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At least 127 records · Page 7Linked to original sources
PubMed1994

alpha 4 beta 2 subunit combination specific pharmacology of neuronal nicotinic acetylcholine receptors in N1E-115 neuroblastoma cells.

Pharmacological characteristics of native neuronal nicotinic acetylcholine receptor-mediated ion currents in mouse N1E-115 neuroblastoma cells have been investigated by superfusion of voltage clamped cells with known concentrations of the agonists acetylcholine, nicotine and cytisine, and the antagonists alpha-bungarotoxin and neuronal bungarotoxin. The sensitivity of the nicotinic acetylcholine receptor for agonists followed the agonist potency rank-order: nicotine approximately acetylcholine >> cytisine. The EC50 values of acetylcholine and nicotine are 78 microM and 76 microM, respectively. Equal concentrations of acetylcholine and nicotine induce inward currents with approximately the same peak amplitude whereas cytisine induces much smaller inward currents. Acetylcholine-induced currents are unaffected by high concentrations of alpha-bungarotoxin. Conversely, at 10 and 90 nM neuronal bungarotoxin reduces the amplitude of the 1 mM acetylcholine-induced inward current to 47% and 11% of control values, respectively. Both the agonist potency rank-order and the differential sensitivity to snake toxins of nicotinic receptors in N1E-115 cells are consistent with the known pharmacological profile of alpha 4 beta 2 nicotinic receptors expressed in Xenopus oocytes and distinct from those of all other nicotinic acetylcholine receptors of known functional subunit compositions. All data indicate that the native nicotinic acetylcholine receptor in N1E-115 cells is an assembly of alpha 4 and beta 2 subunits, the putative major subtype of nicotinic acetylcholine receptor in the brain.

1-Methyl-3-isobutylxanthine↗
PubMed1994

Working memory performance and cholinergic effects in the ventral tegmental area and substantia nigra.

The nicotinic antagonist mecamylamine has been found to impair working memory performance in the radial-arm maze (RAM) after s.c. or i.c.v. administration. Mecamylamine has important interactions with dopaminergic (DA) systems. Mecamylamine-induced memory deficits in the RAM are potentiated by the D2 antagonist raclopride and reversed by the D2 agonist quinpirole. The nicotinic agonist nicotine has been found to improve working memory performance in the RAM after s.c. or i.c.v. administration. Nicotine-induced memory improvement in the RAM is potentiated by the D2 agonist quinpirole. The midbrain DA nuclei, the substantia nigra (SN) and the ventral tegmental area (VTA) have relatively dense concentrations of nicotinic receptors which may be critical sites of action for mecamylamine and nicotine. In the current study, the effects of mecamylamine (1, 3.3 and 10 micrograms/side) infusions into the SN (n = 12) and VTA (n = 13) on working memory in the radial-arm maze were examined in adult female Sprague-Dawley rats. The 10-micrograms/side dose of mecamylamine significantly impaired radial-arm maze working memory performance when infused into either the SN or VTA. No significant effects of mecamylamine on response latency were seen. The nicotinic agonists cytisine (0.1, 0.33 and 1.0 microgram/side) and nicotine (0.3, 1.0 and 3.3 micrograms/side) were administered in a counterbalanced order. The high dose of cytisine (1 microgram/side) nearly caused a significant deficit in choice accuracy. Nicotine slightly depressed choice accuracy but not significantly in this study. The interaction of nicotine and mecamylamine was then studied. A dose of 1.0 microgram/side of nicotine caused a significant decrease in choice accuracy. Interestingly, this was significantly reversed by a 3.3-micrograms/side dose of mecamylamine.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1994

alpha-Bungarotoxin blocks the nicotinic receptor mediated increase in cell number in a neuroendocrine cell line.

Exposure of H69 small cell lung carcinoma cells to nicotinic agonists resulted in a significant increase (up to 100%) in cell number after 6 to 12 days. The effect of nicotine (10(-8) M to 10(-4) M) was both dose and time dependent as was that of another nicotinic agonist cytisine (10(-6) M to 10(-4) M). Interestingly, both the nicotine and cytisine induced increases in H69 cell number were blocked by alpha-bungarotoxin, as well as d-tubocurarine a nicotinic blocker which appears to interact with most nicotinic receptors. These results suggest that the nicotine induced increase in cell number is mediated through an interaction at the nicotinic alpha-bungarotoxin receptor. This idea is further supported by experiments which show (1) that H69 cells possess high affinity alpha-bungarotoxin sites (Kd = 25 nM, Bmax = 10.4 fmol/10(6) cells) with the characteristics of a nicotinic alpha-bungarotoxin receptor and (2) that the potencies of nicotinic receptor ligands in the alpha-bungarotoxin binding assay were similar to those observed in the functional studies. Northern analysis showed that mRNA for alpha 7, a putative nicotinic alpha-bungarotoxin binding subunit, and for alpha 5 were present in H69 cells. The present data provide further evidence that nicotine increases cell number in small cell lung carcinoma and are the first to show that this effect is mediated through an interaction at the nicotinic alpha-bungarotoxin receptor population. These results suggest that the alpha-bungarotoxin site may be involved in modulating proliferative responses in neuroendocrine derived SCLC cells.

