Prof. Toru Nishikawa
ISP2012 Lecture Course Abstract:
Molecular basis of schizophrenia
Schizophrenia is a major brain disorder that has high prevalence, approximately 0.8 % regardless the regions in the world, and a wide variety of long lasting or recurrent symptoms and often produces serious disability to the patients. The rate of the complete recovery with intact individual functioning and social ability and of suicide in schizophrenic patients has been estimated fewer than 20 % and about 10 %, respectively. These difficulties prompt us to clarify the biological mechanisms of schizophrenia and to develop more effective therapies for its intractable symptoms. However, as other psychiatric disorders, the lack of apparent neuropathological changes in schizophrenic brains brings a rough road to the investigations in these research fields.
In the present lecture, successful understandings by pharmacological approaches of the molecular basis of schizophrenia and their applications to the development of a novel pharmacotherapy for its treatment-resistant symptoms in our and other laboratories will be introduced and discussed.
A body of evidence has been accumulated indicating that disturbances in dopaminergic and glutamatergic neurotransmission, which play pivotal roles in expression and regulation of mental functions, may be implicated in the pathophysiology of schizophrenia. Thus, the agents that enhance activity of dopamine synapse such as amphetamines, cocaine and L-DOPA (for Parkinson's disease) cause schizophrenia–like positive symptoms, mainly hallucinations and delusions. Moreover, the hallucinatory-paranoid states in schizophrenic patients and induced by these dopamine agonists are improved by antipsychotic drugs that are potent blockers (antagonists) for the D2 type dopamine receptor in a manner in proportion to their potencies for the D2 receptor. On the other hand, the agents that block (antagonize) the glutamate transmission via the NMDA (N-methyl-D-aspartate) type glutamate receptor (NMDA receptor antagonists) elicit schizophrenia-like not only positive but also negative symptoms and cognitive deficits, the latters of which are resistant to current antipsychotic drugs and include restrictions in the range and intensity of emotional expression (affective flattening), in the fluency and productivity of thought and speech (alogia), and in the initiation of goal-directed behavior (avolition). In support of these hypotheses, schizophrenic patients have been reported to be much more sensitive to dopamime agonists and NMDA receptor antagonist than healthy volunteers.
We have demonstrated that blockade of the NMDA receptor augments dopamine release in the cerebral cotex, bridging the dopamine and glutamate pathology in schizophrenia. Also, we have found that the facilitation of NMDA receptor functions attenuate the animal models of intractable schizophrenic symptoms. Indeed, the agents enhancing NMDA receptor activities have been documented to ameliorate negative and cognitive disturbances in schizophrenic patients. In addition, we have identified in mammalian brains the presence of D-serine (a D-amino acid) that facilitates NMDA receptor functions and is required for physiological activation of the receptor, while D-amino acids had been believed to be uncommon in mammalian tissues. We, therefore, are currently investigating the molecular and cellular mechanisms of D-serine signaling as the new targets for the development of NMDA receptor regulating drugs and their possible defects in schizophrenia.
- Prof. Nishikawa's ISP2012 Profile
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