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At least 451 records · Page 25Linked to original sources
PubMed1985

In vivo regulation of [3H]acetylcholine recognition sites in brain by nicotinic cholinergic drugs.

The in vivo regulation of [3H]acetylcholine [( 3H]ACh) recognition sites on nicotinic receptors in rat brain was examined by administering drugs that increase stimulation of nicotinic cholinergic receptors, either directly or indirectly. After 10 days of treatment with the cholinesterase inhibitor diisopropyl fluorophosphate, [3H]ACh binding in the cortex, thalamus, striatum, and hypothalamus was decreased. Scatchard analyses indicated that the decrease in binding in the cortex was due to a reduction in the apparent density of [3H]ACh recognition sites. In contrast, after repeated administration of nicotine (5-21 days), the number of [3H]ACh recognition sites was increased in the cortex, thalamus, striatum, and hypothalamus. Similar effects were observed in the cortex and thalamus following repeated administration of the nicotinic agonist cytisin. The nicotinic antagonists mecamylamine and dihydro-beta-erythroidine did not alter [3H]ACh binding following 10-14 days of administration. Further, concurrent treatment with these antagonists and nicotine did not prevent the nicotine-induced increase in these binding sites. The data indicate that [3H]ACh recognition sites on nicotinic receptors are subject to up- and down-regulation, and that repeated administration of nicotine results in a signal for up-regulation, probably through protracted desensitization at the recognition site.

Acetylcholine↗
PubMed1985

Biochemical characterization of the nicotinic cholinergic receptors in human brain: binding of (-)-[3H]nicotine.

(-)-[3H]Nicotine was found to bind specifically to membranes of human brains obtained at autopsy. The binding was stereospecific, (-)-nicotine being 40 times more potent than (+)-nicotine in displacing labeled (-)-nicotine. Saturation binding studies revealed the presence of two binding sites with dissociation constant (KD) values of 8.1 and 86 nM, and maximum binding capacity (Bmax) values of 36 and 90 fmol/mg protein, respectively. In competition studies, nicotinic agonists were 1,000 times more potent than ganglionic, neuromuscular, and muscarinic blocking drugs in displacing labeled (-)-nicotine. IC50 values for cholinergic drugs of (-)-[3H]nicotine binding were as follows: (-)-nicotine, 0.51 nM; acetylcholine, 12.6 nM; (+)-nicotine, 19.9 nM; cytisine, 27.3 nM; and carbachol, 527 nM. IC50 values of alpha-bungarotoxin, hexamethonium, d-tubocurarine, and atropine were larger than 50 microM. (-)-[3H]Nicotine binding was highest in the nucleus basalis of Meynert and thalamus and lowest in the cerebral cortex and caudate in the brain regions tested. These results suggest that nicotinic cholinergic receptors are present in human brain and that there are regional differences in the density of these receptors.

Acetylcholine↗
PubMed1969

Some studies on cytisine and its methylated derivatives.

1. In mice cytisine hydrochloride is less toxic intravenously than nicotine hydrogen tartrate, but more toxic by intraperitoneal or oral administration. Compared with cytisine, caulophylline hydrogen iodide is one-fifth to one-tenth as toxic and caulophylline methiodide is less than one-thirtieth as toxic.2. The surprising low oral toxicity of cytisine and nicotine may be ascribed to the method of administration; if the drug is placed directly in the stomach there is no possibility of absorption through buccal mucous membranes.3. The peripheral effects of nicotine, cytisine and caulophylline are similar, though on some preparations those of nicotine last longer. In most tests cytisine is active in doses from a quarter to three-quarters of those of nicotine, caulophylline in doses from 10 to 20 times those of cytisine. Caulophylline methiodide is virtually inactive.4. Cytisine and caulophylline may differ from nicotine in their central effects.5. Cytisine and caulophylline are active as the cations. The pKa of cytisine is 7.92 and that of caulophylline is 7.04; the difference accounts, in part, for the weaker activity of caulophylline. The caulophylline ion is generally one-sixth to one-third as active as the cytisine ion.6. The introduction of the second methyl group to form the quaternary salt does not appear to cause a dramatic change in the conformation of the molecule. Caulophylline methiodide appears to be feebly active because it has feeble affinity.

