Similar results regarding scopolamine administration had also been reported by Pilcher et al. This task may also be used for investigating differences in the consequences of acute vs.
However, when following a chronic drug treatment, the observed deficits were absent, hence hinting at the ability to build a tolerance. The authors also concluded that chronic muscarinic antagonism may exert little or no influence over working memory One possible drawback of this task was raised in a study of Hodges et al. The natural tendency of rodents to alternate between two choices in successive trials is exploited in a variety of simple T-shaped or Y-shaped mazes. Due to the simplicity of the task, alternation has been employed in the bulk of pharmacological studies using the scopolamine-induced amnesia model.
Numerous studies [reviewed in Ref. A article by Givens and Olton demonstrated that intraseptal injections of scopolamine mimicked the detrimental dose-dependent effect of systemic scopolamine injections, indicating a critical contribution of the medial septal area. Further studies supported the central position of the septohippocampal pathway and revealed a more distributed network including a few other limbic and non-limbic structures Intraventricular administration of the M1 antagonist pirenzepine exerts similar effects as scopolamine, suggesting that M1 receptors may dominate in mediating spontaneous spatial alternation On the other hand, M2 knockout mice were found to perform worse only under longer 20 s but not short 5 s delays in reinforced alternation in a T-maze compared to wild-type controls , suggesting a more complex contribution of particular mAChR types.
M5 receptors seem to play a role in alternation as well, but the mechanism of action is likely indirect. In consequence, the low blood supply led to impaired long-term potentiation and consequently to a deterioration of spatial alternation Despite being almost ubiquitous in pharmacological research, the spatial alternation paradigm has some drawbacks.
Investigators do not usually configure the maze to enforce animals to use praxis, taxon, or mapping strategies, or any combination of these. Therefore authors cannot report, in contrast to the MWM, whether effects are due to impairment of a particular mode of place navigation. Furthermore, the variability and consistency of results have been disputed, particularly in the spontaneous alternation paradigm.
However, this drawback can be counterbalanced by the fact that under some circumstances, spatial alternation has been found to be superb at detecting hippocampal dysfunction Active place avoidance [ — , for review see Ref. The position of this sector does not change relative to the room frame; i. A follow-up study 67 compared the performance of two rat strains obtained from the breeding colony of Institute of Physiology, CAS, Prague Long-Evans and Wistar in the MWM and active place avoidance following scopolamine treatment.
As already mentioned, whereas in the MWM the disruption in learning and memory was similar, in active place avoidance the Wistar rats exhibited a higher sensitivity to scopolamine than the Long-Evans group In general, active place avoidance tasks are sensitive to antimuscarinic action elicited by scopolamine, yet the effects are strain-specific and also present at relatively higher doses that can also affect procedural aspects.
Unfortunately, no active place avoidance results on more selective antagonists, mAChR knockouts or other specific manipulations with the mAChR system are available, indicating the need for future research. In the Barnes maze, a rat is placed in the center of a circular platform with holes at the edges. An escape cylinder is placed under one of these holes; the animals are trained to locate the position of this cylinder based on distal external cues.
The use of odor trails is eliminated by rotating the platform in between trials, and animals presumably use a mapping strategy to locate the target Evaluations of antimuscarinic agents employing this paradigm are scarce. Consistent with other cognitive mapping taxing tasks, scopolamine was found to impair performance Seeger et al.
Another example of the usage of this test is the study by Gawel et al. The results showed an improvement in both memory retention and cognitive flexibility, the latter being more pronounced for rivastigmine The cone-field task represents another experimental paradigm for testing spatial learning and memory. The ability of the rat to learn and remember the position of the baited cones is assessed.
A suggested advantage of this test over tasks like the MWM is that it is based on positive reward learning whereas the MWM relies on aversive learning. This task was used for example by Van der Staay et al.
The results showed that metrifonate, but not donepezil, was able to alleviate the working memory disruption produced by scopolamine Specific conclusions on the role of mAChRs in this task are impossible due to the limited data. In the hole-board task, an animal is placed in a rectangular box with a number of holes in the floor. Some of these are baited with a food reward. An animal is evaluated in its ability to learn and remember the position using a mapping strategy of the baited holes as well as the holes it has already visited.
