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Biomedical subjects

M E Kelly

Publications and source records attributed to M E Kelly.

At least 109 records · Page 6Linked to original sources
PubMed1988

The potential anxiolytic activity of GR38032F, a 5-HT3-receptor antagonist.

1. The highly selective 5-HT3-receptor antagonist, GR38032F, has been tested in five animal models predictive for anxiolytic activity. 2. In the social interaction test in the rat and in a light/dark exploration test in the mouse, GR38032F dose-dependently released suppressed behaviour without modifying locomotor activity. 3. In the cynomolgus monkey and the marmoset, GR38032F reduced anxiety-related symptoms without causing sedation. In the marmoset, the effects were clearly dose-related. 4. GR38032F did not have any detectable activity in the water-lick conflict test in the rat. 5. We conclude that GR38032F is potentially a very potent anxiolytic agent without sedative, anticonvulsant or hypnotic activity.

Animals↗
PubMed1988

The anxiolytic and anxiogenic actions of ethanol in a mouse model.

The administration to mice of ethanol in the drinking water for 7 days modified exploratory activity (rearings/line crossings) in an anxiety testing box separated into white and black sections with an interconnecting door. During ethanol intake mice exhibited reduced anxiety responding, shown as increased rearings and line crossings in the white section, to which the mice are normally averse, with corresponding decreased behaviour in the black section. When naive mice were presented with a choice between normal drinking water and drinking water containing ethanol, they consumed sufficient of the latter to secure a full anxiolytic response, making up the total volume of fluid required by also drinking the former. A 48 h withdrawal from a 14 day treatment with ethanol caused a reversed profile of exploratory behaviour, directed preferentially at the black section of the test box, and indicative of an anxiogenic response. Diazepam, tiapride or clonidine given twice daily during withdrawal from ethanol could each secure a reduction in the withdrawal anxiogenesis. It is concluded that the simple model of anxiety described in the mouse may be useful for eludicating the mechanisms involved in the anxiolytic and anxiogenic potential of ethanol and may aid the search for novel agents having potential to suppress withdrawal anxiogenesis.

Animals↗
PubMed1988

Zacopride: anxiolytic profile in rodent and primate models of anxiety.

Zacopride, a substituted benzamide derivative, was compared with diazepam in three models of experimental or provoked anxiety. The drug's action (i) in reducing aversion to a brightly lit environment was assessed in mice using a two compartment black and white test box system, (ii) in disinhibiting a suppressed behaviour was measured in the rat social interaction test under high light/unfamiliar conditions and (iii) in antagonizing a defensive response in the marmoset was assessed using the threat of a human presence. Both zacopride and diazepam enhanced exploratory behaviour and social interaction in the mouse and rat models and antagonized the defensive response in the marmoset, zacopride being 100 times more potent than diazepam. It is concluded that the 5-HT3 receptor antagonist, zacopride, alters rodent and primate behaviour in a manner consistent with that of an anxiolytic agent.

Animals↗
PubMed1988

Actions of buspirone in a putative model of anxiety in the mouse.

In a two-compartment box divided into a dark area and a brightly illuminated white area, mice taken from a dark environment showed aversion to the light and exhibited preference for exploratory rearings and line crossings in the black area. The peripheral administration of buspirone, and its injection into the dorsal raphe nucleus, lead to an increased time spent in the white area associated with enhanced exploratory behaviour with a decreased incidence of rearings and line crossings in the black section. In contrast, the injection of 5-hydroxytryptamine and 2-methyl-5-hydroxytryptamine into the dorsal raphe nucleus increased exploratory behaviour in the black section with decreased activity in the white area: the effects of 2-methyl-5-hydroxytryptamine were antagonized by buspirone administered peripherally. Ritanserin, methysergide, metergoline and cyproheptadine failed, in non-sedative doses, to influence exploratory behaviour in the two-compartment system and ritanserin and methysergide also failed to antagonize the effects caused by 2-methyl-5-hydroxytryptamine. It is concluded that in the mouse model the ability of buspirone to reduce the aversive response to a brightly illuminated area may reflect an anxiolytic action, that the dorsal raphe nucleus may be an important locus of action, and that the effects of buspirone may reflect an interaction at 5-hydroxytryptamine receptors.

Animals↗
PubMed1988

The effects of axotomy on electrophysiological properties of B cells of bullfrog sympathetic ganglia conditioned by a previous lesion.

In bullfrog sympathetic B cells, axotomy decreases the amplitude and decay time of membrane afterhyperpolarization (AHP) and increases action potential (AP) duration. A second (test) axotomy, 7 days after an initial (conditioning) axotomy, did not amplify these changes. No recovery of AHP amplitude or AP duration occurred by 56 days post-axotomy, but AHP decay time recovered 21 days earlier than after test axotomy alone. Conditioning, previously shown to accelerate regeneration, speeds the return to normal of those membrane properties previously shown to recover after axotomy.

Animals↗
PubMed1988

Coronary artery bypass surgery in patients less than 40 years of age.

