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Biomedical subjects

J M Littleton

Publications and source records attributed to J M Littleton.

At least 19 recordsLinked to original sources
PubMed1991

Chronic exposure to anxiolytic drugs, working by different mechanisms causes up-regulation of dihydropyridine binding sites on cultured bovine adrenal chromaffin cells.

Exposure of bovine adrenal chromaffin cells to ethanol [50 mM], alprazolam [10(-7) M] and buspirone [10(-7) M] inhibited basal and carbachol-induced release of catecholamines from these cells. The inhibition produced by alprazolam was prevented, and that produced by ethanol inhibited, by the presence of the benzodiazepine receptor antagonist, flumazenil [10(-8) M]. The inhibition produced by buspirone was unaffected by flumazenil, but was mimicked by the selective 5-HT1A receptor agonist, 8-OH DPAT and prevented by the 5-HT receptor antagonist spiperone [10(-6) M]. These results suggest that bovine adrenal chromaffin cells express GABAA receptors, containing a benzodiazepine recognition site and also 5-HT1A receptors. Ethanol and alprazolam appear to inhibit the excitability of bovine adrenal chromaffin cells by an action related to the former, while buspirone probably inhibits these cells through the latter. Maintaining bovine adrenal chromaffin cells for several days in culture medium, containing inhibitory concentrations of ethanol alprazolam or buspirone, produced a marked increase in binding sites for a [3H]dihydropyridine [DHP] calcium channel antagonist, on cell membranes. The increase in binding sites produced by alprazolam was greater than that produced by the other two agents and was almost completely prevented by the concomitant presence of flumazenil. The effects of ethanol and buspirone on the binding of DHP were not prevented by flumazenil. The results suggest that drugs which decrease excitability of bovine adrenal chromaffin cells by different mechanisms, may evoke a similar adaptive response involving an increase in DHP-sensitive calcium channels.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1991

Characteristics of catecholamine release from adrenal chromaffin cells cultured in medium containing ethanol--I. Spontaneous and K(+)-induced release.

Bovine adrenal chromaffin cells were dissociated and grown in primary culture for 9 days. Three days after plating, half the cultures were grown in a medium containing 200 mM ethanol and the other half in a control medium, for a further 6 days. The catecholamine content of the ethanol-treated cells was increased after 6 days of ethanol treatment, compared to control cells and there was a slight reduction in protein and DNA content. An enhanced spontaneous release of catecholamines was seen, which was Ca(2+)-dependent and was inhibited by cadmium but not by the organic dihydropyridine Ca2+ antagonist nitrendipine. The fraction of catecholamines released by K+ was also enhanced in ethanol-treated preparations, particularly at high K+ or Ca2+ concentrations. Release induced by K+ was sensitive to inhibition by both cadmium and organic dihydropyridine Ca2+ antagonists. The results show many similarities with changes observed in catecholaminergic transmission in rat brain during the development of ethanol physical dependence.

Adrenal Glands↗
PubMed1991

Characteristics of catecholamine release from adrenal chromaffin cells cultured in medium containing ethanol--II. Carbachol and veratrine-induced release.

Dissociated bovine adrenal chromaffin cells were grown in culture either in control medium or in medium containing ethanol (200 mM) and the release of catecholamines induced by veratrine and carbachol was then studied. Cells grown in ethanol showed greater spontaneous release of catecholamines, but both carbachol and veratrine evoked release of a smaller maximum fraction of stored catecholamines than that from control cells. Spontaneous catecholamine release as well as that induced by veratrine were sensitive to inhibition by tetrodotoxin. Catecholamine release induced by veratrine could be prevented almost completely by the Ca2+ channel blocker cadmium, but not to any great extent by the organic dihydropyridine Ca2+ antagonist nitrendipine. Carbachol-induced catecholamine release was similarly resistant to inhibition by nitrendipine, but was inhibited by cadmium. The results suggest that cell cultures grown in ethanol-containing medium show many alterations in the characteristics of catecholamine release. Alterations in receptor- and voltage-operated ion channels in the membrane of ethanol-treated cells may underlie these changes.

Adrenal Glands↗
PubMed1990

Effects of dihydropyridine calcium channel antagonists in ethanol withdrawal; doses required, stereospecificity and actions of Bay K 8644.

