Muscarinic receptors in schizophrenia.
An increasing body of evidence suggests that the muscarinic receptors may present a potential therapeutic target for the treatment of schizophrenia. This argument is supported by studies using postmortem CNS tissue and a neuroimaging study that have shown there are regionally specific decreases in selective muscarinic receptors in the CNS of subjects with schizophrenia. This raises the possibility that drugs specific to individual muscarinic receptors could have beneficial effects on the symptoms of schizophrenia, a posit supported by studies in receptor knockout/knockdown mice where it has been shown that specific behaviours affected by schizophrenia are also abnormal in mice lacking a single muscarinic receptor. Moreover, drugs have been synthesised that are partial agonists at muscarinic receptors and these drugs have been shown to improve the behavioural deficits in humans which are modulated by the muscarinic receptor family. The widespread distribution of muscarinic receptors in the human CNS and the receptor specific changes identified in postmortem CNS from subjects with schizophrenia would suggest that drugs targeting specific muscarinic receptors would also need to partition into selected CNS regions to achieve optimal responses. Some existing compounds show regional selectivity for the same muscarinic receptor in different CNS regions, suggesting that this characteristic could be engineered into muscarinic receptor targeting drugs. This review presents data from diverse areas of research to argue that it is now imperative that the therapeutic potential of manipulating the activity of muscarinic receptors for the treatment of schizophrenia is fully explored.
Dean
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B
The Rebecca L. Cooper Research Laboratories, The Mental Health Research Institute of Victoria, Parkville, Victoria, Australia. bdean@mhri.edu.au
Bymaster
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FP
Scarr
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E
D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology; D002490:Central Nervous System / Q000378:metabolism; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D005810:Multigene Family; D051381:Rats; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D012559:Schizophrenia / Q000188:drug therapy / Q000378:metabolism*
D014150:Antipsychotic Agents; D011976:Receptors, Muscarinic