Biomedical subjects

M E Kelly

Publications and source records attributed to M E Kelly.

At least 91 records · Page 5Linked to original sources

PubMed1990

Ondansetron inhibits a behavioural consequence of withdrawing from drugs of abuse.

The ability of the selective 5-HT3 receptor antagonist ondansetron to influence the behavioural consequences of withdrawal from chronic treatment with ethanol, nicotine or cocaine was investigated in the light/dark exploration test in the mouse and social interaction test in the rat. In both tests acute and chronic (7 days) treatments with ondansetron (0.01-1.0 microgram.kg-1 IP) disinhibited suppressed behaviour; withdrawal from chronic treatment (0.1 mg/kg IP b.i.d.) did not exacerbate the behavioural suppression. Chronic treatment for 14 days with ethanol (8% w/v in the drinking water), nicotine (0.1 mg/kg b.i.d.) or cocaine (1.0 mg/kg b.i.d.) released suppressed behaviour in the mouse and rat tests. Behavioural suppression was increased following withdrawal from ethanol, nicotine and cocaine. The administration of ondansetron (0.01 mg/kg IP b.i.d.) during the period of ethanol, nicotine and cocaine withdrawal prevented the exacerbation in suppressed behaviour. It is concluded that ondansetron potently reduces behavioural suppression during acute and chronic treatments in the rodent models, does not cause a rebound exacerbation of behavioural suppression following withdrawal, and is a highly effective inhibitor of the increased behavioural suppression following withdrawal from the drugs of abuse: ethanol, nicotine and cocaine.

Animals↗

PubMed1990

The differential activities of R (+)- and S(-)-zacopride as 5-HT3 receptor antagonists.

R(+)- and S(-)-zacopride were assessed as potential 5-HT3 receptor antagonists in behavioural and biochemical tests. The S(-)isomer was more potent than the R(+)isomer to antagonise the hyperactivity induced by the injection of amphetamine or the infusion of dopamine into the nucleus accumbens in the rat. In contrast, the R(+)isomer was more potent to reduce the aversive behaviour of mice to a brightly illuminated environment and in a marmoset human threat test, to facilitate social interaction in rats, to increase performance in a mouse habituation test and prevent a scopolamine-induced impairment, and to antagonise the inhibitory effect of 2-methyl-5-hydroxytryptamine to reduce [3H]acetylcholine release in slices of the rat entorhinal cortex. In binding assays, [3H]S(-)-zacopride and [3H]R(+)-zacopride labelled homogenous populations of high-affinity binding sites in the rat entorhinal cortex, R(+)-zacopride compete for a further 10 to 20% of the binding of [3H]R(+)/S(-)-zacopride or [3H]R(+)-zacopride in excess of that competed for by (S)(-)-zacopride. It is concluded that both isomers of zacopride have potent but different pharmacological activities, with the possibility of different recognition sites to mediate their effects.

Animals↗

PubMed1990

Ketotifen and its analogues reduce aversive responding in the rodent.

The abilities of ketotifen and other 4-piperidylidene derivatives (HF200-184, HE36-953, SDZ209-321 and SDZ206-703) to inhibit aversive responding were compared in the mouse light/dark test box and in the rat social interaction test. Ketotifen and HF200-184 reduced aversive responding of the mouse to the brightly illuminated area of the test box and facilitated rat social interaction; HF200-184 was approximately 100 times more potent than ketotifen. The chronic administration and withdrawal from treatment with diazepam, ethanol, nicotine and cocaine in the mouse was associated with increased behavioural suppression which was prevented by the administration of ketotifen and HF200-184 during the period of withdrawal. HE36-953 also prevented the behavioural consequences of withdrawal from diazepam and cocaine. The relative potencies of ketotifen and its analogues to inhibit aversive responding did not correlate with their affinities for the 5-HT3 recognition site. It is concluded that compounds within the 4-piperidylidene series can reduce behavioural suppression in rodent models of anxiety and attenuate the behavioural consequences of withdrawing from treatment with drugs of abuse.

Animals↗

PubMed1990

Neurochemical consequences following injection of the substance P analogue, DiMe-C7, into the rat ventral tegmental area.

