learning dysfunctions by schizophrenia

Abstract

A method of evaluating memory / learning functions with the use of a model with glutamic acid N-methyl-D-aspartate (NMDA) type receptor hypofunction as an animal model for schizophrenia and with the use of reference memory task, wherein there has been found concrete means for detecting any differences in activity between typical anti-psychosis drugs and atypical anti-psychosis drugs is found. An in vivo animal model for screening of a therapeutic agent for improving cognitive dysfunction by schizophrenia is provided.

Description

TECHNICAL FIELD [0001] The present invention relates to an in vivo screening method of a therapeutic agent for improving memory / learning dysfunctions by schizophrenia. BACKGROUND ART [0002] Glutamic acid is a most popular excitatory neurotransmitter in the central nervous system, and the receptors thereof are classified broadly into an NMDA type, an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic (AMPA) type, a kainate type, and a metabotropic type. It is revealed that the NMDA type receptor plays an important role in the completion of the long-term potentiation (LTP), which is an electrophysiologically basal process of the memory / learning functions (cf., Science 285: 1870-1874 (1999)). At the animal level, it is known that an NMDA receptor antagonist may induce memory / learning dysfunctions in various memory / learning tasks such as a passive avoidance response, a radial maze, a T or Y maze, a water maze, a place or object recognition, an autoshaping learning task, and a lever-pressin...

AI Technical Summary

Benefits of technology

[0011] The present invention provides a screening method of a therapeutic agent for memory / learning dysfunctions by schizophrenia. More particularly, the present invention provides an animal model for reference memory dysfunction caused by hypofunction of NMDA type receptor as a simple animal model for schizophrenia providing the predictability of the clinical drug efficacy of the existing therapeutic agents.

[0020] The present invention provides a concrete method for evaluating a memory / learning improving activity being specific to certain atypical anti-psychotic agents but not to a typical anti-psychotic agent haloperidol. The results obtained by this method are in agreement with the clinical findings that haloperidol shows no improving activity of cognitive dysfunctions, and that atypical anti-psychotic agents exhibit an improving activity of cognitive dysfunctions. As a result, it becomes possible to provide a screening method of a therapeutic agent for cognitive dysfunctions by schizophrenia, and further provides a concrete therapeutic agent therefor. Actually, by the present method, the memory / learning improving efficacy is recognized with respect to lurasidone, which is under development as a candidate for a novel therapeutic agent for schizophrenia, noradrenaline α2 receptor antagonist 1-(2-pyrimidyl)piperazine dihydrochloride (hereinafter, referred to as 1-PP), and serotonin 5-HT 1A receptor antagonist in addition to risperidone, clozapine or quetiapine, by which a candidate for a novel agent for improving cognitive dysfunctions by schizophrenia can be provided. In addition, the memory / learning improving activity of clozapine and quetiapine is observed at a dose by 10 times or more lower than the dose at which they exhibit an anti-psychotic activity, and hence, a different action mechanism can be speculated. Further, since it is suggested that the retrieval of reference memory task being acquired with improvement by a drug is done with depending on the state of the NMDA type receptor hypofunction (state-dependent), as a novel and concrete method for evaluating the reference memory dysfunction improving activity of a drug, a method where the NMDA type receptor hypofunction is induced during the period including the training session and the testing session is effective.

Problems solved by technology

Schizophrenia is associated with various cognitive dysfunctions such as attention, memory, learning, executive functions, but it is reported that among these functions, especially a certain memory function is selectively and seriously damaged.

It is reported that in schizophrenia, the declarative memory including both of the working memory and the reference memory is selectively damaged, and further, among them, the damage of the reference memory is most serious.

However, the drug efficacy of these existing drugs are not sufficient enough, and hence, it has been discussed that it is important to develop a therapeutic agent for cognitive dysfunctions by schizophrenia (cf., Science 299: 350-351 (2003)).

However, it is considered that an animal model for cognitive dysfunctions by schizophrenia satisfying such requirements is quite limited at the moment.

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