When given topically, pilocarpine contracts the ciliary body muscle and opens the trabecular meshwork to increase the outflow of aqueous humor. Oral pilocarpine can be used to increase secretion of the salivary glands to treat dry mouth in patients with Sjogren's syndrome or salivary gland dysfunction.
Methacholine is most commonly used to diagnose asthma or bronchial hyperactivity. Methacholine stimulates the muscarinic receptor in the airway when inhaled and induces bronchoconstriction, and increases tracheobronchial secretions.
The lower the dose it takes for methacholine to induce bronchoconstriction, the more reactive the bronchial airway is. Neostigmine is indicated for postoperative and neurogenic ileus, urinary retention, myasthenia gravis, and reversal of neuromuscular junction blockade. Physostigmine indications include glaucoma and anticholinergic toxicity, such as atropine overdose.
Galantamine, donepezil, and rivastigmine are indicated for Alzheimer disease. The medications help with memory loss as well as decrease plaque build-up.
Galantamine, donepezil, and rivastigmine do not cure Alzheimer disease and can only delay the progression of the disease.
The indirect agonists listed below has an indication that acts on nicotinic receptors of the skeletal muscle rather than muscarinic receptors. Edrophonium is a short and rapid-acting anticholinesterase commonly used to evaluate and diagnose patients with myasthenia gravis. Pyridostigmine is indicated for the treatment of myasthenia gravis. Muscarinic agonists are agents that activate the muscarinic acetylcholine receptor.
There are five different muscarinic receptors labeled M1-M5. Muscarinic agonists are parasympathomimetics, and their mechanism of action is different depending on which receptor is activated.
The M1, M3, and M5 are transmembrane receptors that couple to a Gq protein. DAG activates protein kinase C, which activates downstream protein and causes calcium influx.
IP3 causes the sarcoplasmic reticulum to release stored calcium. Increased intracellular calcium causes smooth muscle contraction and exocrine glandular secretions. The M2 and M4 receptors are Gi receptor, which inhibits adenylyl cyclase. The decrease in cAMP concentration subsequently decreases the activation of protein kinase A. The M1 muscarinic receptor is clinically significant in the central nervous system, and it influences neurologic functions.
Muscarinic agonists play an important role in the treatment of Alzheimer disease AD. Memory loss in Alzheimer disease patients is associated with a cholinergic deficit due to the reduced activity of choline acetyltransferase, which synthesizes acetylcholine. Another important feature of AD is the accumulation of amyloid plaques and neurofibrillary tangles. Amyloid plaques are aggregates of amyloid-beta derived from cleaving amyloid precursor protein.
Muscarinic agonists appear to increase the activity of a protease enzyme that cleaves amyloid precursor protein in such a manner that there is no production of amyloid-beta. Through such mechanisms, muscarinic agonists treat memory deficit and amyloid deposition in AD.
The M2 muscarinic receptor is the predominant receptor found in the sinoatrial and atrioventricular nodal cells of the heart. The downstream effect, once the M2 receptor is activated, allows potassium efflux. Potassium efflux results in hyperpolarization and reduction of the action potential duration in the nodal cells.
Therefore, the activation of the M2 receptor in the heart causes decreased heart rate and atrial contractility. The M3 muscarinic receptor is clinically significant in the intestine's smooth muscle, bladder, airway, eye, exocrine glands, and blood vessels. Smooth muscle of the intestine, bladder, airway, and eye contracts when calcium concentration increase within the cell. Calcium binds with calmodulin to form a complex that can now activate the enzyme myosin light chain kinase.
Myosin light chain kinase phosphorylates myosin resulting in contraction. Muscarinic agonists' action on blood vessels results in vasodilatation rather than vasoconstriction. Calcium in the endothelial cells activates nitric oxide synthase, converting L-arginine into nitric oxide.
Nitric oxide diffuses into the underlying smooth muscle causing an increase in cGMP. When the endothelium is damaged, it does not produce nitric oxide, and acetylcholine results in smooth muscle contraction.
Bethanechol is administered orally on an empty stomach two to four times a day to prevent stomach upset and nausea. Carbachol is commonly administered topically ocularly. Pilocarpine is administered topically ocularly or orally. News Our impact Contact us Intranet. Privacy Notice and Terms of Use.
ChEBI Ontology. Automatic Xrefs. ChEBI Name. Supplier Information. Find compounds which contain this structure Find compounds which resemble this structure Take structure to the Advanced Search. Read full article at Wikipedia. In the version of the task employed by Major et al. Persistent activity of PFC neurons encodes the task rule through this memory period Skoblenick and Everling, ; Vijayraghavan et al.
Microiontophoresis employs small electrical currents to eject charged moieties and drugs from the recording electrode Hicks, Moreover, usually, the quantities of drugs ejected are not enough to elicit behavioral effects. Major et al. Thus, some of the effects of systemic muscarinic blockade described by Zhou et al.
