muscarinic hypothesis of schizophrenia

muscarinic hypothesis of schizophrenia - Molecular...

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FEATURE REVIEW Towards a muscarinic hypothesis of schizophrenia TJ Raedler 1 , FP Bymaster 2 , R Tandon 3 , D Copolov 4 and B Dean 4,5,6,7 1 Department of Psychiatry, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; 2 Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, USA; 3 State of Florida, Department of Mental Health, Tallahassee, FL, USA; 4 The Mental Health Research Institute, Parkville, VIC, Australia; 5 Department of Psychiatry, The University of Melbourne, Parkville, VIC, Australia; 6 Department of Pathology, The University of Melbourne, Parkville, VIC, Australia and 7 Department of Psychological Medicine, The Monash University, Clayton, VIC, Australia Although the neurotransmitter dopamine plays a prominent role in the pathogenesis and treatment of schizophrenia, the dopamine hypothesis of schizophrenia fails to explain all aspects of this disorder. It is increasingly evident that the pathology of schizophrenia also involves other neurotransmitter systems. Data from many streams of research including pre- clinical and clinical pharmacology, treatment studies, post-mortem studies and neuroimaging suggest an important role for the muscarinic cholinergic system in the pathophysiology of schizophrenia. This review will focus on evidence that supports the hypothesis that the muscarinic system is involved in the pathogenesis of schizophrenia and that muscarinic receptors may represent promising novel targets for the treatment of this disorder. Molecular Psychiatry (2007) 12, 232–246. doi:10.1038/sj.mp.4001924; published online 5 December 2006 Keywords: schizophrenia; acetylcholine; receptors; muscarinic; muscarinic agonists; muscarinic antagonists; etiology Introduction Schizophrenia is a severe psychiatric illness with a lifetime prevalence of B 1% that imposes a huge toll on patients, their families and public health services worldwide. The diagnosis of schizophrenia is still based on the presence of a typical symptom-con- stellation and time course. The peak onset of symptoms occurs most frequently in early adulthood and in a significant number of cases the disorder is life-long. Delusions, hallucinations, disorganized speech, grossly disorganized or catatonic behavior and nega- tive symptoms (such as apathy, anhedonia and social withdrawal) constitute the core symptoms of schizo- phrenia. These core clinical symptoms of schizo- phrenia are frequently complicated by cognitive deficits, mainly in the areas of attention, memory, executive functioning and intelligence 1,2 and the presence of affective disturbances. 3 Although nega- tive and cognitive symptoms markedly impact on the functional outcome in schizophrenia, 4 they do not respond well to existing treatments. Therefore, the treatment of negative and cognitive symptoms in schizophrenia is a pressing unmet need. Neuropsychopharmacological studies have focused
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muscarinic hypothesis of schizophrenia - Molecular...

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