The effects of dihydropyridine calcium channel antagonists, and the calcium channel activator, Bay K 8644, were examined on the convulsive behaviour induced by handling in mice following withdrawal from chronic ethanol inhalation. Nimodipine and nitrendipine and PN 200-110 significantly decreased the convulsive behaviour, after intraperitoneal doses of the same order of magnitude as have been found by others to be required for displacement of radiolabelled dihydropyridine in the CNS. The (+) isomer of PN 200-110 was effective, but the (-) isomer, which is ineffective in vitro, had no significant action. Bay K 8644 prevented the actions of nimodipine against the ethanol withdrawal syndrome. The behavioural ratings after nimodipine plus Bay K 8644 were significantly higher than after vehicle treatment. Bay K 8644 alone, when given to naive mice, caused convulsive behaviour resembling that seen in withdrawal from chronic ethanol treatment, but when given during ethanol withdrawal did not significantly increase the behavioural signs.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1990

Second messengers involved in genetic regulation of the number of calcium channels in bovine adrenal chromaffin cells in culture.

Bovine adrenal chromaffin cells in culture show an increased formation of [3H]inositol phosphates (after preloading with [3H]inositol) on depolarisation with increased extracellular K+. This increased breakdown of inositol lipid is further increased by the dihydropyridine Ca2+ channel activator BAY K 8644 at nM concentrations, implying that proteins which bind dihydropyridines are involved in this mechanism. Further, pretreatment of adrenal cells with pertussis toxin (100 ng ml-1) prevented the K(+)-induced breakdown of inositol lipids, arguing the involvement of a pertussis toxin-sensitive G protein in the effect. Chronic exposure of bovine adrenal chromaffin cells to a concentration of ethanol which inhibits K(+)-induced breakdown of inositol phospholipid, caused a 70-100% increase in the binding of [3H]DHP sites. In these experiments it was found that excess extracellular Ca2+ would considerably reduce this up-regulation, whereas growth of cells in pertussis toxin closely mimicked the up-regulation obtained by growth of cells in ethanol. These experiments suggest that inhibition of membrane Ca2+ flux, through a G protein-associated channel, is closely involved in the ethanol-induced regulation of [3H]dihydropyridine binding sites. The inositol lipid-protein kinase C second messenger system is also implicated in this regulation, by experiments in which inhibitors of protein kinase C (chronic treatment with phorbol myristyl acetate, or with sphingosine) up-regulated binding sites for [3H]dihydropyridine to a similar extent as that seen with growth in ethanol.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1990

Development of tolerance to ethanol in cultured adrenal chromaffin cells.

Dissociated bovine adrenal chromaffin cells in culture were utilized to study the mechanisms for development of cellular tolerance to ethanol. Three days after plating, cells were grown in either control medium or medium containing 200 mM ethanol for periods up to 6 days. Catecholamine release induced by carbachol, 80 mM K+, BAY K 8644, and veratrine was studied in ethanol-treated and untreated cultures. The presence of ethanol in vitro was inhibitory to all these stimuli in untreated cell cultures, carbachol-induced release being most sensitive (IC50 approximately 30 mM). After growth in ethanol for 6 days, carbachol-induced catecholamine release was completely resistant to the inhibitory effects of ethanol. The resistance to ethanol of carbachol-induced catecholamine release from cells grown in medium containing ethanol also extended to the inhibitory effects of butanol. The results show some similarities with changes observed in the central nervous system during the development of ethanol tolerance, and it is suggested that this model system may be useful in examining the mechanisms by which tolerance occurs.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1979

The rapid development of functional tolerance to ethanol by mice.

A method is described in which the development of tolerance to ethanol in individual mice can be measured during the inhalation of ethanol vapour. This method has been used with two behavioural end-points, loss of righting reflex and loss of rotarod performance. It demonstrates that, in the adult male, TO Swiss mouse, peak tolerance, in which approximately 2 X the original effective blood ethanol concentration is required to produce the behavioural end-point, can develop in 3--5 h. After this time the ability of the animals to perform normally in the presence of continued high concentrations of ethanol in blood begins to fall. The results are discussed in relation to current concepts of tolerance to central nervous system depressant drugs.

Air↗
PubMed1977

Environmental stress as a factor in the response of rat brain catecholamine metabolism to delta8-tetrahydrocannabinol.

In rats housed normally (aggregated, food and water ad lib) for fourteen days delta8-tetrahydrocannabinol (THC) produced mild sedation and minimal hypothermia. An increase in noradrenaline synthesis was observed, but brain dopamine metabolism was unchanged. In rats removed from this 'normal' environment to conditions of isolation and food deprivation for 24 h THC produced immobility, marked hyper-reactivity, and hypothermia. Brain noradrenaline metabolism was unchanged by THC under these conditions, but significant changes in striatal dopamine metabolism were observed. These changes are consistent with increased dopamine reuptake in striatum produced by this combination of THC and novel environment. It is suggested that some of the behavioural effects of cannabis administered under stressful conditions may be related to alterations in striatal dopamine metabolism.

Animals↗