In contrast to Zhou et al. These differences could be due to concentration differences due to systemic application versus local drug ejection or differences in the behavioral task structure.
In the interleaved rule-based antisaccade task, activity of PFC neurons is differentially modulated by the rule prior to the onset of the peripheral stimulus. These prestimulus activity differences are, perhaps in some respects, analogous to the anticipatory activity observed in the delayed match-to-position task in Zhou et al. Figure 3. Effects of local delivery of muscarinic antagonist scopolamine by microiontophoresis on PFC activity during pro- and antisaccade task.
Adapted from Major et al. A Pro- and antisaccade task structure is shown. After central fixation, the fixation spot changes to a colored rule cue which flashes briefly. Subsequently the spot becomes white again. After a delay wherein the trial rule, based on the color of the rule cue, is maintained in WM, the fixation spot disappears, and after a brief gap, the peripheral stimulus appears left or right of the fixation spot. The subject makes a saccade toward prosaccade or away antisaccade from the spot, based on the current trial rule.
Trial temporal structure are also shown. Illustration on the right shows the recording and iontophoresis technique. B Microiontophoresis of increasing doses of scopolamine cause increasing suppression of the activity of a PFC neuron that has delay-period activity preferring the pro-saccade rule. Right panel shows recovery after cessation of drug application. Thus, the findings regarding muscarinic blockade of neuronal selectivity for the peripheral visual stimulus and perisaccadic selectivity in Major et al.
We found that muscarinic blockade reduces selectivity for all task attributes in PFC neurons, including visual stimulus and saccade direction selectivity, having a comprehensive disruptive effect on PFC neuronal task engagement.
Thus, nicotinic receptor subtypes in PFC appear to be more specialized in their actions on prefrontal circuitry that generates and maintains persistent delay activity, whereas general muscarinic receptor modulation appears to affect the gamut of observable PFC task-related activity. Since muscarinic antagonism engendered such pronounced suppression of the activity of PFC neurons during WM, it would be expected that muscarinic and cholinergic agonists may enhance persistent activity and WM representations.
There is some evidence that muscarinic stimulation can sustain persistent activity through intrinsic mechanisms Egorov et al. Rat entorhinal cortical neurons, in the presence of the cholinergic agonist carbachol, respond to current pulse stimulation with long lasting activity that is reminiscent of persistent activity displayed by cortical neurons in WM tasks Figure 4A. This carbachol-induced response is graded with increasing discharge rate after successive stimulations. The persistent responses could be blocked by general muscarinic blockade Figure 4A or by pirenzepine, an antagonist preferentially blocking M1Rs.
Thus, ACh, through muscarinic mechanisms, could facilitate persistent activity in cortical neurons through cell-autonomous intrinsic mechanisms that, in concert with stimulus evoked responses, could engender WM representations. However, traditionally, WM persistent activity is thought to be a network phenomenon, generated by slow reverberatory synaptic activity in a network of neurons Wang, Whether this intriguing phenomenon that manifested in rodent entorhinal cortical slices would also occur in vivo in primate PFC was not clear.
Figure 4. Influence of cholinergic agonist carbachol on persistent activity. A adapted from Egorov et al. A Example of persistent activity evoked in a rat entorhinal cortical neuron by a current pulse in the presence of carbachol. Neuronal discharge persists after cessation of stimulus, and after muscarinic blockade, and after muscarinic blockade.
Neuronal discharge persists after cessation of stimulus in the presence of carbachol, but not during blockade of muscarinic receptors. B Illustration on the right shows experimental design of neuronal recording and carbachol iontophoresis. Shown on the left is the activity of two PFC neurons top and bottom panels with persistent rule-selective activity during the delay period is shown during control left and during carbachol right application.
Carbachol attenuated WM activity for the antisaccade rule in the neuron shown in the top panel , while the activity of the neuron in the bottom panel was augmented by carbachol, but selectivity for the trial rule in the delay period was nevertheless diminished. Gray area shows the last ms of the delay period prior to fixation offset.
Reproduced with permission from Nature Publishing group. To clarify whether carbachol could induce or augment persistent activity in PFC during WM task performance, our group conducted experiments where we microiontophoretically applied carbachol on PFC neurons in rhesus monkeys performing the rule-memory guided pro- and antisaccade task Major et al.
Surprisingly, we found that carbachol had mixed effects on neuronal physiology and persistent activity Figure 4B. Moreover, carbachol increased the activity of broad-spiking presumed excitatory pyramidal neurons, while effects on excitability of narrow-spiking presumed mainly parvalbumin-positive interneurons were more varied.
Rule encoding in the persistent activity during the delay epoch was diminished by carbachol application, especially at higher doses. This decrease in rule selectivity occurred notwithstanding the direction of changes in excitability of the neurons.