The effect on forebrain catecholamine- and indoleamine-related neurochemical levels was investigated following stimulation of the rat ventral tegmental area with the substance P analogue, DiMe-C7. DiMe-C7 (6.0 micrograms) induced a marked hyperactivity in rats with maximal response between 15 and 30 min following the injection. Fifteen min following the DiMe-C7 injection levels of dopamine and/or its metabolites (3,4-dihydroxyphenylacetic acid, homovanillic acid) were significantly increased in the nucleus accumbens, amygdala, entorhinal cortex and striatum relative to vehicle-injected animals. Although the increase in dopamine metabolism in the nucleus accumbens is consistent with the behavioural hyperactivity, it is concluded that other forebrain nuclei may also be involved in the mediation of the hyperactivity response.

Animals↗

PubMed1990

Anxiolytic-like action of DuP753, a non-peptide angiotensin II receptor antagonist.

The potential of DuP753, an angiotensin II receptor antagonist, to inhibit the suppressed behaviour of mice in a light/dark aversion test was investigated. The aversive response to the light compartment of the apparatus was reduced (increase in latency to move from the light to the dark compartment and decreases in rears, line crossings and percentage of time spent in the dark compartment) following treatment with DuP753 (0.1-1000 micrograms kg-1 p.o., 45 min before the test). These results further implicate the modulation of mental function by angiotensin II.

Angiotensin II↗

PubMed1989

Regeneration of frog sympathetic neurons is accompanied by sprouting and retraction of intraganglionic neurites.

Regeneration of frog sympathetic neurons (B-cells) was found to be accompanied by sprouting of neurites within the ganglion. Neurons whose axons had been crushed and allowed to regenerate exhibited sprouts that arose mainly from the axon hillock and initial segment of the axon. Sprouting was apparent by 5-7 days and reached maximal values by 14-21 days, but had decreased to control levels by 42-49 days after injury. In contrast, neurons whose axons were prevented from regenerating (by cut and proximal ligation of nerves) exhibited sprouts which did not retract by 42-49 days. These results suggest that successful regeneration to targets may dictate the recovery of normal B-cell morphology in bullfrog sympathetic ganglia.

Animals↗

PubMed1989

Electrophysiological function of the delayed rectifier (IK) in bullfrog sympathetic ganglion neurones.

Neurones of the bullfrog sympathetic ganglion exhibit at least 5 distinct K+ currents. Two calcium-dependent K+ currents IC and IAHP, the delayed rectifier IK, the muscarinic-sensitive IM and the transient outward current IA. Each current plays a unique role in controlling the shapes and firing patterns of action potentials observed in these neurones. We have found that 3,4-diaminopyridine (DAP) (greater than 0.1 mM) will selectively block IK and IA. Concentrations as high as 2 mM have no effect on IC, IAHP or IM. Since IA is mostly inactivated at resting potentials in these cells, DAP can be used to explore the electrophysiological function of IK. Under normal conditions DAP has no effect on action potential duration or no patterns of repetitive activity. This indicates that IK is normally not involved in modulating these parameters. When IC and IAHP are blocked by removing extracellular calcium, however, inhibition of IK prolongs action potential duration, reduces a fast afterhypolarization and enhances spike frequency adaptation. When IM and IAHP are reduced by barium (1 mM), inhibition of IK by DAP has smaller effects on action potential duration and afterhyperpolarization amplitude, but still enhances spike frequency adaptation. We conclude that electrophysiological effects of blocking IK are critically dependent on the levels of other K+ currents found in these cells.

4-Aminopyridine↗

PubMed1989

Exploration of mice in a black and white test box: validation as a model of anxiety.