Alkaloids↗
PubMed1986

Inhibitory actions of opioid compounds on calcium fluxes and neurotransmitter release from mammalian cerebral cortical slices.

The effects of opioid agonists on veratrine-stimulated Ca2+ influx and amino acid neurotransmitter release in rat cerebrocortical brain slices were studied. Inhibitory effects were seen on both of these parameters with all of the opioid agonists used. None of the drugs used affected basal 45Ca2+ uptake, basal K+ content or basal amino acid release from the slices. At high concentrations (100 microM) fentanyl, tifluadom, U50,488H, butorphanol and bremazocine greatly inhibited the depolarization of the slices by veratrine as determined by the reduced release of K+. The opioid receptor subtypes at which the drugs were acting were characterized by the antagonistic effects of naloxone and WIN44441-3. The opioid-induced inhibition of stimulated Ca2+ uptake and amino acid release were not antagonized by WIN44441-2, the inactive enantiomer of WIN44441-3. It is concluded that opioid agonists acting through mu- and kappa-receptors and probably through delta- and sigma-receptors, have an inhibitory effect on Ca2+ uptake into cerebrocortical brain slices and the subsequent release of aspartate, glutamate and gamma-aminobutyric acid (GABA).

Amino Acids↗
PubMed1986

Stereospecific antiarrhythmic effect of opioid receptor antagonists in myocardial ischaemia.

The effects of the stereoisomers of two different antagonists at opioid receptors were examined on the ventricular arrhythmias that result from acute coronary artery ligation in anaesthetized male rats. (-)-Mr 1452(but not the (+)-isomer, Mr 1453) reduced, in a dose-dependent manner, the number of ventricular ectopic beats and the incidence or duration of both ventricular tachycardia and fibrillation. (-)-WIN 44,441-3 (but not its (+)-isomer, WIN 44,441-2) had a similar protective effect in ischaemia. These results suggest that antagonism of the effects of endogenous opioid peptides at specific receptors results in reduced severity of arrhythmias in myocardial ischaemia.

Animals↗
PubMed1989

Relations between structure and nicotine-like activity: X-ray crystal structure analysis of (-)-cytisine and (-)-lobeline hydrochloride and a comparison with (-)-nicotine and other nicotine-like compounds.

1. Although (-)-cytisine is a rigid structure, it occurs in the crystal in two distinct but very similar conformations in which the pyridone ring is tilted relative to the charged nitrogen atom at much the same angle as the pyridine ring is in (-)-nicotine hydrogen iodide. The carbonyl group in the pyridone ring of (-)-cytisine, however, is on the side of the ring opposite to pyridine nitrogen in (-)-nicotine. 2. The pKa of (-)-lobeline HCl at 25 degrees C is 8.6 (approx), indicating that (-)-lobeline is at least 90% in the protonated form at physiological pH (7.6). It is probably the phenyl 2-keto-ethyl part of (-)-lobeline, rather than the phenyl 2-hydroxy-ethyl part, which interacts with the receptor. 3. The combination within one molecule of a charged ('onium') nitrogen atom lying out of the plane of, and some distance (4.5-6.5 A) from, an aromatic ring is common to many compounds with nicotine-like activity (e.g. nicotine, cytisine, choline phenyl ether bromide, dimethyl-phenyl-piperazinium (DMPP) iodide, coryneine iodide and m-hydroxyphenylpropyl trimethyl ammonium iodide). In some molecules the aromatic ring can be replaced by an unsaturated group, such as carbonyl (e.g. acetylcholine) or double-bonds (e.g. anatoxin). 4. Activity at nicotinic receptors appears to involve interactions between the positively charged nitrogen atom and a negatively charged group, probably close to cysteine residues 192 and 193 in the receptor. It is suggested that rather than specific groups in the molecule also being involved, activity at nicotinic receptors depends on interactions between a flat part of the drug containing double-bonds, or systems of double bonds, and a planar area in the receptor, possibly tyrosine or phenylalanine residues.

