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Transmitter/Receptor Mechanisms in Cardiovascular Control by the NTS: Excitatory Amino Acids, Acetylcholine, and Substance P
Published in I. Robin A. Barraco, Nucleus of the Solitary Tract, 2019
Although genes encoding four muscarinic acetylcholine receptor subtypes have been isolated,42 selective agonists and antagonists are available for only two muscarinic receptor subtypes (M1 and M2).43-46 Cloning studies have revealed that M1 and M2 receptors represent distinct gene products and have different amino acid sequences.47 At the present time, pirenzepine and McN-A343 are considered the best antagonist and agonist for M2 receptors, respectively. AFDX-116 and cis-methyldioxolane (CD) are the best antagonist and agonist for M2 receptors, respectively (see Table 1 for doses used and chemical names).43-46 Bilateral microinjections of the M2 receptor agonist (CD), but not those of a relatively selective M1 receptor agonist (McN-A343), into the NTS elicited a decrease in blood pressure and heart rate (Figure 6). Bilateral vagotomy did not affect the hypotensive and bradycardic effects of CD. Previous microinjections of the selective competitive M2 receptor antagonist (AFDX-116), but not those of the selective M1 receptor antagonist (pirenzepine), into the NTS blocked the effects of CD. These results indicated that the muscarinic receptors mediating depressor and bradycardic responses in the NTS are of M2 type.15
Imaging Neuroreceptors to Study Drug Action in Living Human Brain
Published in Edythe D. London, Imaging Drug Action in the Brain, 2017
Multiple subtypes of the muscarinic acetylcholine receptor have been recognized, and several selective antagonists have been developed (Hedlund et al., 1979; Hammer et al., 1980; Watson et al., 1982; Berrie et al., 1979; Gibson et al., 1983a, 1983b; Doods et al., 1987; Waelbroeck et al., 1986). However, work in this area has been limited by the lack of ligands that are highly selective for any single receptor subtype. An additional complication is caused by the presence of multiple affinity states for each receptor subtype and the concurrent interconversion of these affinity states (Birdsall et al., 1983; Gurwitz et al., 1984; Horvath et al., 1986). Using cloning techniques, genes for four receptor subtypes have been identified (Bonner et al., 1987; Peralta et al., 1987).
Urinary Incontinence
Published in David M. Luesley, Mark D. Kilby, Obstetrics & Gynaecology, 2016
Dudley Robinson, Linda Cardozo
Molecular cloning studies have revealed five distinct genes for muscarinic acetylcholine receptors in rats and humans and it has been shown that there are five receptor sub-types (M1–M5). In the human bladder there are M2 and M3 receptors and the latter is thought to cause a direct smooth muscle contraction. Whilst the role of the M2 receptor has not yet been clarified it may oppose sympathetically mediated smooth muscle relaxation. In general it is thought that the M3 receptor is responsible for the normal micturition contraction although in certain disease states, such as neurogenic bladder dysfunction, the M2 receptors may become more important in mediating detrusor contractions.
Motor-evoked potentials after focal electrical stimulation predict drug-induced convulsion potentials in rats
Published in Toxicology Mechanisms and Methods, 2023
Kazuhiro Kuga, Harushige Ozaki, Minoru Fujiki
We tested the effects of three different convulsion-inducing drugs on different targets (GABA, glutamatergic, and muscarinic-acetylcholine receptors). Continuous and dose-dependent increase in MEP amplitude persisted for up to 60 min for all the convulsion-inducing drugs. The increase in MEP amplitude may indicate an increase in excitatory sensitivity, such as synaptic transmission, and could be an indicator of convulsions. Inhibition of SICI by paired ES trains was also commonly observed in all three convulsion-inducing drugs in this study, suggesting that SICI is also a possible indicator of convulsions. SICI is known for its GABAergic interneuronal function in human TMS (Cash et al. 2017). We demonstrate a clear inhibition of SICI in rats with PTZ (GABAA receptor antagonist), likely comparable that in humans. SICI was also inhibited by KA-type glutamate receptor agonists. It has been reported that kainite receptor activation decreases the GABAergic inhibition (Rodríguez-Moreno et al. 1997), suggesting that KA might affect the GABAergic functional connectivity of interneurons in the motor cortex.
Atropine in topical formulations for the management of anterior and posterior segment ocular diseases
Published in Expert Opinion on Drug Delivery, 2021
Ines García Del Valle, Carmen Alvarez-Lorenzo
Atropine is an alkaloid extracted from Atropa belladonna (deadly nightshade), Datura stramonium (jimsonweed), and Hyoscyamus niger (henbane) plants that belong to the Solanaceae family. It is synthetized in the roots, with an alkaloid content that runs between 0.01% and 3% [2]. Atropine acts as a competitive, nonselective muscarinic acetylcholine receptor antagonist, affecting the central and peripheral nervous system by blocking receptors in exocrine glands, smooth and cardiac muscle, ganglia and intramural neurons [3]. According to different studies conducted on animals and humans, this alkaloid is widely distributed in tissues [4] and has a binding affinity constant in the range of 0.4–0.7 nM [5] for all five subtypes of muscarinic acetylcholine receptors (M1 to M5) [6,7]. Therapeutically, atropine has a wide range of indications [2,3]. It is used as premedication for anesthesia and surgical procedures, as antisialagogue to inhibit salivation and excessive secretions, and as antivagal agent to prevent cholinergic effects during surgery [8]. Furthermore, this compound is able to reverse muscle relaxant effects [9].
Reduced systemic exposure and brain uptake of donepezil in rats with scopolamine-induced cognitive impairment
Published in Xenobiotica, 2020
Jiajia Zhao, Tianjing Ren, Mengbi Yang, Yufeng Zhang, Qianwen Wang, Zhong Zuo
Scopolamine, an antagonist of muscarinic acetylcholine receptors, induces cognitive deficits by dysregulating the cholinergic signals in the central nervous system (Klinkenberg & Blokland, 2010). Scopolamine-induced model of cognitive impairment is characterized by increased AchE activity in rats’ brain ( Hosseini et al., 2015; Ionita et al., 2017; Ngoupaye et al., 2017; Ozarowski et al., 2017; Qu et al., 2017). Since DPZ, an AchE inhibitor, can exert its pharmacological effect on such model by attenuating the increased AchE activity induced by scopolamine (Qu et al., 2017), scopolamine-induced model allows preclinical evaluation of symptomatic efficacy of cholinomimetics, such as DPZ, (Van Dam & De Deyn, 2011) and was chosen in our current study. Although it has been reported that pharmacokinetic and biodistribution may be affected by pathological status (Shi et al., 2014), such as hepatic fibrosis (Yang et al., 2015) and Aβ-induced AD (Lv et al., 2013), comparative studies on pharmacokinetics of DPZ and its major three metabolites between normal and scopolamine-induced rats in plasma and brain after oral administration of DPZ have never been reported.