The validity of a black and white test box to measure changes in mouse exploratory behaviour relevant to assessment of anxiety was investigated by variation of the illumination within the test box, the use of different strains of mice, holding conditions and drug treatments. The suppression of exploratory activity in the white section caused by bright illumination was antagonised by anxiolytic agents from the benzodiazepine series, buspirone, 5-HT3 receptor antagonists, alcohol, nicotine, morphine and SCH23390. The anxiogenic agent FG7142 exacerbated the behavioural suppression. Black C57/BL/6, brown DBA2 and albino BKW mice were sensitive to the effects of drug treatments, whereas albino Tuck mice were less responsive. It is concluded that the characteristic change in mouse exploratory behaviour caused by anxiolytic agents is to preferentially increase exploratory behaviour in the white aversive section of the black and white test box. It is most consistently shown by (a) an increased time spent in the white section with proportional increases in (b) rearings and (c) ambulation and (d) a delay in the initial transition from the white to the black section.

Animals↗

PubMed1989

The effects of ondansetron (GR38032F) in rats and mice treated subchronically with diazepam.

Using rat and mouse models of aversive behaviour, we have further investigated the properties of the 5-HT3 receptor antagonist ondansetron (GR38032F) that are relevant to its proposed use as an anxiolytic agent. Tolerance to the disinhibitory properties of diazepam was readily demonstrated in the social interaction test in the rat, but did not occur after subchronic treatment with ondansetron. In both the light/dark exploration test in mice and the social interaction test in rats, withdrawal from subchronic treatment with diazepam increased behavioural suppression, whereas this was not observed with ondansetron. The behavioural suppression and weight loss induced by either the withdrawal of diazepam or the administration of the benzodiazepine receptor antagonist, flumazenil, in animals treated subchronically with diazepam, was prevented or antagonised by diazepam or ondansetron. Buspirone was ineffective. It is concluded that, in rats and mice, tolerance to the disinhibitory effects of ondansetron does not occur, that withdrawal from subchronic treatment with ondansetron is not associated with any behavioural disturbances and that ondansetron is highly effective in preventing the behavioural suppression and weight loss following withdrawal from subchronic diazepam treatment. These data suggest that ondansetron may have major therapeutic advantages over currently available anxiolytic agents, particularly in patients who have previously received prolonged benzodiazepine therapy.

Animals↗

PubMed1989

The effects of ACE inhibitors captopril and SQ29,852 in rodent tests of cognition.

The ACE inhibitors captopril and SQ29,852 enhanced a habituation response to bright illumination in young adult and aged mice measured in a two-compartment light/dark test box. The treatments also antagonised a scopolamine-induced impairment and SQ29,852 was approximately 100 times more potent than captopril. In rats trained on a reinforced alternation paradigm in a T-maze, aged rats, as compared to young adults, showed a reduction in choice performance which was antagonised by SQ29,852. The impairment in choice performance in the T-maze induced by scopolamine in young adult rats was antagonised by SQ29,852 whilst captopril only delayed the onset of the scopolamine-induced impairment. SQ29,852 also antagonised scopolamine-impaired escape latency in a spatial learning/memory paradigm in a water-maze test. The effects of SQ29,852 in the rat were achieved within a somewhat restricted dose range. The ability of captopril and SQ29,852 to increase performance in the behavioural tests is discussed in terms of an antagonism of angiotensin converting enzyme to remove an inhibitory role of angiotensin II on central cholinergic function.

Age Factors↗

PubMed1989

The actions of nicotine and cocaine in a mouse model of anxiety.

The acute administration of nicotine (0.01-1.0 mg/kg IP) to the mouse increased the time spent and rearings and line crossings in the aversive brightly illuminated white area of a two compartment white/black test box, with a corresponding decrease in the black. This profile of change was maintained during twice daily administration (0.1 mg/kg IP) for 14 days. Eight to 96 hr following withdrawal of nicotine (14-day treatment), the behavioural profile was reversed to a preference for the black area: by 240 hr values had returned to control levels. In contrast to the effects of nicotine, an acute injection of cocaine (0.1-10 mg/kg IP) exacerbated the aversive response to the white area. However, similarly to nicotine, the administration of cocaine (1.0 mg/kg IP) twice daily for 14 days reduced the aversion to the white area and exacerbated the response following cocaine withdrawal. The effects of nicotine and cocaine to reduce and enhance responsiveness to the aversive properties of the white area are discussed in terms of an anxiolytic and anxiogenic response and the possibility of a serotonergic involvement.