Alkaloids↗
PubMed1995

Alteration of brain nicotinic receptors induced by immobilization stress and nicotine in rats.

Immobilization stress (2 h.day-1, for 2 weeks) caused downregulation of the nicotinic receptors ([3H]cytisine binding sites) in the rat brain (cerebral cortex and midbrain). However, chronic nicotine treatment abrogated stress induced downregulation of the [3H]cytisine binding sites, suggesting that chronic nicotine treatment may block stress activated nicotinic receptor-mediated neurotransmission.

Alkaloids↗
PubMed1996

Characterization of nicotinic receptors in immortalized hippocampal neurons.

Nicotinic acetylcholine receptors, particularly nicotinic alpha-bungarotoxin (alpha-BGT) receptors, are present in relatively high concentrations in rat hippocampus. Because of the difficulties encountered in studying receptors using primary cells in culture, especially for biochemical work, we investigated the possibility of using an immortalized cell line from embryonic rat hippocampus (H19-7). RNase protection assays show that alpha 4, alpha 7 and beta 2 neuronal nicotinic receptor subunit mRNAs are present in differentiated but not undifferentiated H19-7 cells, while alpha 2, alpha 3, alpha 5 and beta 3 subunit mRNAs were not detectable under either condition. In line with these results, the present data demonstrate that the H19-7 cells express cell surface nicotinic alpha-BGT binding sites, which were maximal after seven days of differentiation in culture. The receptors were saturable, of high affinity (Kd = 1.30 nM and Bmax = 11.70 fmol/10(5) cells) and had a pharmacological profile similar to that observed for CNS alpha-BGT receptors. On the other hand, although alpha 4 and beta 2 neuronal nicotinic subunit mRNAs were present in differentiated H19-7 cells, no [3H]cytisine binding was observed. Because immortalized cell lines have the advantage that they provide a limitless supply of cells as compared to primary cell cultures, but yet are not malignant in origin, the present results may suggest that the H19-7 immortalized hippocampal cell line represent a useful CNS model system for examining alpha-BGT nicotinic receptors.

Alkaloids↗
PubMed1996

Cholinergic deafferentation enhances rat hippocampal pyramidal neuron responsiveness to locally applied nicotine.

We tested whether cholinergic denervation of the hippocampus of young rats would result in an enhancement of CA1 pyramidal cell responsiveness to nicotine. Electrolytic lesions of the medial septal area were performed in young male Fisher 344 rats. One month later the rats were anesthetized with pentobarbital and nicotine was locally applied to CA1 pyramidal neurons using pressure microejection. The dose of nicotine required to excite the pyramidal neurons was significantly lower for cells recorded from rats with septal lesions. However, no changes in hippocampal cytisine or alpha-bungarotoxin binding were found.

Alkaloids↗
PubMed1996

Chronic nicotine treatment delays the developmental increase in brain muscarinic receptors in rat neonate.

Developmental increase in the muscarinic receptors ([3H]quinuclidinyl benzylate binding sites) of rat neonate brain (cerebral cortex and cerebellum) was significantly inhibited by chronic nicotine treatment of the dams during pregnancy and lactation. However, development of the nicotinic receptors ([3H]cytisine binding sites) was not inhibited and rather was up-regulated in the cerebral cortex and brainstem by the nicotine treatment. Such inhibition and up-regulation were not seen in nicotine-withdrawn rats after birth. These results suggest that nicotine treatment during lactation may cause a remarkable delay in development of muscarinic neurotransmission in rat neonates.

Aging↗
PubMed1996

The novel inotropic agent CGP 48506 alters force primarily by Ca(2+)-independent mechanisms in porcine skinned trabeculae.

