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Muscarinic M1 and M2 receptors, fasting and seizure development in animals/M1 ve M2 muskarinik reseptorler, aclik ve hayvanlarda nobet gelisimi.

INTRODUCTION

Subtypes, regional distribution and synaptic localization of muscarinic receptors

Five muscarinic receptor subtypes, [M.sub.1], [M.sub.2], [M.sub.3], [M.sub.4] and [M.sub.5] have been identified. Their regional distribution and function in the brain are shown in Table 1. Muscarinic receptors in brain are located in neurons and glia cells. The most prevalent subtypes in rat brain are [M.sub.1] and [M.sub.2] receptors (1).

[M.sub.1], [M.sub.3] and [M.sub.5] receptors preferentially couple to G[alpha]q subunit that activate phospholipase C and generate second messengers, inositol triphosphate (IP3) and diacyl glycerol (DAG) and so intracellular calcium levels increase (Figure 1). These receptors may also activate phospholipase [A.sub.2] and phospholipase D in certain cells (2). On the other hand muscarinic [M.sub.2] and [M.sub.4] receptors preferentially couple to G[alpha]i/o subunit that inhibits adenylate cyclase and reduce the production of second messenger cyclic adenosine monophosphate (cAMP).

In brain, [M.sub.1] receptors are most commonly located postsynaptically while [M.sub.2] receptors are most commonly located presynaptically (3) (Figure 1). Blockade of postsynaptic muscarinic receptors reduces the effects of acetylcholine, whereas blockade of presynaptic muscarinic autoreceptors causes an increase in acetylcholine release (4). [M.sub.2] receptor was shown to be the main presynaptic autoreceptor in hippocampus and cerebral cortex (4), while both [M.sub.1] and [M.sub.2] receptors are located presynaptically and postsynaptically in cerebral cortex and hippocampus (3, 4, 5). Blockade of the [M.sub.2] receptors increases acetylcholine release in rat cerebral cortex and hippocampus (5, 6), whereas does not change acetylcholine release in human cerebral cortex cell culture (7). Presynaptic muscarinic autoreceptors ([M.sub.1], [M.sub.2], [M.sub.3], [M.sub.4]) inhibit acetylcholine release and are also located on noncholinergic nerve terminals as heteroreceptors and contribute to the effects of acetylcholine (8, 9). Blockade of [M.sub.1] heteroreceptors leads to a decrease in dopamine release (10) and blockade of [M.sub.2] heteroreceptors leads to an increase in glutamate release (8).

Muscarinic agonists and antagonists

Muscarine, pilocarpine and arecoline are the naturally occurring muscarinic agonists. Methacholine, carbachol, bethanechol and oxotremorine are the most known synthetic muscarinic agonists. Oxotremorine-M is the most potent N-methyl quaternary derivative of oxotremorine and cannot pass through the blood brain barrier. Arecoline and pilocarpine are the partial agonists. Selectivity and affinity for the muscarinic receptor subtypes differ between the muscarinic agonists and antagonists. Pilocarpine demonstrated selectivity for [M.sub.1] and [M.sub.3] subtypes regarding the intrinsic relative activity ([RA.sub.i]) (11). In this study arecoline, carbachol and oxotremorine-M lacked marked selectivity among [M.sub.1] to [M.sub.4] receptors. Xanomeline, the synthetic muscarinic agonist demonstrated functional selectivity for the [M.sub.1] and [M.sub.4] (12) muscarinic receptor subtypes. However binding studies showed similar affinity of xanomeline at all five subtypes (13).

The affinities of atropine, scopolamine, biperiden and pirenzepine, the main muscarinic receptor antagonists are shown in Table 2. Atropine, the nonselective muscarinic receptor antagonist has equal affinity for all muscarinic receptor subtypes, however scopolamine has lower affinity for [M.sub.2] receptors than the other subtypes. Biperiden has highest affinity for [M.sub.1] receptors. And pirenzepine is the selective antagonist of [M.sub.1] subtype. According to the in vitro muscarinic receptor radio ligand binding assays, the affinities of pirenzepine, biperiden, scopolamine (14) and atropine (15) were 98, 46, 6 and 2 fold higher for [M.sub.1] subtype than [M.sub.2] subtype (Table 2). Additionally atropine and scopolamine had showed 10 times higher affinity for presynaptic receptors than postsynaptic receptors (16).

