Muscarinic receptors (mAChRs) are typical members of the G protein-coupled receptor (GPCR) family and exist in five subtypes from M1 to M5. Muscarinic receptor subtypes do not sufficiently differ in affinity to orthosteric antagonists or agonists; therefore, the analysis of receptor subtypes is complicated, and misinterpretations can occur. Usually, when researchers mainly specialized in CNS and peripheral functions aim to study mAChR involvement in behavior, learning, spinal locomotor networks, biological rhythms, cardiovascular physiology, bronchoconstriction, gastrointestinal tract functions, schizophrenia, and Parkinson's disease, they use orthosteric ligands and they do not use allosteric ligands. Moreover, they usually rely on manufacturers' claims that could be misleading. This review aimed to call the attention of researchers not deeply focused on mAChR pharmacology to this fact. Importantly, limited selective binding is not only a property of mAChRs but is a general attribute of most neurotransmitter receptors. In this review, we want to give an overview of the most common off-targets for established mAChR ligands. In this context, an important point is a mention the tremendous knowledge gap on off-targets for novel compounds compared to very well-established ligands. Therefore, we will summarize reported affinities and give an outline of strategies to investigate the subtype's function, thereby avoiding ambiguous results. Despite that, the multitargeting nature of drugs acting also on mAChR could be an advantage when treating such diseases as schizophrenia. Antipsychotics are a perfect example of a multitargeting advantage in treatment. A promising strategy is the use of allosteric ligands, although some of these ligands have also been shown to exhibit limited selectivity. Another new direction in the development of muscarinic selective ligands is functionally selective and biased agonists. The possible selective ligands, usually allosteric, will also be listed. To overcome the limited selectivity of orthosteric ligands, the recommended process is to carefully examine the presence of respective subtypes in specific tissues via knockout studies, carefully apply "specific" agonists/antagonists at appropriate concentrations and then calculate the probability of a specific subtype involvement in specific functions. This could help interested researchers aiming to study the central nervous system functions mediated by the muscarinic receptor.

• Keywords
• allosteric, multitarget, muscarinic agonist, muscarinic antagonist, muscarinic receptors, orthosteric,
• Publication type
• Journal Article MeSH
• Review MeSH

We studied the changes in the heart and the activity biorhythms in mice exposed to acute (one 120-minute session) and repeated (7 two-hour sessions) restraint stress in 129J1/CF1 mice (WT) and in mice without M2 muscarinic receptors (M2KO) during the prestress period, during stress (STR) and for five days after the last stress session (POST). There were changes in the mesor (a midline based on the distribution of values across the circadian cycles; decreased in M2KO by 6% over all POST), day means (inactive period of diurnal rhythm in mice; higher in M2KO and further increased on STR and on the second to the fifth POST) and night means (active period; lower by 13% in M2KO and remained decreased in STR and in POST). The total area under the curve was decreased both in the WT and M2KO on STR and in all POST. Repeated stress caused changes over all days of STR, but the initial values were restored in POST. The average night values were decreased, and the day means were increased by 16% over all STR in M2KO. The day means decreased by 14% in the 4 POST in WT. The activity biorhythm parameters were almost unchanged. We show here that stress can specifically affect heart biorhythm in M2KO mice, especially when the stress is acute. This implies the role of M2 muscarinic receptor in stress response.

• MeSH
• Restraint, Physical * MeSH
• Stress, Physiological * MeSH
• Mice, Knockout MeSH
• Mice MeSH
• Periodicity * MeSH
• Receptor, Muscarinic M2 genetics   physiology   MeSH
• Heart Rate * MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Receptor, Muscarinic M2 MeSH

Muscarinic acetylcholine receptors (mAChRs) have been found to regulate many diverse functions, ranging from motivation and feeding to spatial navigation, an important and widely studied type of cognitive behavior. Systemic administration of non-selective antagonists of mAChRs, such as scopolamine or atropine, have been found to have adverse effects on a vast majority of place navigation tasks. However, many of these results may be potentially confounded by disruptions of functions other than spatial learning and memory. Although studies with selective antimuscarinics point to mutually opposite effects of M1 and M2 receptors, their particular contribution to spatial cognition is still poorly understood, partly due to a lack of truly selective agents. Furthermore, constitutive knock-outs do not always support results from selective antagonists. For modeling impaired spatial cognition, the scopolamine-induced amnesia model still maintains some limited validity, but there is an apparent need for more targeted approaches such as local intracerebral administration of antagonists, as well as novel techniques such as optogenetics focused on cholinergic neurons and chemogenetics aimed at cells expressing metabotropic mAChRs.

• Keywords
• acetylcholine, behavior, biperiden, learning, memory, receptor, rodents, scopolamine,
• Publication type
• Journal Article MeSH
• Review MeSH