It is noteworthy that carbachol is a general cholinergic agonist that has agonist activity at both muscarinic and nicotinic receptors. However, as discussed earlier, studies heretofore report that stimulation of the major nicotinic receptor subtypes in PFC appear to be generally excitatory Yang et al. Given the pervasiveness of scopolamine-induced suppression of PFC neurons described above Major et al. Since they are localized postsynaptically at asymmetric synapses on dendritic spines of pyramidal neurons, M1R constitutes an attractive candidate for mediating the general suppression of PFC by muscarinic blockade.
M1R stimulation inhibits the M-current and can thereby increase cortical neuronal excitability McCormick and Prince, ; Marrion, ; Shirey et al. A selective M1R antagonist and scopolamine both produce antidepressant actions in rodents due to actions in medial PFC Navarria et al.
M1R knockout mice have been found to have selective deficits in non-match-to-sample tasks while, surprisingly, showing performance enhancement in match-to-sample tasks, with a reduction in theta burst stimulation, and long-term potentiation in mice Anagnostaras et al.
An M1R positive allosteric modulator was found to enhance cognitive task performance in macaques, including self-ordered spatial search, and an object retrieval detour task Uslaner et al. M1R also mediates long-term excitability changes in striatal neurons Lv et al.
KCNQ channels that generate the M-current are active near the action potential threshold Brown and Adams, , and inhibition of the M-current by pharmacological blockade of KCNQ channels increases PFC delay period activity during oculomotor delayed response Wang et al.
Since M1R is coupled to G q signaling and the inositol phosphate pathway Popiolek et al. On the other hand, M1R could have inhibitory influences by direct activation of parvalbumin-positive interneurons Yi et al.
In rhesus macaque areas V1 and MT, the majority of parvalbumin-positive interneurons are found to express M1Rs Disney and Aoki, ; Disney and Reynolds, , although it is not clear if this is also the case in PFC. The transient suppression is usually followed by long lasting depolarization of the neuron. Metabotropic glutamate receptors also mobilize this IP3-receptor and SK channel-dependent mechanism to cause transient suppression of cortical neurons as well Hagenston et al.
One confound in the interrogation of subtype-selective muscarinic actions has been the lack of subtype selectivity of orthosteric muscarinic agonists and antagonists, the ACh binding motif is conserved among the receptor subtypes Jones et al. Among the older generation of orthosteric compounds, some, such as the agonist McN-A and the antagonist pirenzepine have a pharmacological preference for M1Rs Mitchelson, but are not highly subtype-selective Giachetti et al.
Recently, however, a new class of M1R agents have been synthesized that show pharmacological activity by binding at allosteric sites on the receptor and show considerable subtype selectivity and clinical promise Bubser et al. These comprise allosteric agonists and antagonists, that act on non-ACh receptor sites and activate or inhibit the receptor directly, and positive allosteric modulators, that do not activate the receptor alone, but in concert with endogenous ACh can augment the ACh response.
Furthermore, application of the allosteric M1R agonist disrupted the rule selectivity of the persistent delay activity of many PFC neurons Figure 5B , while a few neurons showing increases in persistent activity and increase in rule representation Vijayraghavan et al. However, the proportion of neurons that displayed suppression did not increase with higher doses and, at the population level was pirenzepine induced suppression was milder than that observed previously with general antagonist scopolamine and milder than the suppression with the high doses of the M1R-selective allosteric agonist.
Moreover, in contrast to the effects of scopolamine, although application of the M1R-selective antagonist altered the rule-selectivity in the delay period activity in some individual PFC neurons, the rule selectivity at the level of the population was not significantly altered.
M1R stimulation did not differentially affect narrow-spiking putative interneurons and regular-spiking putative pyramidal neurons, indicating that increased inhibition from parvalbumin-positive interneurons could not explain the physiological suppression caused by the agonist or antagonist. Figure 5. Adapted from Vijayraghavan et al. A Experimental design of iontophoresis and recording experiments shown on the left.
Pie-charts show number of neurons in the population that were significantly inhibited, excited or unaffected by drug application. Left-most panel shows the net drug effect on neurons tested at any both low and high doses of the M1R agonist.
Middle panel , low doses; Right panel , High doses. B Left panel shows the effects of two doses of the M1R agonist on a PFC neuron with delay period activity selective for antisaccades over prosaccades. High dose of the M1R agonist strongly suppresses the neuron and disrupts rule selectivity in the delay period.
Recovery shown in bottom left panel. Right panel shows the activity of a PFC neuron before and during application of M1R antagonist pirenzepine. This neuron showed ramping persistent activity during the delay period that was selective for prosaccades.