CLINICAL AND RESEARCH CONSEQUENCES

Roles of musarinic receptors in physiological functions and pathological processes

As shown in Table 1, muscarinic receptors participate in many physiological functions including learning and memory formations, locomotor activity, sleep-wake cycle, regulation of heart rate, growth hormone, prolactin, gastric acid and salivary secretions and contraction of smooth muscles.

Muscarinic receptors contribute to the pathophysiology of various neurological disorders. It is known that cognitive function is impaired in Alzheimer's disease and schizophrenia. Selective [M.sub.1] agonism has been shown to retard the age, Alzheimer's disease or schizophrenia related dementia and cognitive deficits with few side effects (17). Additionally [M.sub.1] receptors have been demonstrated to control amyloid precursor protein (APP) processing and the generation of the neurotoxic APP fragment, amyloid [beta]-peptide (A[beta]) in Alzheimer's disease (18). Various researchers have suggested that cholinergic function may be improved by selective blockade of [M.sub.2] receptors alone or together with [M.sub.1] agonism in early stages of Alzheimer's disease. Post-mortem and brain-imaging studies have shown that [M.sub.1] muscarinic receptor protein and [M.sub.1] receptor mRNA were reduced in different brain regions of patients with schizophrenia (19). Benztropine, a selective [M.sub.1] receptor antagonist, reduces the adverse side effects of antipsychotic treatments in schizophrenic patients (20). However [M.sub.1] agonists are promising for reversing some of the cognitive impairments associated with schizophrenia (19). So the efficient way for the treatment of schizophrenia regarding the [M.sub.1] muscarinic receptor agonism vs antagonism remains unclear. In the caudate putamen, muscarinic [M.sub.2] receptors act as inhibitory heteroreceptors on dopaminergic terminals. Therefore, selective [M.sub.2] antagonism may provide beneficial effects in schizophrenia, where dopaminergic transmission is increased (21). Dopaminergic neurons in the striatum are lost in Parkinson's disease and this causes an imbalance between dopaminergic and cholinergic effects with an excess of cholinergic effects. This is associated with increased striatal acetylcholine levels, which contributes to the development of the motor signs typically associated to Parkinson's disease. Selective [M.sub.1] receptor antagonists are used for the prevention and the treatment of dyskinesia and the treatment of dystonia (20). Muscarinic [M.sub.4] receptor knockout mice displays enhanced locomotor activity and [D.sub.1] dopaminergic receptor related effects (21). [M.sub.4] muscarinic receptors seem to suppress [D.sub.1] receptor function. So, selective blockade of [M.sub.4] receptors are being investigated in the treatment of Parkinson's disease.

Convulsions induced by muscarinic agonists

Enhancement of cholinergic activity by [M.sub.1] and [M.sub.2] muscarinic receptor agonists carbachol (22) and pilocarpine (23) or the acetylcholinesterase inhibitor soman (24) produce convulsions in animals.