Alkaloids↗
PubMed1990

Locomotor activity in rats after administration of nicotinic agonists intracerebrally.

1. Nicotine (0.13 and 0.4 mg kg-1, s.c.) increased the ambulatory component of locomotor activity in rats previously exposed to the drug. Nicotine did not increase repeated movements reliably. 2. An infusion of either nicotine (8 micrograms) or the potent nicotinic agonist cytisine (4 micrograms) into the ventral tegmental area of the forebrain increased ambulation but not repeated movements. 3. An infusion of nicotine or cytisine into the nucleus accumbens, striatum, dorsal hippocampal formation or motor thalamus did not increase ambulatory or repeated movements. 4. Mecamylamine (0.1-1.0 mg kg-1, s.c.) blocked increases in locomotor activity produced by an infusion of nicotine or cytisine into the ventral tegmental area. 5. The locomotor activity produced by systemically administered nicotine may be mediated, in part, through nicotinic receptors located in the ventral tegmental area of the mesolimbic dopamine system.

Alkaloids↗
PubMed1991

Anti-arrhythmic activities of opioid agonists and antagonists and their stereoisomers.

1. A series of opioid agonists, antagonists and their (+)-stereoisomers were tested for antiarrhythmic activity in the rat coronary artery occlusion model. 2. Naloxone (0.01-2 mg kg-1) significantly reduced the incidence and severity of cardiac arrhythmias, in accordance with previous published studies. 3. The non-opioid stereoisomer, (+)-naloxone, was equipotent with naloxone against occlusion-induced arrhythmia. 4. Similar non-stereospecific antiarrhythmic effects were induced by another opioid antagonist, Win 44,441-3 and its stereoisomer Win 44,441-2. 5. The opioid agonists, morphine and levorphanol, protected against occlusion-induced arrhythmia as did the opioid antagonists, and the (+)-stereoisomer, dextrorphan, was equipotent to levorphanol. 6. It is concluded that the antiarrhythmic effects of opioid drugs are not mediated by opioid receptors. A direct effect on ionic currents in cardiac muscle is suggested as the mechanism of opioid antiarrhythmic activity.

Animals↗
PubMed1996

Release of [3H]-noradrenaline from rat hippocampal synaptosomes by nicotine: mediation by different nicotinic receptor subtypes from striatal [3H]-dopamine release.

1. The aim of the present experiment was to characterize nicotine-evoked [3H]-noradrenaline ([3H]-NA) release from rat superfused hippocampal synaptosomes, using striatal [3H]-dopamine release for comparison. 2. (-)-Nicotine, cytisine, DMPP and acetylcholine (ACh) (with esterase inhibitor and muscarinic receptor blocker) increased NA release in a concentration-dependent manner (EC50 6.5 microM, 8.2 microM, 9.3 microM, and 27 microM, respectively) with similar efficacy. 3. Nicotine released striatal dopamine more potently than hippocampal NA (EC50 0.16 microM vs. 6.5 microM). (+)-Anatoxin-a also increased dopamine more potently than NA (EC50 0.05 microM vs. 0.39 microM), and maximal effects were similar to those of nicotine. Isoarecolone (10-320 microM) released dopamine more effectively than NA but a maximal effect was not reached. (-)-Lobeline (10-320 microM) evoked dopamine release, but the effect was large and delayed with respect to nicotine; NA release was not increased but rather depressed at high concentrations of lobeline. High K+ (10 mM) released and NA to similar extents. 4. Addition of the 5-hydroxytryptamine (5-HT) reuptake blocker, citalopram (1 microM) to hippocampal synaptosomes affected neither basal NA release nor nicotine-evoked release. 5. The nicotinic antagonist, mecamylamine (10 microM), virtually abolished NA and dopamine release evoked by high concentrations of nicotine, ACh, cytisine, isoarecolone, and anatoxin-a. Although NA release evoked by DMPP (100 microM) was entirely mecamylamine-sensitive, DMPP-evoked dopamine release was only partially blocked. Dopamine release evoked by lobeline (320 microM) was completely mecamylamine-insensitive. 6. The nicotinic antagonists dihydro-beta-erythroidine and methyllycaconitine inhibited nicotine-evoked dopamine release approximately 30 fold more potently than NA release. In contrast, the antagonist chlorisondamine, displayed a reverse sensitivity, whereas trimetaphan and mecamylamine did not preferentially block either response. None of these antagonists, given at a high concentration, significantly altered release evoked by high K+. 7. Blockade of nicotine-evoked transmitter release by methyllycaconitine and dihydro-beta-erythroidine was surmounted by a high concentration of nicotine (100 microM), but blockade by mecamylamine, chlorisondamine, and trimetaphan was insurmountable. 8. Nicotine-evoked NA release was unaffected by tetrodotoxin, whereas veratridine-evoked NA release was virtually abolished. 9. We conclude that presynaptic nicotinic receptors associated with striatal dopamine and hippocampal NA terminals differ pharmacologically. In situ hybridization studies suggest that nigrostriatal dopaminergic neurones express mainly alpha 4, alpha 5, and beta 2 nicotinic cholinoceptor subunits, whereas hippocampal-projecting noradrenaline (NA) neurones express alpha 3, beta 2 and beta 4 subunits. Pharmacological comparisons of recombinant receptors suggest that release of hippocampal NA may be modulated by receptors containing alpha 3 and beta 4 subunits.

