1. The influence of some intracerebroventricularly administered sympathomimetic amines on leptazol-induced convulsions has been investigated.2. Noradnamine and high doses of dopamine proved to be anticonvulsant and also antagonized the facilitative effects of reserpine.3. Noradrenaline and octopamine also antagonized reserpine-induced facilitation but were without effect on leptazol alone; by contrast tyramine and small doses of dopamine lowered the threshold for leptazol convulsions.4. A possible interpretation of these results is presented.

Animals↗

PubMed1968

The quantiative measurement of motor inco-ordination in naive mice using an acelerating rotarod.

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Acceleration↗

PubMedDate not supplied

Pharmacological characterization of the apparent splice variants of the murine 5-HT3 R-A subunit expressed in Xenopus laevis oocytes.

The actions of 5-hydroxytryptamine3 (5-HT3) receptor agonists and antagonists have been determined on the recombinant murine 5-HT3 R-A and an apparent splice variant of this subunit, termed 5-HT3 R-AS. When expressed in Xenopus laevis oocytes, both forms of the subunit functioned as a homo-oligomeric complex and exhibited inward current responses to bath applied 5-HT. Analysis of the 5-HT concentration-response curve obtained with either homo-oligomer gave Hill coefficients greater than two, suggesting positive co-operativity within the receptor complex. The rank order of potency of a range of 5-HT3 receptor agonists [m-chlorophenylbiguanide > 5-HT > 2-methyl-5-HT (2-Me-5-HT) > or = phenylbiguanide] was identical for both subunits. Indeed, with the exception of 2-Me-5-HT, for the agonists tested there was little difference across the subunits in either their potency, or the maximal current response that they elicited relative to 5-HT. Although 2-Me-5-HT exhibited a similar potency for both subunits, the maximal response evoked by this agonist at the 5-HT3 R-AS subunit was much reduced when compared to the 5-HT3 R-A subunit. The 5-HT-induced current mediated by either form of the subunit was inhibited by the 5-HT3 receptor selective antagonists BRL 46470, granisetron and ondansetron and the non-selective antagonists (+)-tubocurarine, metoclopramide and cocaine in a reversible and concentration-dependent manner. These antagonists did not discriminate between the subunits and their potencies were similar to those reported previously for 5-HT3 receptors native to murine neuronal cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMedDate not supplied

Importance of h5-HT1B receptor selectivity for 5-HT terminal autoreceptor activity: an in vivo microdialysis study in the freely-moving guinea-pig.

The importance of h5-HT1B receptor selectivity for 5-HT terminal autoreceptor activity was investigated with the selective h5-HT1B receptor ligands SB 219085, SB 220272, SB 224289 and SB 216641. The studies employed measurement of compound affinity and efficacy in vitro and the measurement of extracellular 5-HT in the frontal cortex of the freely-moving guinea-pig using in vivo microdialysis. All compounds had high affinity and selectivity for the h5-HT1B receptor, with SB 224289 the most selective for h5-HT1B over h5-HT1D receptors. Compounds exhibited a range of efficacies at both receptors: SB 224289 and SB 219085 were inverse agonists, SB 220272 was an antagonist and SB 216641 was a partial agonist. SB 220272, SB 216641 and SB 224289 had no effect on extracellular 5-HT following systemic administration, however, SB 219085 produced a significant increase. The SB 219085-induced increase in extracellular 5-HT was attributed to the compounds non-specific releasing properties as it was also demonstrated to increase basal release of [3H]5-HT from pre-loaded guinea-pig cortical slices. The lack of effect of the above h5-HT1B receptor selective compounds and the decrease in extracellular 5-HT elicited by the non-selective compounds GR 127935, GR125743 and methiothepin suggest that antagonism of 5-HT1D receptors may mediate this decrease in 5-HT levels. It is plausible that blockade of 5-HT1D receptors increases 5-HT levels in the raphe, this activates 5-HTtA receptors which results in an overall decrease in terminal 5-HT release. Definitive proof now awaits elucidation of the action of a selective 5-HT1D receptor antagonist.

Animals↗

PubMedDate not supplied

Prosthesis for malignant oesophago-respiratory fistula.

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Bronchial Neoplasms↗

PubMedDate not supplied

Identification and distribution of 5-HT3 receptors in rat brain using radioligand binding.

Functional serotonin (5-hydroxytryptamine, 5-HT) receptors have been divided into three subtypes: 5-HT1-like, 5-HT2 and 5-HT3 (ref. 1). Brain binding sites have been identified for both the 5-HT1 and 5-HT2 subtypes. Receptors of the 5-HT3 type have been characterized on isolated peripheral tissue models such as the rat vagus nerve, guinea-pig ileum and isolated rabbit heart. Using these models, selective 5-HT3 receptor antagonists such as MDL 72222 (ref. 5), ICS 205-930 (ref. 6), GR38032F (ref. 7) and BRL 43694 (ref. 8) have been developed. Recently, GR38032F, MDL 72222 and ICS 205-930 have been shown to have behavioural effects in rodents and primates that undoubtedly reflect an action in the central nervous system (refs 9-11 and unpublished observations), suggesting the existence of 5-HT3 receptors in the brain. Here we report direct evidence for the existence of 5-HT3 receptors in rat brain tissue and their distribution, based on high affinity binding of the potent 5-HT3 receptor antagonist 3H-GR65630 to homogenates of rat entorhinal cortex. Selective 5-HT3 receptor antagonists and agonists inhibited binding of 3H-GR65630 with high affinities which correlated well with their actions on the rat isolated vagus nerve. Binding was differentially distributed throughout the brain with high concentrations in cortical and limbic areas.

Animals↗

PubMedDate not supplied

Postinfective diarrhoea and bile acid malabsorption.

Postinfective irritable bowel syndrome with diarrhoea and idiopathic bile acid malabsorption remains an enigma. We examined the records of 84 patients whose 75SeHCAT scans were indicative of bile acid malabsorption (< 15% one week retention). Identifiable causes of bile acid malabsorption were: previous ileal surgery (7), Crohn's disease (22), radiation enteritis (13), vagotomy, gastrectomy or cholecystectomy (10) and miscellaneous (3). Sixteen of 29 patients with apparently idiopathic bile acid malabsorption gave a clear history of acute gastroenteritis before the onset of chronic diarrhoea lasting from 0.25-18 years until their positive 75SeHCAT scan. Only four cases of campylobacter, and one each of shigella and salmonella were documented. Extensive investigation failed to detect other possible pathologies. In response to bile acid sequestrants, mean stool frequency fell from 7.2 per day to 2.1 per day (p < 0.001). We have observed that postinfective chronic diarrhoea is associated with chronic bile acid malabsorption, which can be successfully treated with bile acid sequestrants such as cholestyramine.

Adult↗