Pilocarpine, a nonspecific muscarinic receptor ago nist is commonly used to induce seizures in mice and rats with high systemic or intracerebral administrations. Pilocarpine-treated animals demonstrate structural dam ages (23) and tonic-clonic generalized seizures (25) like in humans with temporal lobe epilepsy. Animals display status epilepticus (SE) followed by a latent period. After this seizure-free period, spontaneous recurrent seizures (SRSs) are generated (25). [M.sub.1] muscarinic receptor knockout pilocarpine treated animals display no seizure activity. So [M.sub.1] receptors seem to be responsible for the seizure development (26). After binding to [M.sub.1] receptors, phospholipase C is activated. DAG and IP3 are produced, [Ca.sup.++] and [K.sup.+] currents are altered. Consequently, neuronal excitation is increased. The activity of ATPases in the hippocampus may be reduced. So, the plasma membrane could not be repolarized. As the [Ca.sup.++] ions could not be extruded, the increased [Ca.sup.++] levels elevates glutamate release and this leads to SE. The glutamate permits [Na.sup.+] and [Ca.sup.++] influx, thus the [Mg.sup.++] is moved out of the cell. [Mg.sup.++] acts as a blocker on the N-methyl-D-aspartate (NMDA) receptors. When [Mg.sup.++] is extruded, glutamate activates the NMDA receptors. This causes excessive [Ca.sup.++] entry and subsequent excitation and death of the cell. On the other hand, [M.sub.2] receptor activation by pilocarpine inhibits adenylate cyclase. This causes a reduction in the acetylcholine release and the excitability of the brain (27).

Convulsions induced by muscarinic antagonists

Enginar et al. showed that mice deprived of food displayed seizures after food intake in a study exploring the effects of scopolamine on memory and learning processes (28). In a series of experiments, mice and rats fasted for [less than or equal to] 48 h and treated with antimuscarinics, scopolamine, atropine or biperiden developed convulsions soon after finding and eating the food pellet (29, 30). Antimuscarinic pretreatment and access to food are required in the generation of convulsions. Hypoglycaemia was prevented by glucose intake but convulsion development not. So, the contribution of a hypoglycaemic effect during fasting was ruled out (29). The binding characteristics of glutamatergic receptors were changed after fasting for 48 h. These changes were moderately blocked by scopolamine pretreatment and eating food (31). The convulsions seem similar with a form of reflex seizures called eating epilepsy regarding the triggering factors, exhibition of the seizure activity and response to antiepileptics (32). This new method/technique may provide insight into the seizures in patients.

It is very interesting that scopolamine has actually anticonvulsive effect. Scopolamine prevents seizures induced by anticholinesterase soman (24) and muscarinic agonist pilocarpine (22). The convulsive effects of scopolamine, atropine and biperiden have been suggested to be an anticholinergic effect arising from the antagonism of postsynaptic [M.sub.1] and/or [M.sub.2] muscarinic receptors. These receptors show different postsynaptic and presynaptic localizations and distributions in the brain and have different autoreceptor and heteroreceptor characteristics as mentioned above. Which of these receptors is responsible for the convulsions has not been fully understood yet. It has been reported that the topical administration of high concentrations of antimuscarinics to the brain produced seizures (33, 34). This effect has been suggested to imply an anticholinergic as well as cholinergic activity due to their efficacy in increasing the release of acetylcholine.

Prolonged fasting has been shown to alter the expression or binding characteristics of various receptors in brain. For instance; fasting for 48 h produced changes in glutamatergic receptors (31) and 120 h food deprivation decreased the gamma aminobutyric acid (GABA) receptors in the cerebellum (35). In the studies investigating the receptor binding and gene expression changes in rats with insulin-induced hypoglycaemia, [M.sub.1], [M.sub.2] and [M.sub.3] receptors in the cerebral cortex (36) and [M.sub.1] receptor expression in the hippocampus (37) were decreased. In a model of posttraumatic stress, the increase of [M.sub.2] expression in the frontal cortex and [M.sub.1] expression in the hippocampus show the effect of stress on receptor expression (38). Muscarinic receptor expression is also altered in various pathological conditions including schizophrenia (19), epilepsy (39) and cancer (40). There may such changes occur in the expression of muscarinic receptors leading to the convulsions. Thus, the relationship between receptor expression and fasting and the muscarinic receptor subtype which plays a role in the occurrence of convulsions need to be investigated.

Conclusion

Acetylcholine has prominent functions in the brain. Various physiological and pathological processes involve alterations in muscarinic receptor expression. Studies using [M.sub.1] and/or [M.sub.2] agonists and antagonists may clarify the underlying mechanisms of convulsions regarding the contribution of cholinergic/anticholinergic activities.

Author contributions: Concept; Literature Search; Writing; Merve Saygi Bacanak, Pharm. PhD.