Acetylcholine↗
PubMed2005

A robust homogeneous binding assay for alpha4beta2 nicotinic acetylcholine receptor.

AIM: To develop a homogeneous high-throughput screening (HTS) assay based on scintillation proximity assay (SPA) technology for identification of novel alpha4beta2 nicotinic acetylcholine receptor (nAChR) modulators. METHODS: Membrane preparation of HEK293 cells expressing alpha4beta2 nAChR, [(3)H]cytisine and wheat germ agglutinin (WGA)-coupled microbeads were used to develop an HTS assay based on SPA technology. This method was validated against a conventional filter binding approach and applied to large-scale screening of a library containing 32 000 synthetic compounds. Intracellular calcium measurement was carried out to verify the bioactivities of the hits found by the SPA assay. RESULTS: IC(50) values of 2 reference compounds (epibatidine and RJR 2403) determined by SPA and filter binding methods were comparable and consistent with those reported elsewhere. A total of 54 compounds, showing more than 60% competitive inhibition on [(3)H]cytisine binding to alpha4beta2 nAChR, were identified initially following an HTS campaign. Secondary screening confirmed that 17 compounds with novel chemical structures possessed relatively high binding affinity to alpha4beta2 nAChR (K(i)<2 micromol/L). Eight compounds displayed antagonistic effects with >50% inhibition on ABT-594-induced calcium mobilization while none showed any agonist activity. CONCLUSIONS: This homogeneous binding assay is a highly efficient, amenable to automation and robust tool to screen potential alpha4beta2 nAChR modulators in an HTS setting. Its application may be expanded to other membrane receptors and ion channels.

Alkaloids↗
PubMed1988

Endorphin mechanisms are responsible for the beneficial effects of opioid antagonists on cerebral function during relative cerebral ischaemia in rats.

The present study was conducted to examine the mechanisms behind the previously reported beneficial effects of high doses of naloxone on impaired cerebral function due to hypotensive haemorrhage in spontaneously hypertensive rats (SHR). The stereospecificity of the effects of two opioid receptor antagonists, naloxone (Nal) and Win 44.441-3 (Win), was tested. The effects of thyrotropin releasing hormone (TRH) were also examined, because this peptide has been shown to have beneficial effects in neuronal ischaemia due to spinal injury. In addition, we were interested in seeing what effect the GABA antagonist, bicucculine (Bic), had on cerebral function during relative ischaemia, because Nal in high doses is suspected to antagonize GABA transmission. Mean arterial pressure (MAP), heart rate (HR) and somatosensory evoked potentials (SEP) were recorded in chloralose-anaesthetized SHR. The rats were bled and MAP was rapidly lowered to 50 mmHg. This resulted in transient bradycardia and attenuated SEP. When the first SEP component had decreased to 40-50% of control, the animals were retransfused to a MAP of 60-80 mmHg, to prevent further deterioration of SEP, and maintained at the new pressure level for the rest of the experiment. Fifteen to twenty minutes later, Nal, Win, TRH or Bic was injected i.v. Both (-)Nal (5 mg kg-1) and (-)Win (1 mg kg-1) improved SEP in a stereospecific manner. (+)Naloxone or (+)Win did not affect SEP significantly. Thyrotrophin releasing hormone (2 mg kg-1) caused further attenuation of a late SEP component.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1997