Coronary bypass patients less than 40 years of age were identified and compared with a control group previously studied at our hospital. In patients less than 40 years, the average age was 35 years. Men comprised 90.1 percent of group 1, and 83.4 percent of group 2. Operative mortality was 2.89 percent for group 1 and 2.1 percent for group 2. Patients less than 40 years were more likely to have positive family history (46.3 percent vs 21.94 percent), elevated cholesterol levels (25.62 vs 11.36 percent), and be smokers (59.09 vs 39.9 percent). Group 1 patients were less likely to have diabetes (4.54 vs 13.37 percent) or hypertension (18.18 vs 31.43 percent). The percentage of late deaths was much higher for younger patients. Postoperative angina and the need for reoperation was higher in group 1.

Adult↗
PubMed1987

The effects of some polyamines on putative behavioural indices of mesolimbic versus striatal dopaminergic function.

The presence of polyamines in the brain, together with the previous reports of a structural similarity with neuroleptics, has led to the hypothesis that polyamines may have a modulatory role in the control of cerebral dopamine function. In this study, the effects of two polyamines, spermine and spermidine, were therefore tested on indices of dopamine-mediated behaviour in rats and mice. Spermine and spermidine caused a dose-dependent inhibition of mouse spontaneous climbing behaviour and wheel running at doses between 5 and 40 mg/kg IP but failed to cause catalepsy in the rat or to antagonise the stereotyped behaviour induced by apomorphine. When polyamines were given by intracerebral injection a similar regional selectivity was seen. Both spermine and spermidine (5-20 micrograms) when given bilaterally into the nucleus accumbens inhibited the hyperactivity caused by amphetamine injected into the same nucleus. However, when injected into the rat corpus striatum, neither polyamine was able to initiate any asymmetry or circling either spontaneously or after apomorphine injection IP. These results indicated a selective action of polyamines on mesolimbic dopamine behaviour. Possible implications for the understanding of psychosis and future work are suggested.

Amphetamine↗
PubMed1987

The action of dazopride to enhance gastric emptying and block emesis.

The substituted benzamide derivatives, dazopride and metoclopramide, enhanced field stimulation-induced contractions of guinea-pig stomach strips and gastric emptying in the guinea-pig after peripheral, intracerebroventricular and intrahypothalamic injection. In the isolated vagal nerve preparation from the rabbit, both compounds were shown to be 5-hydroxytryptamine M-receptor antagonists. Dazopride and metoclopramide were equipotent in antagonising cisplatin-induced emesis in the ferret, whereas metoclopramide was approximately 200 times more potent than dazopride in antagonising the emesis caused by the dopamine agonist 2-di-n-propylamino-5,6-dihydroxytetralin in the marmoset. In behavioural tests which indicate dopamine receptor antagonism in the rat, metoclopramide induced catalepsy, antagonised amphetamine-induced stereotypy and the hyperactivity induced by the intrastriatal injection of dopamine, caused body asymmetry on unilateral injection into the striatum and also antagonised apomorphine-induced climbing and circling behaviour in the mouse. In contrast, dazopride had little or no action in these tests and failed to displace [3H]spiperone in radioligand binding assays. The use of dazopride provides evidence to dissociate a dopamine receptor blockade from an ability to facilitate gastric emptying and to antagonise cisplatin-emesis, and indicates that antagonism of 5-hydroxytryptamine M-receptors is the essential basis of action for dazopride and plays an important role in the actions of metoclopramide.

Animals↗
PubMed1987

Withdrawal syndrome following subchronic treatment with anxiolytic agents.

The acute administration of diazepam (0.1-2.5 mg/kg IP), sulpiride (0.5-20 mg/kg IP) and tiapride (0.5-40 mg/kg IP) to the mouse enhanced exploratory activity (rearings/line crossings) in the brightly illuminated white area of a two compartment white/black anxiety test box, with a corresponding decrease in the black, indicating an anxiolytic action. This profile of change was maintained during a twice daily administration for 7 days with diazepam (2.5 and 10 mg/kg), sulpiride (5 and 20 mg/kg) and tiapride (10 and 40 mg/kg). However, 8 and 48 hr following withdrawal of diazepam, the profile of exploratory behaviour was reversed to a preference for the black area: by 96 hr values for behaviour had returned to control levels. In contrast, an anxiolytic profile of action was maintained 8 and 48 hr following the withdrawal of sulpiride and tiapride, the values returning to control levels after 96 hr. It is concluded that a sub-chronic treatment with diazepam, sulpiride and tiapride induces an anxiolytic profile of action in the mouse model, that an anxiogenic profile follows the abrupt withdrawal of diazepam but that this is not recorded following the abrupt withdrawal of sulpiride and tiapride.

Animals↗
PubMed1987

The effects of axotomy on bullfrog sympathetic neurones.