Different variations and adaptions of this task have been used. For example, Post et al. Regarding the involvement of particular types of receptors, M1 receptors were shown to be important for reference memory for non-baited holes in a study evaluating biperiden in pigs On the other hand, M2 receptors were shown to be important for working memory memory for already-visited holes in a study using transgenic mice The muscarinic system of the brain plays a pivotal role in advanced cognitive processes such as spatial navigation and learning, an extensively studied ability, not only to gain insight into the way humans and animals orient themselves in both familiar and unfamiliar environments, but because spatial memory represents a rodent model of human perceptual memory.
Research in this field provides new findings regarding the neurophysiology of higher cognitive processes, as well as pathologies such as those seen in AD and other neurodegenerative diseases, and indicates potential pathways for the therapy and treatment of these conditions. However, as the muscarinic system is important not only for learning, memory and cognition but also takes parts in other processes such as attention, motivation, sensory perception, and other non-cognitive aspects of behavior, it is no surprise that the blockage of mAChRs also yields a wide range of non-cognitive effects, thus hindering cognition-focused research and complicating interpretations of the effects observed in rodent behavioral experiments.
There have been attempts to isolate the purely cognitive effects of muscarinic antagonism from the procedural and motivational aspects, and some have been relatively successful. One of the more promising ways to study the effects of mAChRs in place navigation lies in the exploitation of local intracerebral administration of antagonists, which ensures no peripheral effects, or the use of specific conditional mutations.
Moreover, despite attempts to use more specific muscarininc ligands to eliminate the procedural adverse effect of non-selective antagonists such as scopolamine and atropine, they have often provided ambiguous results. However, Sambeth et al. It seems that with some caution, a general recommendation of using either non-specific or highly specific antagonists can be provided in conditions with defined place learning strategies having known involvement of the mAChR system.
Nonetheless, the ultimate need and relevance lies in the exploitation of novel techniques such as optogenetics focused on cholinergic neurons, and chemogenetics aimed at cells expressing metabotropic mAChRs.
As these methods provide a more precise way to target the mAChR in the CNS, it is conceivable that relatively soon the systemic or even focal application of non-specific antimuscarinic drugs may become a rather obsolete tool for this research. However, the pharmacological development of more specific ligands for mAChRs may yet bring a revival of this traditional neuropharmacology approach.
It should also be noted that the choice of a specific behavioral test plays an essential role in the research of cognition, as various tasks examine different aspects of learning and memory e.
Furthermore, not all tasks are hippocampus-dependent, and even among those which are not all employ M1 as a crucial part Table 1. Careful attention should also be paid to the rodent strain used; for example, albino rats such as the Wistar strain have difficulty learning vision-reliant tasks.
Well-planned rodent behavioral studies with carefully thought-out experimental designs will continue to provide a useful tool for research on the muscarinic system and its role in learning and memory. Table 1. Summary of the overall effects positive, negative, none of particular groups of antimuscarinergic agents or transgenic manipulations on spatial performance.
JS and AS contributed to revisions of the manuscript. AS provided scientific leadership and student supervision. The article is based on the thesis of AP.
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.
We thank laboratory technicians for their support and David W. Hardekopf for proofreading. All rights reserved. Drug Discov Today 22 1 — The cholinergic system, circadian rhythmicity, and time memory. Behav Brain Res — Nicotinic receptors in addiction pathways. Mol Pharmacol —8. Cholinergic circuits in cognitive flexibility. Neuroscience — Involvement of the cholinergic system in conditioning and perceptual memory. The cholinergic system and spatial learning. Schliebs R, Arendt T.
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J Neurosci — PubMed Abstract Google Scholar. Perspectives on transdermal scopolamine for the treatment of postoperative nausea and vomiting. J Clin Anesth — Biperiden selectively induces memory impairment in healthy volunteers: no interaction with citalopram. Psychopharmacology Berl — By highlighting the of the acetylcholine receptor, it is also easy to see how the secondary structure is concentrated to specific regions of the molecule.
Alpha helicies span the majority of the transmembrane and cystolic regions, and beta sheets with the exception of only a few alpha helicies make up the majority of the exoplasmic receptor face. Atropine interacts with the of the exoplasmic face. It interacts so well, it is actually considered to be a "pure antagonist" by some [8]. Atropine first enters the acetylcholine receptor and binds to the at the top of the receptor.