Bioremediation using composting or anaerobic treatment for ordnance-contaminated soils.

This paper presents the results of the pilot-scale testing of these technologies conducted from December 1994 through March 1995 at the Bangor Naval Submarine Base (Silverdale, Washington). Goals of the pilot study were to provide cost and design information for the implementation of the full-scale remediation scheduled for mid-1996. Both aerobic composting and the Simplot Anaerobic Bioremediation (SABRE) process were evaluated for soils contaminated with 2,4,6-trinitrotoluene and other ordnance compounds. Cleanup goals of 33.3 mg/kg (soil D) and 33.0 mg/kg (soil F) were established for TNT. A goal of 9.1 mg/kg was additionally determined for RDX. For soil F, TNT cleanup goals were achieved within 9 days for composting (637 mg/kg to 3 mg/kg) and 40 days for anaerobic treatment (488 mg/kg to 0.7 mg/kg). For soil D, TNT goals were not statistically achieved using composting (147 mg/kg to 41 mg/kg) or anaerobic treatment (725 mg/kg to 77 mg/kg) during the treatment period. The nature of contamination in soil D (burn disposal of ordnance) may have influenced the treatment performance of both processes.

Anaerobiosis↗
PubMed1997

A microcosm study on remediation of explosives-contaminated groundwater using constructed wetlands.

Anaerobic degradation of TNT and TNB in gravel systems was rapid and similar to removal rates in parrot feather lagoons. Planted and unplanted anaerobic gravel systems were the only treatments that provided significant reduction of RDX and HMX. Planted systems with parrot feather had no effect on removal rates of explosives in anaerobic gravel systems. Reciprocating wetlands were not effective in biodegrading RDX or HMX, but were very efficient at removing COD. A scaled-up concept for bioremediating contaminated groundwater can be envisioned with the data obtained in the current study. The effectiveness of anaerobic gravel systems indicate an anaerobic subsurface-flow constructed wetland can be established as the primary treatment for remediation with C added to the influent or step fed down the length of the wetland. Another option would be to add compost as a more permanent source of C to the gravel substrate. With time, the need for C supplementation may be reduced with the C exudates and redox lowering potential of certain plants like canarygrass (Phalaris arundinacea). As a secondary treatment, a reciprocating wetland would appear to be a logical choice to quickly remove C released in effluent waters of the anaerobic wetland.

Animals↗
PubMed1997

First production-level bioremediation of explosives-contaminated soil in the United States.