1. The effects of axotomy on the electrical properties of B cells in paravertebral sympathetic ganglia were studied using standard intracellular recording techniques. The effects were apparent after 1 week and persisted throughout the 47 days of study. 2. Action potential duration (spike width) and amplitude (spike height) were significantly increased in axotomized neurones. 3. The duration of the after-hyperpolarization which followed the action potential showed considerable scatter in control neurones (mean +/- S.E. of mean, 159.0 +/- 5.8 ms for 100 cells). Following axotomy, the duration was significantly reduced (50.9 +/- 2.3 ms for 97 cells). The amplitude of the after-hyperpolarization was also significantly smaller in axotomized neurones. 4. Changes in the characteristics of the action potential and the after-hyperpolarization in axotomized neurones were not due to alteration in resting membrane potential or input resistance which were unchanged after axotomy. Rheobase current was significantly increased. 5. There was neither a significant depression of the rate of rise or the amplitude of orthodromically evoked nicotinic e.p.s.p.s nor any obvious ultrastructural alteration following axotomy. 6. Despite the decrease in the duration of the after-hyperpolarization, the rate of discharge in response to constant current injection was little changed in axotomized neurones. 7. Although axotomy produces significant changes in several measurable electrophysiological parameters in bullfrog sympathetic ganglion cells, the present results imply that mature neurones are able to maintain relatively normal electrical activity despite injury.

Action Potentials↗
PubMed1986

Axotomy affects calcium-sensitive potassium conductance in sympathetic neurones.

Following peripheral nerve section, the cell body and proximal axon undergo various physiological and morphological changes which may be associated with regrowth. We found that axotomy reduced the amplitude and duration of the afterhyperpolarization (AHP) of the action potential (AP) of bullfrog sympathetic neurones. In addition, the repolarization of the AP was slowed. The Ca2+-channel blocker, Cd2+ (200 microM) produced similar effects in normal cells by blocking the Ca2+-sensitive K+ conductances (gK, Ca) which contribute to the AHP and to AP repolarization. Although Ca2+-channel function was preserved after axotomy, Cd2+ did not affect axotomized neurones. This suggests that axotomy promotes a functional loss of gK, Ca which could reflect a regenerative response of the cell to injury.

Action Potentials↗
PubMed1986

The effect of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on striatal and limbic catecholamine neurones in white and black mice. Antagonism by monoamine oxidase inhibitors.

Albino mice and pigmented mice were treated for 6 days with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) at the maximum tolerated doses (2 days at 30 mg/kg i.p., 2 days at 40 mg/kg i.p. and 2 days at 50 mg/kg i.p. in white mice, 6 days at 30 mg/kg i.p. in pigmented mice) and the effects of simultaneous treatment with the monoamine oxidase inhibitors, deprenyl (1 mg/kg, i.p.), MDL 72145 (0.5 mg/kg, i.p.) and clorgyline (5 mg/kg, i.p.), determined behaviourally (daily for 6 days and for 4 days after withdrawal) and biochemically (92 hr after withdrawal of drug). In albino mice MPTP caused depletions of dopamine (90%), dihydroxyphenylacetic acid (DOPAC; 82%) and homovanillic acid (HVA; 65%) in the striatum and in dopamine (54%), DOPAC (51%) and HVA (53%) in the nigra. However, MPTP was not selective in its action since the levels of dopamine and its metabolites were also reduced in limbic tissue. Further, MPTP affected the function of noradrenaline, with reduced levels in tissues of the striatum (74%) and nigra (46%). Pigmented mice were as susceptible as albino mice to the actions of MPTP to reduce the levels of dopamine and metabolites in the striatum. However, the limbic areas and substantia nigra of the pigmented mouse were more resistant to the actions of MPTP. Treatment with deprenyl and MDL 72145 (but not clorgyline) could be shown to reduce the biochemical and behavioural consequences of the action of MPTP (although behavioural changes, development of severe motor incapacitation and prostrate appearance, appeared to be non-specific).(ABSTRACT TRUNCATED AT 250 WORDS)

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1986

MPP+ can disrupt the nigrostriatal dopamine system by acting in the terminal area.

Acute intracerebral injections of MPP+ in the mouse can cause behavioural and biochemical correlates of nigrostriatal dopamine dysfunction, but these are most marked and consistent when injections are directed at the dopamine nerve terminal area (CP) rather than the cell body area (SN). This adds further support to the hypotheses that a locus of neurotoxic action of MPTP/MPP+ may reside in the dopamine cell terminal regions.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1986

5-Hydroxytryptamine M-receptor antagonism in the hypothalamus facilitates gastric emptying in the guinea-pig.

The injection of 5-hydroxytryptamine (5-HT) and 2-methyl-5-HT into the perifornical area of the hypothalamus of the guinea-pig reduced the emptying of barium sulphate spheroids from the stomach. In contrast, the injection of the 5-HT M-receptor antagonist ICS 205-930 into the same area of the hypothalamus enhanced gastric emptying and attenuated the inhibitory effect of 5-HT. Similar injections of methysergide and ritanserin were without effect. It is concluded that an endogenous hypothalamic 5-HT system may inhibit gastric emptying through a 5-HT M-receptor mechanism which may afford a site of action for 5-HT agonist and antagonist drugs to modify gastric emptying.

Animals↗