They then interact with the, residues which define a hydrophobic region through which a dehydrated ion could pass through. These residues can be seen more clearly through this representation. The interaction of atropine and phospholipase 2A will be discussed in detail later in this article.
The image to the left depicts a synapse. A neurotransmitter, such as acetylcholine, goes across the synaptic cleft and binds to its receptor, which can be seen in great detail in the 3D image. Atropine inhibits the effect of acetylcholine by complexing the acetylcholine receptor on the other side of the cleft, subsequently inhibiting the binding of acetylcholine. If atropine does not allow acetylcholine to bind to the acetylcholine receptor, then the effects of acetylcholine are inhibited.
This prevents activation of the parasympathetic nervous system and has a wide variety of medical effects. Since atropine affects the parasympathetic nervous system, it has a wide variety of effects. It is largely and perhaps most commonly used as an ophthalmic drug, as it paralyzes the accommodation reflex and dilates the pupil [10]. The mechanism for dilation involves blocking the contraction of the circularly pupillary sphincter muscle, which is normally stimulated by acetylcholine release [11].
Outside of ophthalmic use, Atropine is also used in the treatment of heart conditions such as bradychardia low heart rate , asystole, and subsequently, cardiac arrest. Because atropine blocks acetylcholine, and therefore the parasympathetic nervous system, the vagus nerve cannot slow the heart and it remains at a constant rate [12].
Muscarinic receptors are coupled to the Gi-protein ; therefore, vagal activation decreases cAMP. Gi-protein activation also leads to the activation of K ACh channels that increase potassium efflux and hyperpolarizes the cells. Increases in vagal activity to the SA node decreases the firing rate of the pacemaker cells by decreasing the slope of the pacemaker potential phase 4 of the action potential ; this decreases heart rate negative chronotropy. The change in phase 4 slope results from alterations in potassium and calcium currents, as well as the slow-inward sodium current that is thought to be responsible for the pacemaker current I f.
By hyperpolarizing the cells, vagal activation increases the cell's threshold for firing, which contributes to the reduction the firing rate. Similar electrophysiological effects also occur at the AV node; however, in this tissue, these changes are manifested as a reduction in impulse conduction velocity through the AV node negative dromotropy.
Normal distribution was tested by the Kolmogorov-Smirnov test. All data are included in the manuscript and as supplementary information. Electronic supplementary material. Supplementary information accompanies this paper at Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
National Center for Biotechnology Information , U. Sci Rep. Published online Nov 9. Ruwan K. Perera , 1, 2 Thomas H. Bork , 1, 5 Lars S. Nikolaev 1, 5. Thomas H. Nadja I. Lars S. Viacheslav O. Author information Article notes Copyright and License information Disclaimer.
Nikolaev, Email: ed. Corresponding author. Received Aug 2; Accepted Oct This article has been cited by other articles in PMC. Abstract Atropine is a clinically relevant anticholinergic drug, which blocks inhibitory effects of the parasympathetic neurotransmitter acetylcholine on heart rate leading to tachycardia. Introduction The autonomic nervous system regulates functions of various organs via the sympathetic and parasympathetic neurotransmitters norepinephrine and acetylcholine ACh.
Open in a separate window. Figure 1. Figure 2. PDE4 inhibition is involved in atropine induced positive inotropic and chronotropic effects in vitro and in vivo What are the functional implications of this atropine effect on cardiac function?
Figure 3. Heart rate measurements Mice were sacrificed by cervical dislocation. Single-cell contractility measurements Freshly isolated ventricular cardiomyocytes were plated onto laminin-coated glass coverslides. In vivo telemetry in awake mice All animal experiments were performed according to institutional and governmental guidelines. Contractility measurements in human atrial trabeculae Thin human atrial trabeculae cross section area 0.
Statistical analysis Normal distribution was tested by the Kolmogorov-Smirnov test. Data availability All data are included in the manuscript and as supplementary information. Electronic supplementary material Supplementary Information 1. Author Contributions R.
Notes Competing Interests The authors declare that they have no competing interests. Footnotes Electronic supplementary material Supplementary information accompanies this paper at
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