Effects of the selective M1 muscarinic receptor antagonist dicyclomine on emotional memory.
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The nonselective muscarinic antagonist scopolamine is known to impair the acquisition of some learning tasks such as inhibitory avoidance. There has been recent research into the effects of this drug in contextual fear conditioning and tone fear conditioning paradigms. The purpose of the present study was to assess the role of the selective M1 muscarinic antagonist dicyclomine in these paradigms and in the inhibitory avoidance test. Rats were administered different doses of dicyclomine or saline 30 min before acquisition training. The animals were tested 24 hr later, and it was observed that 16 mg/kg of dicyclomine impaired both contextual fear conditioning and inhibitory avoidance. However, dicyclomine (up to 64 mg/kg) did not affect tone fear conditioning. These results suggest that the selective M1 muscarinic antagonist dicyclomine differentially affects aversively motivated tasks known to be dependent on hippocampal integrity (such as contextual fear conditioning and inhibitory avoidance) but does not affect similar hippocampus-independent tasks. (+info)
Experimental analysis of antimicrobial action of dicyclomine hydrochloride.
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Dicyclomine hydrochloride is an antispasmodic agent. The MIC of dicyclomine against standard strains of Gram positive and Gram negative bacteria were performed by NCCLS broth dilution technique. These drugs showed a rapid killing action on Gram positive bacteria, Staphylococcus aureus NCTC 6571, 8530 and several other reference strains. The killing effect against Gram negative bacteria, Shigella boydii 8 NCTC 254/66 and Salmonella typhimurium NCTC 74 showed that the drug was bacteriostatic with respect to these strains. High rate of killing was achieved for most strains of Gram positive bacteria within 2 h. When administered to Swiss strain of white mice at doses of 30 and 60 microg/g of mouse, the drug could significantly protect the animals challenged with 50 MLD of Salmonella typhimurium NCTC 74. According to chi2 test, the in vivo data were highly significant (p<0.001). Since dicyclomine showed a remarkable inhibitory action against several pathogenic bacteria, in the course of time, it may be developed as a potent antimicrobial agent for many bacterial infections. (+info)
M1 receptors play a central role in modulating AD-like pathology in transgenic mice.
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We investigated the therapeutic efficacy of the selective M1 muscarinic agonist AF267B in the 3xTg-AD model of Alzheimer disease. AF267B administration rescued the cognitive deficits in a spatial task but not contextual fear conditioning. The effect of AF267B on cognition predicted the neuropathological outcome, as both the Abeta and tau pathologies were reduced in the hippocampus and cortex, but not in the amygdala. The mechanism underlying the effect on the Abeta pathology was caused by the selective activation of ADAM17, thereby shifting APP processing toward the nonamyloidogenic pathway, whereas the reduction in tau pathology is mediated by decreased GSK3beta activity. We further demonstrate that administration of dicyclomine, an M1 antagonist, exacerbates the Abeta and tau pathologies. In conclusion, AF267B represents a peripherally administered low molecular weight compound to attenuate the major hallmarks of AD and to reverse deficits in cognition. Therefore, selective M1 agonists may be efficacious for the treatment of AD. (+info)
Evidence for facilitatory and inhibitory muscarinic receptors on postganglionic sympathetic nerves in mouse isolated atria.