OBJECTIVES: The aim was to determine whether, and by what mechanism(s), a novel inotropic agent 5-methyl-6-phenyl-1,3,5,6-tetrahydro-3, 6-methano-1,5-benzodiazocine-2,4-dione (BA 41899) and its enantiomers directly alter the Ca2+ sensitivity of cardiac myofilaments. METHODS: Porcine ventricular trabeculae were permeabilised with Triton X-100. The relationship between force and pCa (-log[Ca2+]) was determined in the presence and absence of ATP. Troponin I was extracted, using vanadate, to produce unregulated maximally activated myofilaments. Force and actomyosin ATPase activity were measured simultaneously to determine tension cost (ATPase activity/tension). The effects of the (+) enantiomer (CGP 48506) on the twitch of intact muscle were demonstrated using rat papillary muscle. RESULTS: 100 microM BA 41899 had a pronounced Ca2+ sensitising effect on force production by porcine skinned cardiac fibres, increasing the pCa required for 50% maximal activation by 0.64 units, while suppressing maximum force by 18.3%. Resting tension was unaffected. These actions were primarily caused by CGP 48506 and were concentration dependent. At concentrations less than 100 microM, CGP 48506 also increased twitch amplitude in intact papillary muscles with no effect on resting tension, whereas 100 microM CGP 48506 increased resting force due to a slowing of relaxation. 100 microM CGP 48506 potentiated Ca(2+)-independent rigor tension in skinned trabeculae, indicating a Ca2+ sensitising mechanism unrelated to Ca2+ binding to troponin C. Tension cost was unaffected by 100 microM CGP 48506 over the entire range of activating Ca2+ concentrations. Suppression of maximum force by CGP 48506 was independent of both Ca2+ concentration and the regulatory troponin complex. CONCLUSIONS: Both the increase in Ca2+ sensitivity during submaximal activation and the depression of maximum force which are induced by CGP 48506 in skinned trabeculae occur at least partly through Ca(2+)-independent mechanisms.

Actin Cytoskeleton↗
PubMed1982

Beneficial action of a new opiate antagonist (Win 44,441-3) in hemorrhagic shock.

The new opiate antagonist Win 44,441-3 (-)-isomer was infused intravenously in cats at a rate of 2 mg . kg-1 . h-1 to determine its effect in hemorrhagic shock. Hemorrhaged cats treated with Win 44,441-3 maintained post reinfusion mean arterial blood pressure (MABP) at a higher value compared to cats receiving only the vehicle. Final MABP was 70 +/- 11 mm Hg for cats receiving vehicle compared to 103 +/- 7 mm Hg for cats receiving Win 44,441-3. These values represent 60 +/- 9% and 85 +/- 6% of initial MABP for the vehicle- and Win 44,441-3-treated cats respectively. Win 44,441-2 (+)-isomer, the inactive stereoisomer of Win 44,441-3, was also infused at 2 mg . kg-1 . h-1 in cats subjected to hemorrhagic shock. The final pressure in this group was 72 +/- 8 mm Hg which is 61 +/- 8% of the initial pressure for this group. Win 44,441-3 and Win 44,441-2 were both ineffective in moderating increases in circulating lysosomal hydrolase activity in shocked cats. Neither isomer stabilized lysosomal membranes or retarded proteolysis in vitro. Plasma myocardial depressant factor was significantly reduced by the opiate antagonist, Win 44,441-3 during shock. Our results show that the systemic infusion of an opiate antagonist improves the hemodynamic state of cats subjected to hemorrhagic shock while the (+)-isomer which lacks opiate antagonist activity produces no such improvement.

Animals↗
PubMed1982

Potency of three opiate antagonists to reverse the inhibitory activity of dynorphin, enkephalins and opioid-like alkaloids on the guinea pig ileum.

To test the hypothesis that dynorphin is a K-opiate agonist acting on the myenteric plexus, the potency of two benzomorphan antagonists (Win 44, 441 and Mr 2266) to block the inhibitory action of dynorphin, enkephalins and opioid alkaloids was determined on the longitudinal muscle preparation of the guinea pig ileum. The effectiveness of these antagonists was compared to that of naloxone. Antagonistic potency was established by calculating the apparent antagonist dissociation constant, Ke, as derived from Schild plots. Win 44, 441 and Mr 2266 were about 7-8 times more potent than naloxone against dynorphin, dynorphin-(1-13) or ethylketocyclazocine. Although the Ke obtained with Win 44, 441 or Mr 2266 against dynorphin or ethylketocyclazocine were significantly lower than those of naloxone, the values obtained for these antagonists did not differ significantly in the case of each of these agonists. With respect to the antagonism of the enkephalins or normorphine, Win 44, 441 was the most potent antagonist. Its Ke value for the enkephalins was 2.5-3 times lower than those for dynorphin or ethylketocyclazocine and in comparison to naloxone, Win 44, 441 was about 5 times more potent. Although Mr 2266 was a potent antagonist of dynorphin, ethylketocyclazocine, the enkephalins or normorphine, it showed no selectivity of action. The fact that the 3 opiate antagonists evidenced similar Ke values for dynorphin and ethylketocyclazocine, but different ones for the enkephalins or normorphine supports the conclusion that dynorphin activates preferentially K- but not mu-opiate receptors in the myenteric plexus.

