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Biomedical subjects

B Costall

Publications and source records attributed to B Costall.

At least 109 records · Page 6Linked to original sources
PubMed1989

Angiotensin II inhibits the release of [3H]acetylcholine from rat entorhinal cortex in vitro.

The effects of angiotensin I and II on basal potassium-induced release of [3H]acetylcholine were investigated in slices of rat entorhinal cortex. Potassium (10-25 mM) produced a concentration-dependent increase in the release of [3H]acetylcholine in the presence of extracellular calcium. Angiotensin II (10(-9)-10(-5) M) (but not angiotensin I) reduced the potassium-induced release of [3H]acetylcholine in a concentration-related manner to 60% of control levels, but did not effect basal tritium release. The effect of angiotensin II was antagonised by [1-sarcosine, 8-threonine] angiotensin II, an angiotensin II receptor antagonist, but not by agents acting on alpha- and beta-adrenoceptors, muscarinic, nicotinic, histamine or 5-hydroxytryptamine receptors nor by the angiotensin converting enzyme (ACE) inhibitor SQ 29852. The results indicate that angiotensin II acting via an angiotensin II receptor can inhibit the release of [3H]acetylcholine in slices of the rat entorhinal cortex. It is hypothesised that the ability of ACE inhibitors to facilitate cognitive processes may be related to a reduced availability of angiotensin II.

Acetylcholine↗
PubMed1989

5-HT3 receptors mediate inhibition of acetylcholine release in cortical tissue.

The release of cerebral acetylcholine from terminals in the cerebral cortex has been shown to be regulated by 5-hydroxytryptamine (5-HT) but it is not known which subtype of the 5-HT receptor is involved. 5-HT receptor agonists increase acetylcholine levels in vivo, indicating a reduced turnover, and reduce release of acetylcholine from striatal slices in vitro. Depleting 5-HT by inhibiting synthesis or by destroying the neurons containing 5-HT potentiates acetylcholine release, and increases acetylcholine turnover in the cerebral cortex and hippocampus. Selective antagonists for the 5-HT3 receptor subtypes which seem to have effects on mood and activity may exert their effect through the regulation of acetylcholine release in the cortex and limbic system. Radioligand binding studies show a high density of 5-HT3 receptors in the cholinergic-rich entorhinal cortex and we provide evidence that a reduction in cortical cholinergic function can be effected in vitro by 5-HT3 receptors.

Acetylcholine↗
PubMed1989

Desenkephalin-gamma-endorphin is an antagonist of the hyperactivity response induced by infusion of dopamine into the nucleus accumbens of rat and ventral striatum of marmoset.

The ability of desenkephalin-gamma-endorphin (DE gamma E; ORG5878) to antagonise a raised limbic dopamine function was investigated in the rat and common marmoset. Dopamine was infused for 13 days directly into the nucleus accumbens of the rat and ventral striatum of the marmoset and increased locomotor activity. Such increases in both the rat and marmoset were antagonised by the subcutaneous injection of DE gamma E, administered in a range 10-500 micrograms/kg (t.i.d.), during the 13 day period of infusion of dopamine. Treatment with dopamine alone or in combination with DE gamma E failed to influence the level of spontaneous locomotor activity after discontinuing treatment. In contrast, in experiments performed in the rat, the level of spontaneous locomotor activity was increased 2- to 3-fold after cessation of a regimen of infusion of dopamine and haloperidol. The increases in activity were antagonised by DE gamma E (50 and 100 micrograms/kg t.i.d., s.c., for 2 days). In additional experiments in the marmoset, using animals initially selected as "high activity" responders to challenge with (-)N-n-propylnorapomorphine, the infusion of dopamine caused a reversal in responsiveness to the stimulant effects of (-)N-n-propylnorapomorphine on locomotor activity some 2-4 weeks after discontinuing the infusion of dopamine. The administration of fluphenazine (0.01-2.5 mg/kg b.d.), during the infusion of dopamine, failed to prevent the subsequent change in responsiveness to (-)N-n-propylnorapomorphine, whereas a regimen of dopamine and DE gamma-E (25-100 micrograms/kg t.i.d.) prevented such changes.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
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

Identification and characterisation of 5-hydroxytryptamine 3 recognition sites in human brain tissue.