Umatilla Army Depot Activity (UMDA) near Hermiston, Oregon was the location of the first production-level bioremediation of explosives-contaminated soil in the U.S. Soil from munitions washout lagoons contained high concentrations of TNT (2,4,6-Trinitrotoluene) and RDX (Hexahydro-1,3,5-trinitro-1,3,5- triazine) as well as HMX (Octahydro-1,3,5,7-tetranitro-1,3,5,7-tetrazocine). In addition to these primary contaminants, laboratory tests were performed for Tetryl (Methyl-2,4,6-trinitrophenylnitramine), 4-Am-DNT (4-Amino-2,6-dinitrotoluene), 2-Am-DNT (2-Amino-4,6-dinitrotoluene), 2,4 DNT (2,4-Dinitrotoluene), 2,6 DNT (2,6-Dinitrotoluene), 1,3,5-TNB (1,3,5-Trinitrobenzene), 1,3,-DNB (1,3-Dinitrobenzene) and NB (Nitrobenzene) during the pilot-scale treatability tests. The clean-up goal established by the Record of Decision (ROD) was 30 mg/kg each for TNT and RDX. Degradation progress was monitored using immunoassay field screening Methods SW 846,4050 and 4051. Confirmational analysis consisted of EPA Method 8330. Treatment time on a 2,700 cubic yard batch (810 cubic yards of soil) was 10-12 days. A composting technique developed by the Army Environmental Center and implemented by Bioremediation Service, Inc., Portland, Oregon was used at the site. Agricultural waste products (or amendments including cow manure, chicken manure, potato waste, sawdust and alfalfa) were blended with the contaminated soil during treatment. Specialized soil turning equipment mixed the compost for optimum biological action and homogeneity. Homogeneity of the compost mix ensured rapid degradation of all contaminants. Physical and chemical properties were closely monitored to ensure that thermophilic bacteria played a dominant role in the degradation process. Nearly 5,000 cubic yards of soil have been successfully treated, and more than 70% of all analyses indicate non-detectable levels of both TNT and RDX. The U.S. Army Corps of Engineers estimates that over $2.6 million is being saved using bioremediation at Umatilla.

Azocines↗
PubMed1999

The role of beta 2-subunit-containing nicotinic acetylcholine receptors in the brain explored with a mutant mouse.

Neuronal nicotinic receptors comprise a family of pentameric oligomers made up of a combination of 10 different subunits. The beta 2 subunit has the widest pattern of expression in the brain and is thus likely to form a significant fraction of neuronal nicotinic receptors. Using mice lacking the beta 2 subunit, we have shown that nAChRs containing this subunit are responsible for most of the high-affinity binding sites for nicotine, cytisine, and epibatidine in the brain. Functional receptors containing the beta 2-subunit are found in the somatodendritic compartment as well as the axonal compartment of neurons. We have examined the contribution of these receptors to the effects of nicotine on the mesolimbic DA system, which mediates the reinforcing properties of many addictive drugs (including nicotine). Submicromolar doses of nicotine, corresponding to the concentrations of nicotine in vivo in self-administration paradigms, increased the firing rate of dopaminergic neurons in vitro in normal mice but not in mice lacking the beta 2 subunit. Consistently, systemic injection of nicotine induced an increase in extracellular dopamine in normal mice but not in mutant mice, and nicotine self-administration was reduced or suppressed in mutant mice. These data support the view that the beta 2-containing receptors are involved in mediating the reinforcing properties of nicotine.

Alkaloids↗
PubMed1990

The importance of nucleus accumbens in nicotine-induced locomotor activity.

Bilateral injections of either nicotine (200 micrograms) or cytisine (30 or 60 micrograms) into the nucleus accumbens elicited locomotor hyperactivity in rats. Pretreatment with mecamylamine (2 mg kg-1, s.c.) was effective in attenuating the stimulatory effect of either nicotine or cytisine. This study suggests that nicotinic agonists such as nicotine and cytisine produce their locomotor excitatory effects through stimulation of the mesolimbic dopaminergic pathway.

Alkaloids↗
PubMed1991

Opioidergic inhibition of reflexes evoked by selective stimulation of sural nerve C fibres in the rabbit.

Reflexes were evoked in the gastrocnemius medialis (GM) muscle nerve by selective electrical stimulation of the non-myelinated C fibres of the ipsilateral sural nerve of decerebrated, spinalized rabbits. The opioid antagonist (-)-quadazocine (555 micrograms/kg i.v.) enhanced responses to sural C fibre stimulation to an average of 236% of pre-drug levels. In addition, C fibre-evoked reflexes were depressed for 7-9 min after repetitive activation of the high threshold axons of the common peroneal nerve, and this effect was reversed after quadazocine. Thus, GM responses to stimulation of non-myelinated sural afferent fibres are suppressed by endogenous opioid peptides, but the degree of inhibition does not appear to be as profound as that previously reported for reflexes evoked by myelinated fibres.

Animals↗