Animals↗
PubMed1983

Opioid antagonists and drinking: evidence of kappa-receptor involvement.

Diprenorphine, naloxone, MR-2266-BS and WIN-44,441-3 were compared for their ability to antagonize morphine analgesia and to decrease deprivation-induced drinking in rats. Diprenorphine and naloxone were markedly more potent (32x) than MR-2266-BS and WIN-44,441-3 in antagonizing the analgesic effects of morphine. In contrast, diprenorphine, naloxone and MR-2266-BS decreased deprivation-induced drinking over a similar dose range. The doses required to reduce fluid consumption were higher than those necessary to antagonize morphine. WIN-44,441-3 was ineffective in decreasing drinking. The relatively similar potencies of diprenorphine, naloxone and MR-2266-BS for decreasing deprivation-induced drinking suggest that the effect on drinking involves antagonist activity at a kappa-opioid receptor.

Animals↗
PubMed1984

Kappa-opiates and urination: pharmacological evidence for an endogenous role of the kappa-opiate receptor in fluid and electrolyte balance.

In prehydrated rats, the administration of kappa-opiate agonists such as bremazocine, ethylketocyclazocine or compound Upjohn-50,488 produced a dose-dependent increase in urine output and decreased the concentration of Na+ and K+ in the urine as compared to that of saline-treated rats. The diuretic effect of bremazocine lasted at least 3 h. The increase in urine output was independent of the hydration state of the rat since in non water-loaded animals, bremazocine produced proportionally as much diuresis and a decrease in the output of urine electrolytes of about the same magnitude as that observed in the prehydrated animals treated with the opioid. In contrast to the diuretic action of kappa-opiate agonists, the administration of antagonists with high affinity for the kappa-opiate receptor (Win 44,441 or Mr 2266) decreased dose dependently the output of urine and reduced very significantly the total output of Na+ and K+. Whereas 2 mg/kg naloxone did not block the bremazocine-induced urinary effects, 1 mg/kg Win 44,441 or Mr 2266 antagonized competitively the renal activity of bremazocine. The results are interpreted to suggest that the kappa-opiate receptor may be involved in the regulation of fluid and electrolyte balance.

Animals↗
PubMed1990

Kappa opioid receptor-mediated depression of activity evoked in convergent dorsal horn cells by thermal and non-thermal noxious stimulation.

The response of convergent dorsal horn cells to tonic and phasic noxious heating and to noxious pinching was studied before and after topical application of a solution (30 nmol) of the kappa agonist U-50,488H to the dorsal surface of the spinal cord. U-50,488H depressed the discharge of convergent units evoked by thermal and mechanical nociceptive stimuli. The opiate antagonist WIN 44,441-3 reversed the effect of U-50,488H. It is concluded that kappa opioids are effective in preventing the depolarization of convergent dorsal horn neurons evoked by either thermal or non-thermal noxious stimuli.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1992

Ganglionic nicotinic receptor agonists exhibit anti-muscarinic effects in guinea-pig olfactory cortical brain slices.

The action of some nicotinic acetylcholine receptor agonists was re-examined on the surface field potentials (N-waves) evoked by electrical stimulation of the lateral olfactory tract in guinea-pig olfactory cortical brain slices. Bath superfusion of nicotine or the nicotinic stimulants dimethylphenylpiperazinium (DMPP), lobeline, cytisine, tetramethylammonium or suberyldicholine (up to 100 microM) had little or no effect on the extracellular N-wave amplitude, or the membrane potential, input resistance or excitability of olfactory neurones recorded intracellularly. In contrast, the muscarinic agonists, carbachol or oxotremorine-M consistently depressed the field in a reversible dose-dependent manner. Interestingly, in the presence of the ganglionic stimulants DMPP (n = 6 slices) or lobeline (n = 5 slices) (10-50 microM), the effects of carbachol or oxotremorine-M were antagonized in a weak competitive-type manner (pA2 values = 5.58 and 5.63 respectively, estimated from Schild plots, constrained to unity slope). This anti-muscarinic action was unaffected by d-tubocurarine or hexamethonium. Nicotine, cytisine, tetramethylammonium and suberyldicholine showed much weaker and inconsistent carbachol-blocking effects. Combination of DMPP with atropine produced dose ratio shifts close to those predicted for a common-site interaction of two competitive antagonists. In conclusion, consistent pre- or postsynaptic nicotinic agonist actions could not be detected in olfactory cortex slices; however, some ganglionic nicotinic agonists were shown to exhibit significant anti-muscarinic effects on this preparation. We suggest this action might be due to a direct atropine-like mechanism.