[3H]Zacopride displayed regional saturable specific binding to homogenates of human brain tissues, as defined by the inclusion of BRL43694 [endo-N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-1-methylindazole-3- carboxamide] in the incubation media. Scatchard analysis of the saturation data obtained from amygdaloid and hippocampal tissues identified the binding as being of high affinity and to a homogeneous population of binding sites (KD = 2.64 +/- 0.75 and 2.93 +/- 0.41 nmol/L and Bmax = 55 +/- 7 and 44 +/- 9 fmol/mg of protein in the amygdala and hippocampus, respectively). 5-Hydroxytryptamine 3 (5-HT3) receptor agonists and antagonists competed for the [3H]zacopride binding site, competing with up to 40% of total binding with a similar rank order of affinity in both tissues; agents acting on various other neurotransmitter receptors failed to inhibit binding. Kinetic data revealed a fast association that was fully reversible (k+1 = 6.61 X 10(5) and 7.65 X 10(5)/mol/L/s and k-1 = 3.68 X 10(-3) and 3.45 X 10(-3)/s in the amygdala and hippocampus, respectively). It is concluded that [3H]zacopride selectively labels with high affinity 5-HT3 recognition sites in human amygdala and hippocampus and, if these binding domains represent 5-HT3 receptors, may provide the opportunity for 5-HT3 receptor antagonists to modify 5-HT function in the human brain.

Adult↗
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

Reserpine, para-chlorophenylalanine and fenfluramine antagonise cisplatin-induced emesis in the ferret.

The involvement of 5-hydroxytryptamine (5-HT) with cisplatin-induced emesis in the ferret was investigated using reserpine, para-chlorophenylalanine and fenfluramine. Pretreatment with reserpine (5 mg/kg, 24 hr), fenfluramine (5 mg/kg, 4 days) or para-chlorophenylalanine (100 or 400 mg/kg, 4 days) antagonised cisplatin-induced emesis. All treatments reduced the levels of 5-HT in the area postrema and at other cerebral sites, but whilst this action was relatively selective for small doses of para-chlorophenylalanine [only modest effects on noradrenaline (NA) and no change in the content of dopamine (DA) in the area postrema], other treatments reduced levels of dopamine and noradrenaline. Data are discussed in terms of an involvement of 5-HT/catecholamines in the area postrema with the mediation of emesis induced by cisplatin.

Animals↗
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

[3H]zacopride: ligand for the identification of 5-HT3 recognition sites.

[3H]Zacopride displayed saturable binding to homogenates of the rat entorhinal cortex as measured by the inclusion of the 5-HT3 receptor antagonist BRL43694 in the incubation media. Scatchard analysis indicated a single high affinity binding site (KD 0.76 +/- 0.08 nM, Bmax 77.5 +/- 6.5 fmol (mg protein)-1) with a Hill slope close to unity. Other 5-HT3 receptor antagonists (zacopride, ICS 205-930, GR38032F, GR65630, metoclopramide and cocaine) also competed for the binding site displacing 60% of the total [3H]zacopride binding. 5-HT and 2-methyl-5-HT also were competitive antagonists for [3H]zacopride binding whereas 5-HT1/5-HT2 agonists and antagonists, and agents acting on other neurotransmitter receptors had Ki values greater than 10(-5) M. It is concluded that [3H]zacopride may prove a useful ligand for the study of 5-HT3 recognition sites.

Animals↗
PubMed1988

Identification of 5-HT3 recognition sites in the ferret area postrema.

The 5-HT3 receptor antagonist [3H]zacopride was used to identify 5-HT3 recognition sites in the ferret area postrema. Specific binding was determined by the inclusion of the 5-HT3 receptor antagonist BRL 43694 in the incubation media, and was shown to be much higher in the area postrema than in other brain regions. The increased binding in the area postrema may reflect either a greater number of binding sites, a higher affinity for such sites, or both. The results indicate that 5-HT3 recognition sites are present within the area postrema and may afford an antiemetic site of action for zacopride and other 5-HT3 receptor antagonists.

Animals↗