M1R blockade inhibited this neuron and also diminished rule selectivity. Modified with permission from Elsevier Neuron. In summary, these results indicated that M1R blockade could not account for the pervasive neuronal suppression and general disruption of task selectivity that was observed with general muscarinic blockade with scopolamine Major et al.
Galvin et al. They further reported that inhibiting the M-current could restore delay-related firing which had been suppressed by selective M1R antagonist, telenzepine.
Figure 6. Effects of M1R stimulation on spatial delayed response performance and delay period persistent activity. Adapted from Galvin et al. A Schematic of trial structure of oculomotor delayed response and iontophoresis technique from Galvin et al. After central fixation, a peripheral cue briefly flashes at one of eight locations.
The cue location is maintained in WM during the delay period, when central fixation continues to be maintained. At the end of the delay indicated by fixation spot offset, the subject makes a saccade to the remembered location. B Behavioral dose response curves for systemic administration of M1R positive allosteric modulator VU during spatial delayed response performance in by an aged monkey.
M1R stimulation has an inverted-U effect on WM performance. WM performance degrades at doses higher than the optimal dose. C Microiontophoresis of increasing doses of M1 allosteric agonist, VU on persistent spatially tuned delay period activity of a PFC neuron. Left panel shows rasters and histograms for neurons preferred direction.
Right panel shows rasters and histograms for neurons non-preferred direction. M1R agonist application at low dose enhances WM activity, while higher dose application suppresses the neuron.
Reproduced with permission from Elsevier Neuron. The effects of different muscarinic actions on neuronal physiology in the PFC from the studies discussed above have been summarized in Table 1.
These surprising results with M1R agonists point to the possibility that M1R overstimulation in primate PFC may trigger signaling mechanisms that lead to neuronal suppression. Thus, the actions of ACh in PFC in alert behaving primates may involve mechanisms that engender non-trivial suppression of cortical activity through M1Rs. Further the results in Vijayraghavan et al. Table 1. Qualitative comparison of the physiological effects of local muscarinic receptor manipulation on PFC WM activity from various reports discussed in this review.
Several mechanisms may account for the suppression due to M1R overstimulation. One possibility is that M1R excitation of interneurons at high doses of stimulation leads to a suppression of PFC neurons. However, this is unlikely, as noted above because Vijayraghavan et al. This, of course, does not account for other classes of interneurons which are not narrow spiking, the increase in activity of which may well have caused suppression of the pyramidal neurons.
It is noteworthy, that previous iontophoretic studies examining G q protein-coupled receptors have found that stimulating these receptors has inhibitory effects on PFC neurons in primates and in some rodent studies.
Indeed, they show that retigabine, a positive allosteric modulator that preferentially targets KCNQ2 channels and increases the open state of the channels reduces persistent activity of PFC neurons. Future experiments must address the underlying mechanism involved in the suppression of persistent activity in the PFC by M1R overstimulation. Vijayraghavan et al. This suggests that there are other muscarinic excitatory mechanisms independent of M1Rs active in the PFC.
As discussed in this review, M2R is present postsynaptically in both pyramidal neuron dendritic spines and in the dendrites of interneurons. Thus, in addition to their documented role in autoinhibition and heteroinhibition as presynaptic receptors Murakoshi, , post-synaptic M2R signaling may lead to increase in PFC neuronal excitability and augmentation of persistent activity.
In support of this hypothesis, preliminary data from our group suggests that M2R antagonism suppresses the delay activity of PFC cells engaged in the rule-memory guided pro- and antisaccade task. These results with M1R compounds in monkey PFC are of particular interest, because M1R-selective agents are being actively investigated for cognitive enhancement and amelioration of cognitive deficits in neuropsychiatric disorders Bubser et al.
M1R based therapeutics, such as KarXT, a coformulation of M1R agonist xanomeline and trospium, a peripheral muscarinic M2R antagonist that ameliorates non-target side effects of xanomeline, are showing promising results in clinical trials for the treatment of schizophrenia Brannan et al.
In this review, we have discussed the neuromodulatory influence of the corticopetal cholinergic system through muscarinic receptors on primate PFC WM circuits that manifest persistent memory-related activity. The anatomical localization of these receptors shows exquisite specificity and correspondence with network connections within the PFC.
Cortical muscarinic receptors play a pivotal role in arousal and brain state transitions, and their activation is necessary for the proper functioning of recurrent circuits in the PFC that generate persistent activity in WM tasks. Recent work shows that their role in primate PFC may be quite different from what would be expected from prior studies in other model systems like rodents and moreover, diverges from their role in sensory cortical areas.
Further elucidation of muscarinic neuromodulation of PFC cognitive circuitry promises to be a rewarding endeavor for translational research and the development of new targets for the treatment of neuropsychiatric and neurological disorders.
SV and SE wrote and edited the manuscript. Both authors contributed to the article and approved the submitted version. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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