Conflict of Interest: There is no conflict of interest.

Hakem Degerlendirmesi: Dis Bagimsiz.

Yazar Katkilari: Fikir; Literatur taramasi; Yaziyi Yazan; Dr. Ecz. Merve Saygi Bacanak

Cikar Catismasi: Yoktur.

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Merve Saygi Bacanak (1,2)

(1) Department of Medical Pharmacology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey

(2) First and Emergency Aid Program, Department of Medical Services and Techniques, Vocational School of Health Services, Marmara University, Istanbul, Turkey

ORCID IDw of the authors: M.S.B. 0000-0001-9774-2657

Correspondence Author/Sorumlu Yazar: Merve Saygi Bacanak E-mail/E-posta: saygimerve@hotmail.com
Table 1: Distribution and function of muscarinic receptor subtypes

Muscarinic receptor subtype  Widely distributed region in the brain

[M.sub.1]                    Cerebral cortex, hippocampus,
                             striatum (41)
                             Forebrain, thalamus, motor neurons
[M.sub.2]                    (1)
                             Hypothalamus, hippocampus (21)

[M.sub.3]
                             Corpus striatum (21) (*)
[M.sub.4]
                             Substantia nigra pars compacta,
                             ventral tegmental area (21) (**)
[M.sub.5]

Muscarinic receptor subtype  Associated physiological functions

[M.sub.1]                    Receptor stimulation [right arrow]
                             Regulation of learning and memory like
                             cognitive functions (18), regulation of
                             locomotor activity (42), increases
                             wakefulness while reducing delta sleep
                             (43)
                             Receptor blockade a Increased cognitive
                             performance including memory (21),
                             decreased REM sleep-like state (44)
[M.sub.2]                    Receptor stimulation [right arrow]
                             antinociceptive effect (45)
                             Receptor knockout [right arrow]
                             Reduced food intake and increased
                             locomotor activity, decreased pituitary
                             and serum growth hormone (GH) and
                             prolactin (46)
                             Receptor stimulation [right arrow]
[M.sub.3]                    regulation of metabolic functions and
                             longitudinal growth (46), regulation of
                             learning and memory like cognitive
                             functions (47)
                             Receptor knockout [right arrow]
                             Increased locomotor activity and
                             dopaminergic activity so contribution
                             to antiparkinsonian effect (21)
                             Receptor stimulation [right arrow]
[M.sub.4]                    Contribution to antipsychotic effect
                             (21), antinociceptive effect (45)
                             Receptor knockout [right arrow]
                             Abolished cholinergically induced
                             cerebral vasodilation (48)
                             Receptor stimulation [right arrow]
[M.sub.5]                    Increased dopamine release in substantia
                             nigra pars compacta, inhibition of dopamine
                             release in striatum (49)

(*) [M.sub.4] receptors are distributed in the corpus striatum being
co-localized with dopamine receptors (21).
(**) [M.sub.5] is the only muscarinic subtype expressed by the
dopamine-containing neurons of the substantia nigra pars compacta (21).

Table 2: Comparison of binding affinities for atropine, scopolamine,
biperiden and pirenzepine at human muscarinic receptors as Ki values

             [M.sub.1]    [M.sub.2]    [M.sub.3]      [M.sub.4]

Atropine      0,17           0,339       0,209          0,107
Scopolamine   0,83 (0,05)    5,3 (1,4)   0,34 (0,06)    0,38 (0,07)
Biperiden     2,2 (0,23)   102 (24)      5,3 (1,3)      3,1 (0,8)
Pirenzepine  43 (14)      4200 (1370)  468 (172)      148 (53)

             [M.sub.5]

Atropine       0,316
Scopolamine    0,34 (0,11)
Biperiden      4,4 (1,4)
Pirenzepine  237 (122)

Human cloned receptors were expressed in Chinese hamster ovary cell
membranes. Binding was measured as competition with
[3H]N-methyl-scopolamine. Data represent as Ki (mean [+ or -] S.E.M.)
in nanomolar (14, 15).
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