Showing papers on "Arecoline published in 1986"

Enhanced elevation of corticosterone following arecoline administration to rats selectively bred for increased cholinergic function.

Abstract: Serum corticosterone levels were determined following administration of the cholinergic agonist arecoline (4 mg/kg) to rats selectively bred for differences in cholinergic function. The Flinders Sensitive Line (FSL) of rats exhibited both greater suppression of behavioural activity and enhanced elevation fo serum corticosterone than the Flinders Resistant Line of rats. These enhanced responses to arecoline in the FSL rats parallel those reported in depressed humans, suggesting that these rats may provide a new animal model of affective disorders.

Prostanoid synthesis by the rat urinary bladder: evidence for stimulation through muscarine receptor-linked calcium channels.

Abstract: An in vitro model for the study of muscarine receptor-mediated synthesis of prostacyclin (PGI2) and other prostanoids (PGE2 and PGF2α) by the rat urinary bladder is described. PGI2 synthesis was stimulated by parasympathomimetic agents (carbachol > methacholine > arecoline; McNA 343, nicotine and dimethyl phenyl piperazinium were without effect). Methacholine (3×10−6 mol·l−1)-stimulated PGI2 synthesis was inhibited by muscarinic antagonists (atropine > ipratroprium bromide > gallamine > pirenzepine) and was completely abolished by the presence of ethylene diamine tetraacetic acid (EDTA: 10 mmol·l−1). Verapamil also inhibited methacholine-stimulated PGI2 synthesis in a dose-dependent manner. The antagonistic action of atropine was shown to be competitive, but had no effect on calcium ionophore A23187-stimulated PGI2 synthesis. High concentrations of [K+] (up to 0.11 mol·l−1) were without effect on PGI2 synthesis. PGE2, PGF2α and PGI2 synthesis were all equally stimulated with methacholine, carbachol, arecoline and A23187, and methacholine-stimulated synthesis of these prostanoids was equally inhibited by atropine, ipratroprium bromide, gallamine, verapamil and EDTA.

A novel class of conformationally restricted heterocyclic muscarinic agonists.

Abstract: A series of conformationally restricted compounds containing the 4,5,6,7-tetrahydroisoxazolo[4,5-c]pyridin-3-ol (THPO) skeleton, including O-methyl-THPO (10a) and O,5-dimethyl-THPO (11a), were synthesized. The compounds were designed by bioisosteric replacement of the methyl ester groups of the muscarinic cholinergic agonists norarecoline and arecoline by the 3-methoxyisoxazole group, and their interactions with central and peripheral muscarinic receptors were tested in vitro. The compounds 10a, 11a, O-ethyl-THPO (10b), O-propargyl-THPO (10j), and O-ethyl-5-methyl-THPO (11b) were inhibitors of the binding of the muscarinic mustard [3H]PrBCM to rat brain membranes with an increasing order of potency. There was, however, a very low degree of correlation between these binding data and the effects of the compounds on peripheral (ileal) muscarinic receptors, where 11a, 10j, 11b, and 10a were agonists with a decreasing order of potency, whereas O-isopropyl-THPO (10e) showed antagonistic effects. The relatively low pKa values of the compounds (7.5-7.7 for compounds with secondary and 6.1-7.0 for compounds with tertiary amino groups) are likely to allow the compounds to penetrate the blood-brain barrier.

Action of arecoline on the levels of acetylcholine, norepinephrine and dopamine in the mouse central nervous system.

Abstract: Modifications caused by arecoline (2 mg/kg and 10 mg/kg injected subcutaneously) in the levels of acetylcholine (ACh), norepinephrine (NE) and dopamine (DA) in the mouse cortex and “subcortex” were studied. The animals were killed by microwave irradiation of the head 15 minutes after drug administration. Arecoline 10 mg/kg caused a reduction in levels of ACh in the cortex and “subcortex” at the limit of statistical significance ( p 5–10%) and a statistically reduction in levels on NE. A statistically significant icncrease in DA was observed only in the cortex after 2 mg/kg and 10 mg/kg of arecoline.

Characterization of muscarinic cholinergic receptors in the crab nervous system.

Abstract: The selective muscarinic antagonist L-[3H]-quinuclidinyl benzilate (L-[3H]QNB) binds reversibly and with high affinity (KD= 0.3 nM) to a single population (Bmax= 105 fmol/mg protein) of specific sites in nervous tissue of the crab Cancer magister. The binding site is stereoselective; (-)QNB is over 200 times more potent than (+)QNB as an inhibitor of specific L-[3H]QNB binding. The muscarinic antagonists scopolamine and atropine are over 10,000 times more potent inhibitors of L-[3H]QNB binding than the nicotinic antagonists deca-methonium and d-tubocurarine. The muscarinic agonists oxotremorine, pilocarpine, arecoline, and carbachol also compete effectively for the L-[3H]QNB binding site. This pharmacological profile strongly suggests the presence of classical muscarinic receptors in the crab nervous system. These receptors are localized to nervous tissue containing cell bodies and neuropil, whereas specific L-[3H]QNB binding is low or absent in peripheral nerve, skeletal muscle, and artery.