Animals↗

PubMed1989

Amphibian sympathetic ganglia as a model system for investigating regeneration in the vertebrate peripheral nervous system.

1. The paravertebral sympathetic ganglion of the bullfrog serves as an excellent experimental system in which to study the response of vertebrate neurones to axotomy and the mechanisms associated with regeneration. 2. Various types of lesions to the axons (axotomy) of these neurones promote distinct and reproducible changes in the electrophysiological properties of the cell bodies which are not a consequence of changes in cell body morphology. 3. The axotomy-induced increase in spike width and decrease in the amplitude of the action potential after-hyperpolarization may allow an increase in Ca2+ influx and thereby promote regrowth. 4. The axotomy-induced decrease in after-hyperpolarization duration may reflect the disconnection of the neurone with its target and the loss of available nerve growth factor (NGF) from the target. 5. Experiments with NGF antibodies provide evidence that an NGF-like substances serves to maintain the normal electrophysiological characteristics of amphibian sympathetic neurones.

Amphibians↗

PubMed1989

In vitro photosensitization of tumour cell enzymes by photofrin II administered in vivo.

The ability of injected Photofrin II, a preparation enriched in hydrophobic dihaematoporphyrin ethers and esters, to photosensitize selected mitochondrial and cytosolic enzymes during illumination in vitro was examined. Preparations of R3230AC mammary tumours, obtained at designated times after a single dose of Photofrin II, displayed a time-dependent photosensitivity. Maximum inhibition of mitochondrial enzymes occurred at 24 hours post-treatment, whereas no inhibition of the cytosolic enzyme, pyruvate kinase, was observed over the 168 hour time course. At the selected 24 hour time point, mitochondrial enzyme photosensitisation was found to be drug dose (5.25 mg kg-1 Photofrin II) and light dose dependent, the rank order of inhibition being cytochrome c oxidase greater than F0F1 ATPase greater than succinate dehydrogenase greater than NADH dehydrogenase. We conclude that porphyrin species contained in Photofrin II accumulate in mitochondria of tumour cells in vivo and produce maximum photosensitisation at 24-72 hours after administration to tumour-bearing animals. The time course observed here with Photofrin II is similar to that seen previously with the more heterogenous haematoporphyrin derivative preparation in this in vivo-in vitro model.

Adenosine Triphosphatases↗

PubMed1989

Neuroanatomical sites of action of 5-HT3 receptor agonist and antagonists for alteration of aversive behaviour in the mouse.

1. The cerebral topography of the action of diazepam and the action of the 5-hydroxytryptamine 5-HT3 receptor antagonists GR38032F and ICS 205-930 in attenuating an aversive response was studied in the mouse. 2. Mice which had been cannulated to allow drug injection into the dorsal and median raphe nuclei, the amygdala, nucleus accumbens or caudate-putamen were placed in a two compartment black (dimly illuminated) and white (brightly illuminated) test box. Measurements were made of the time spent, rearing and line crossings in the two sections and the latency of initial movement from the white to the black area. 3. The injection of diazepam (0.1-10 ng), GR38032F (0.01-1.0 ng) and ICS 205-930 (1.0-10 ng) into the dorsal raphe nucleus and amygdala, and the injection of diazepam (0.1-10 ng) into the median raphe nucleus, reduced an aversive response to the brightly illuminated white area, delaying the initial movement into the black section and increasing the time spent, rearings and line crossings in the white area. Concomitantly such activities were decreased in the black section. 4. The injection of the 5-HT3 agonist 2-methyl-5-hydroxytryptamine (0.1-10 ng) into the dorsal raphe nucleus and amygdala caused the opposite response, decreasing the time taken to move into the black section and increasing the time spent, rearings and line crossings in the black section, decreasing such activities in the white area. 5. The 5-HT3 agonist and antagonists showed little or no effect following injection into the median raphe nucleus and there were no changes in exploratory behaviour following their injection, or injection of diazepam, into the nucleus accumbens or caudate-putamen. 6. It is concluded that in the mouse the cerebral topography of action of GR38032F and ICS 205-930 in attenuating an aversive response follows that of diazepam in the dorsal raphe nucleus and amygdala but that diazepam may have additional effects mediated via the median raphe nucleus.

