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Keywords: scopolamine, biperiden, acetylcholine, receptor, behavior, learning, memory, rodents. Psychiatry The use, distribution or reproduction in other forums is permitted, provided the original author s or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. For example, in the presence of the allosteric modulator thiochrome the affinity of acetylcholine at the M 4 -muscarinic receptor is increased, but the affinity of acetylcholine for the other muscarinic receptor subtypes is unaffected [ 21 ].
In addition, subtype-selective agonists, which bind to and activate the receptor via binding domains distinct from the orthosteric binding site have also been reported. These novel agonists have considerable therapeutic potential, but how their signalling properties compare to orthosterically acting agents are only beginning to be explored [ 30 ].
In addition, the allosteric modulators that act by regulating the affinity of the natural ligand will have the potential to only be active when and where acetylcholine is present and therefore reduce potential side effects [ 24 ].
The role of muscarinic receptors in the contraction of smooth muscle, particularly of airway, ileum, iris and bladder, are considered a classical muscarinic response mediated primarily by M 3 -muscarinic receptors expressed on the smooth muscle cells [ 8 , 11 ]. Co-expressed with the M 3 -muscarinic receptors in smooth muscle is an often larger population of M 2 -muscarinic receptors [ 11 ] which appear to play a much smaller role in the smooth muscle contractile response [ 35 ].
In contrast, M 2 -muscarinic receptors expressed in the heart have a profound role in the control of cardiac myocyte contraction [ 5 , 8 , 35 ]. Here the release of acetylcholine from vagal parasympathetic neurones reduces heart beating frequency almost exclusively by acting at M 2 -muscarinic receptors [ 5 , 9 , 33 ].
Exocrine secretion, particularly of saliva [ 14 , 22 ], and as shown more recently, insulin [ ], is primarily mediated by M3-muscarinic receptors with a smaller role played by M 1 -receptors particularly in salvation [ 14 ]. The generation of transgenic muscarinic receptor knockout mice, where M 1 -M 5 genes have been ablated, has revealed numerous novel muscarinic receptor functions [ 23 , ]. Muscarinic receptor knockout mice are viable and fertile with no major physiological defects, allowing the study of the physiological role of these receptors in adult mice in vivo.
Particularly intriguing have been the numerous behavioural and neurological phenotypes observed, revealing the important neuromodulatory role played by this receptor family.
M 1 -muscarinic receptor knockout mice demonstrate a pronounced increase in locomotor activity [ 26 ], which has been suggested to impact on memory and learning and may provide a model for learning deficits in conditions such as attention deficit hyperactivity disorder [ ]. Further locomotor phenotypes are observed in M 4 -muscarinic receptor knockout animals, where this receptor subtype is thought to mediate an inhibitory affect on striatal dopamine-mediated locomotor activity [ 6 , 16 , 19 , 36 ].
M 2 -muscarinic receptors expressed in the thermo-regulatory centres of the hypothalamus are likely to be involved in the regulation of body temperature [ 15 ], whereas M 3 -muscarinic receptors have been reported to modulate appetite by the regulation of the melanin-concentrating hormone MCH neurones in the hypothalamic feeding centre [ 37 ]. In line with a greater understanding of the neuromodulatory role of muscarinic receptors has come a greater focus on the possibility that this receptor family may be effective therapeutic targets in a number of neurological and psychiatric diseases [ 36 ].
Historically this focus has centred on Alzheimer's disease, which is associated with a loss of cholinergic innervation in the cerebral cortex and hippocampus, and is currently treated by enhancing cholinergic transmission via pharmacological inhibition of cholinesterase activity[ 25 ].
Whereas for many years this treatment was thought to have its beneficial affects by stimulation of the M 1 -muscarinic receptor subtype [ 7 ], work on the M 1 -receptor knockout mice has suggested that this receptor subtype may not play such an important role in cognition as previously thought [ 36 ]. Thus, novel anti-Alzheimer drugs that target other muscarinic receptor subtypes, such as the M 2 -, M 4 - and M 5 -muscarinic receptors, are now under more intense consideration.
Interestingly, muscarinic receptor modulation of dopaminergic transmission has provided the impetus for the development of muscarinic receptor ligands in the treatment of schizophrenia and Parkinson's disease [ 36 ]. In both cases the focus has been on the M 1 and M 4 -muscarinic receptors, where it has been indicated that agonists to these receptors might be beneficial in schizophrenia and antagonists are likely to be of benefit in Parkinson's disease.
In addition to the therapeutic potential of targeting specific muscarinic receptors in CNS disorders there is still considerable therapeutic potential in the development of muscarinic ligands to the more classical muscarinic-centred disease targets.
For example, in the case of chronic obstructive pulmonary disease COPD and asthma, that are currently treated with the non-selective muscarinic antagonists ipratropium and tiotropium [ 10 ], there might be significant clinical benefit derived from the development of selective M 2 and M 3 -muscarinic receptor ligands.
Similarly, in overactive bladder, improved selectivity of muscarinic receptor ligands would help to reduce unwanted side effects [ 10 ]. Table 2 adapted from ref [ 36 ] provides a list of the potential therapeutic applications of compounds that specifically target muscarinic receptor subtypes.
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