Alkaloids↗
PubMed1993

Epibatidine is a nicotinic analgesic.

Epibatidine, an alkaloid isolated from skin of the poison frog, Epipedobates tricolor, has been shown to be a very potent analgesic with a non-opioid mechanism of action. We found that epibatidine was about 120 times more potent and has longer duration than nicotine in analgesia, which could be antagonized by pretreatment with mecamylamine. Furthermore, epibatidine competed with high affinity (IC50 = 70 pM, Ki = 43 pM) for [3H]cytisine binding in rat brain preparations. These results indicated that the analgesic activity of epibatidine is attributed to its unique property as the most potent nicotinic acetylcholine receptor agonist.

Alkaloids↗
PubMed1993

Nicotinic receptor agonists exhibit anxiolytic-like effects on the elevated plus-maze test.

The effects of nicotinic receptor agonists on the elevated plus-maze test of anxiety were investigated in CD1 mice after intraperitoneal injections. Nicotine and lobeline, but not cytisine, exhibited a significant increase in the time spent by the mice in the open arms, a measure of anxiolytic activity. Nicotine also increased the total number of arm entries, a measure of general activity, but this effect was secondary to its anxiolytic-like properties. Nicotinic receptor antagonists on their own did not modify the behavior of mice in the maze. The effect of nicotine was mediated by central nicotinic receptors as it was blocked by the centrally-acting nicotinic antagonists mecamylamine and chlorisondamine, but not by hexamethonium (a peripherally acting blocker). Cotinine, the major metabolite of nicotine, was evaluated at different times after systemic injections and had no effect in the plus-maze. The anxiolytic-like profile induced by nicotinic receptor stimulation was not associated with potentiation of alcohol effects, a liability associated with the benzodiazepine therapy. This study demonstrates the anxiolytic-like properties of nicotine and lobeline in mice, and suggests that central nicotinic receptors are involved in the expression of emotional behavior.

Alkaloids↗
PubMed1994

Nicotinic receptor binding of [3H]cytisine, [3H]nicotine and [3H]methylcarbamylcholine in rat brain.

Three radiolabeled nicotinic receptor agonists were examined for their binding characteristics and for inhibition by cholinergic compounds in order to distinguish possible differential affinities for subtypes of neuronal nicotinic acetylcholine receptors. KD and Bmax values for [3H]cytisine, [3H]methylcarbamylcholine and [3H]nicotine were determined from Scatchard analysis using an enriched whole-brain membrane fraction from male Sprague-Dawley rats. Respective KD values were 0.15, 1.07 and 0.89 nM while Bmax values were 99, 64 and 115 fmol/mg protein respectively. All three ligands fit a one-site model of receptor-ligand interaction. Concentration-inhibition curves were used to determine Ki values for 16 cholinergic compounds. The rank order of potencies for displacement of the three ligands was: (-)-cytisine > (-)-nicotine > (-)-lobeline = methylcarbamylcholine > 1,1-dimethyl-4-phenylpiperazinium, (+)-nicotine, dihydro-beta-erythroidine, (+/-)-nornicotine > carbachol > arecoline >> oxotremorine, tetrahydroaminoacridine, AF102B >> (-)-cotinine > RS86 = heptylphysostigmine. Correlations of the affinities of these compounds determined with the three ligands were very near to unity. In contrast, there was a negative correlation of affinities for [3H]cytisine compared to affinities for the muscarinic receptor agonist, [3H]oxotremorine-M, and the muscarinic receptor antagonist, [3H]quinuclidinyl benzoate. Using membranes from whole rat brain yields data suggesting that all three nicotinic ligands bind to the same nicotinic acetylcholine receptor subtype, and are unable to distinguish subtypes of neuronal nicotinic acetylcholine receptor at the level examined.

Alkaloids↗