Animals↗

PubMed1988

The histological effects of intracerebral injection or infusion of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) and MPP+ (1-methyl-4-phenylpyridinium) in rat and mouse.

Bilateral infusion of MPTP into the substantia nigra, ventral tegmental area or putamen of the rat brain provoked accumulation of leucocytes, but the periphery of nigral lesions showed no significant nerve cell loss. Tyrosine hydroxylase labelling of dopaminergic perikarya showed a normal staining pattern. In contrast, MPP+ was more destructive. After one day there was local degeneration of neuronal and glial elements. After one month there was tissue necrosis and central cavitation, but, like MPTP, there was no evidence of selective nigral cell loss. Striatal injection of MPP+ also failed to produce retrograde nigral damage. It is concluded that the toxicity of MPP+ applied directly to the dopamine system is a consequence of a severe non-selective necrotic lesion.

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

PubMed1988

Regeneration restores some of the altered electrical properties of axotomized bullfrog B-cells.

In bullfrog B-type sympathetic neurones axon injury produces substantial changes in somal membrane properties. These include a shortening of action potential afterhyperpolarization (AHP) and an increase in action potential (AP) duration. In the present experiments we compared two injury situations: nerve crush, which was followed by regeneration, and nerve cut, after which regeneration to the original target was prevented, to investigate whether these electrophysiological changes were related to axon regeneration. Both crush and cut injuries produced a similar maximum decrease in AHP duration (to 33 and 30%) by 14 days after axotomy. After nerve crush, AHP duration recovered to within control values by 42 days, while after cut it remained depressed. AHP amplitude decreased to the same extent after nerve crush or cut (to 62 and 58%), but the rate of decrease was slower following crush when compared with cut, and following both types of injury it still remained depressed at 42 and 49 days. Changes in AP duration also took longer to occur following nerve crush, reaching maximal values at 35-42 days, at which time AHP duration had returned to within the normal range. The early reduction in AHP duration and its rapid recovery in regenerating neurones suggests that the current underlying this membrane property is regulated by events associated with axon outgrowth and peripheral reconnection. In contrast, changes in AHP amplitude and AP repolarization appeared to be independent of the occurrence of axon regeneration and remained abnormal at 49 days despite the recovery of AHP duration. These results imply that the electrophysiological changes seen in B-cells following injury are differentially regulated during subsequent regeneration.

Animals↗

PubMed1988

Use of the sucrose-gap technique for quantitative pharmacological studies on isolated adult spinal cord of small mammals.

We describe here the development of an isolated hemisected adult spinal cord preparation suitable for use with the sucrose-gap technique for pharmacological studies of spinal circuitry in small mammals. Optimum conditions for viable activity and high-quality recordings are described together with examples of the use of this system to study the effect of the putative transmitter GABA and a known antagonist, bicuculline, on primary afferent terminal excitability and dorsal root potentials (DRP). Application of GABA to the spinal cord resulted in a depolarization of primary afferent terminals (PAD), which could be recorded in sucrose-gap as a DRP. This depolarizing potential was depressed but not eliminated by low Cl- ringer and was competitively antagonized by the application of varying concentrations of bicuculline. The results demonstrate both the viability and potential of this technique for pharmacological studies of adult mammalian spinal cord.

Animals↗

PubMed1988

Are emotion and motivation localized in the limbic system and nucleus accumbens?

Groups of control rats without surgery or groups of rats prepared with surgical lesions of the septal nuclei, amygdala, cingulate cortex, accumbens nucleus, section of the fornix, or sham surgical operations, were tested in a simple autonomic conditioning situation (conditioned defecation). Control rats and rats with lesions of the accumbens nucleus were also tested in a straight alley maze under varying conditions of water deprivation. In general, the lesions had little effect except that amygdaloid damage impaired acquisition of conditioned defecation. The theory that 'emotion' and 'motivation' can be localized in the 'limbic system' and nucleus accumbens is discussed critically.

Animals↗