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1. McNeil A 343 (10 microM-30 microM) enhanced the fractional stimulation-induced (S-I) outflow of radioactivity from mouse isolated atria which had been incubated with [3H]-noradrenaline. The enhancing effect of McNeil A 343 was not altered by hexamethonium (300 microM) suggesting that it was not due to an action at nicotinic receptors. It is also unlikely that McNeil A 343 enhanced the S-I outflow of radioactivity in mouse atria by blocking neuronal reuptake of noradrenaline since the effect persisted in the presence of cocaine (30 microM). 2. The facilitatory effect of McNeil A 343 on the S-I outflow of radioactivity was attenuated by atropine (0.3 microM), pirenzepine (0.2 microM or 1.0 microM), dicyclomine (1.0 microM) and methoctramine (1.0 microM) and was thus due to activation of muscarinic receptors. 3. In contrast to the effect of McNeil A 343, another muscarinic receptor agonist, carbachol (3.0 microM) significantly decreased the S-I outflow of radioactivity. The receptors through which McNeil A 343 acts to enhance the S-I outflow of radioactivity appear to be distinct from inhibitory prejunctional muscarinic receptors. The relatively M 1-selective antagonist, pirenzepine (0.2 microM), attenuated the facilitatory effect of McNeil A 343 whereas a higher concentration (1.0 microM) was required to block the inhibitory effect of carbachol. Conversely, the relatively M2-selective antagonist, methoctramine (0.1 microM), blocked the inhibitory effect of carbachol but a higher concentration of methoctramine (1.0 microM) was required to block the facilitatory effects of McNeil A 343. These results tentatively ascribe facilitatory muscarinic receptors as belonging to the Ml subtype and inhibitory muscarinic receptors as belonging to the M2 subtype. 4. The non-selective muscarinic receptor antagonist, atropine, enhanced the S-I outflow of radioactivity, suggesting that there was tonic activation of inhibitory prejunctional muscarinic receptors by endogenous acetylcholine released from parasympathetic nerves. However, pirenzepine (0.03 pM-LO microM) did not decrease the S-I outflow of radioactivity, suggesting that under the conditions of the present study, facilitatory muscarinic receptors are not tonically activated by endogenous acetylcholine. (+info)
Dicyclomine, an M1 muscarinic antagonist, reduces biomarker levels, but not neuronal degeneration, in fluid percussion brain injury.
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Investigation into atropine-induced antinociception.
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1. The effect of atropine on the nociceptive system was examined in mice and rats by use of the hot-plate, writhing and tail-flick tests. 2. Atropine dose-dependently produced analgesia, no effect and hyperalgesia. Analgesia was observed in both species with doses ranging from 1 to 100 micrograms kg-1 while hyperalgesia was obtained with 5 mg kg-1. 3. Atropine antinociception was prevented by pirenzepine (0.1 microgram per mouse, i.c.v.), dicyclomine (10 mg kg-1, i.p.), atropine-methylbromide (0.5 microgram per mouse, i.c.v.) and hemicholinium-3 (1 microgram per mouse, i.c.v.). Naloxone (1 mg kg-1, i.p.), alpha-methyl-p-tyrosine (100 mg kg-1, s.c.) and reserpine (2 mg kg-1, i.p.) were ineffective. 4. The site of atropine analgesia is in the CNS since it exerts its antinociceptive effect also when injected i.c.v. (1-10 ng per mouse). Moreover drugs which do not cross the blood-brain barrier, such as hemicholinium-3, pirenzepine and atropine methylbromide, were unable to antagonize atropine analgesia if administered i.p. 5. Atropine also in vitro, showed a biphasic action on electrically-evoked guinea-pig ileum contractions. Concentrations between 10(-14) and 10(-12) M increased electrically and nicotine-evoked contractions but did not affect acetylcholine- and oxotremorine-evoked contractions. Concentrations above 10(-9) M inhibited both electrically- and drug (acetylcholine, nicotine and oxotremorine)-evoked contractions while they were ineffective on unstimulated ileum. 6. On the basis of the above findings, amplification of cholinergic transmission by very low doses of atropine is postulated, through a selective blockade of presynaptic muscarinic autoreceptors, as the likely mechanism of action. 7. Atropine antinociception, unlike oxotremorine antinociception, was obtained without any impairment of mouse rota-rod performance. 8. The antagonism by pirenzepine and dicyclomine of oxotremorine and atropine antinociception suggests that M1 muscarinic receptor subtypes are responsible for cholinergic analgesia. (+info)
Comparison of the pattern, efficacy, and tolerability of self-medicated drugs in primary dysmenorrhea: a questionnaire based survey.
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