Cholinergic agonists suppress play fighting in juvenile rats.

Abstract: Previous research has suggested that acetylcholine might activate play fighting in juvenile rats through its actions on central muscarinic receptors. To test this hypothesis we evaluated the effects on play fighting by the muscarinic agonists pilocarpine and arecoline given alone or in combination with the muscarinic antagonists scopolamine or methylscopolamine. Scopolamine, but not methylscopolamine which penetrates the brain poorly, suppressed play as indexed by frequency of pinning. Pilocarpine and arecoline also suppressed pinning at higher doses. Concurrent treatment with various agonist-antagonist dose combinations produced additive rather than counteractive effects. These data do not support the supposition that central muscarinic circuits are involved in the activation of play fighting.

Behavioural tolerance to arecoline in rats: cross-tolerance to oxotremorine and prevention by pretreatment with atropine.

Abstract: In two experiments tolerance development to the effects of arecoline on operant responding for a water reward was shown to be dose-dependent, complete tolerance developing to a daily dose of 4 mg/kg, but only partial tolerance developing to a daily dose of 8 mg/kg. However, rats chronically treated with the higher dose of arecoline were least affected by a challenge dose of oxotremorine (0.2 mg/kg); i.e. the high dose group exhibited the greatest cross-tolerance to oxotremorine. Moreover, atropine (4 mg/kg) pretreatment prior to arecoline (4 mg/kg) prevented cross-tolerance to oxotremorine, indicating that dispositional mechanisms are unlikely to be involved in tolerance to arecoline.

Evaluation of the cardiovascular effects of arecoline in the anesthetized dog

Abstract: Arecoline has been reported to improve memory deficits, but a relatively short half-life and adverse cardiovascular effects have limited its use The purpose of this study was to compare the cardiovascular effects of a bolus administration with those of an infusion of arecoline in anesthetized beagle dogs Arecoline was administered either as a 15 sec bolus (group I), as a constant infusion (group II), or as an infusion after pretreatment with 01 mg/kg methyl scopolamine (group III) In group I, mean arterial blood pressure (MABP) was immediately reduced (ie, which 1 min) after each dose of arecoline, but had returned to the baseline value by 5 min after doses of 001 to 10 μg/kg, and by 20 min after a 30 μg/kg dose However, blood pressure was still depressed 20 min after a 100 μg/kg dose of arecolin Cardiac output (CO) was significantly reduced only after the 30 or 100 μg/kg doses In group II, MABP, heart rate (HR), and CO were unchanged after a 03 or 10 μg/kg/min infusion of arecoline An infusion of 30 or 10 μg/kg/min produced dose-dependent decreases in MABP (–15 and –56%, respectively) and HR (–13 and –71%, respectively) CO was unchanged at 3 μg/kg/min but was reduced by 50% at 10 μg/kg/min (P < 005) Plasma levels of arecoline were 469 ± 55 ng/ml after an arecoline infusion of 10 μg/kg/min Pretreatment with methyl scopolamine significantly attenuated the cardiodepression produced by 10 μg/kg/min arecoline Moveover, infusions of 30 and 100 μg/kg/min of arecoline produced less than 40% reductions in MABP, HR, and CO After pretreatment with methyl scopolamine, plasma arecoline levels were 29 ± 4 and 259 ± 387 ng/ml with an infusion of 10 or 100 μg/kg/min, respectively These data indicate that the continuous administration of a low dose of arecoline may minimize the undesired cardiovascular effects Pretreatment with methyl scopolamine further attenuated the cardiovascular responses produced by arecoline, suggesting that a greater therapeutic ratio may be achieved in the presence of a peripheral muscarinic blocking agent

A Novel Class of Conformationally Restricted Heterocyclic Muscarinic Agonists.

Abstract: A series of conformationally restricted compounds containing the 4,5,6,7-tetrahydroisoxazolo[4,5-c]pyridin-3-ol (THPO) skeleton, including O-methyl-THPO (10a) and O,5-dimethyl-THPO (11a), were synthesized. The compounds were designed by bioisosteric replacement of the methyl ester groups of the muscarinic cholinergic agonists norarecoline and arecoline by the 3-methoxyisoxazole group, and their interactions with central and peripheral muscarinic receptors were tested in vitro. The compounds 10a, 11a, O-ethyl-THPO (10b), O-propargyl-THPO (10j), and O-ethyl-5-methyl-THPO (11b) were inhibitors of the binding of the muscarinic mustard [3H]PrBCM to rat brain membranes with an increasing order of potency. There was, however, a very low degree of correlation between these binding data and the effects of the compounds on peripheral (ileal) muscarinic receptors, where 11a, 10j, 11b, and 10a were agonists with a decreasing order of potency, whereas O-isopropyl-THPO (10e) showed antagonistic effects. The relatively low pKa values of the compounds (7.5-7.7 for compounds with secondary and 6.1-7.0 for compounds with tertiary amino groups) are likely to allow the compounds to penetrate the blood-brain barrier.