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Biomedical subjects

B Costall

Publications and source records attributed to B Costall.

At least 91 records · Page 5Linked to original sources
PubMed1990

Fluphenazine, ICS 205-930 and dl-fenfluramine differentially antagonise drug-induced emesis in the ferret.

The intravenous injection of cisplatin (10 mg/kg), the subcutaneous injection of apomorphine (0.125-1 mg/kg) and lisuride (0.001-0.1 mg/kg), the oral administration of ipecacuanha (0.3-2.4 mg/kg) and the intragastric administration of copper sulphate (25-100 mg/kg), induced a vomiting and retching response in the ferret. Pretreatment with dl-fenfluramine (5 mg/kg i.p.) prevented or reduced the emesis induced by cisplatin, apomorphine, ipecacuanha and lisuride but failed to significantly antagonise copper sulphate-induced emesis. The 5-HT3 receptor antagonist ICS 205-930 (0.1 mg/kg i.p.) prevented emesis induced by cisplatin and ipecacuanha but failed to prevent or significantly reduce the emesis induced by apomorphine, lisuride or copper sulphate. Dopamine receptor antagonists, including fluphenazine (0.1-1.0 mg/kg i.p.) prevented apomorphine- and lisuride-induced emesis but were less potent or had inconsistent actions to antagonise cisplatin- or ipecacuanha-induced emesis and failed to inhibit the emesis induced by copper sulphate. The data indicate that dopamine and/or 5-HT3 receptor systems are involved in drug-induced emesis but that emesis caused by gastric irritation induced by copper sulphate is mediated by different receptor mechanisms.

Animals↗
PubMed1990

Effects of captopril and SQ29,852 on anxiety-related behaviours in rodent and marmoset.

The abilities of the ACE inhibitors captopril and SQ29,852 to modify aversive behaviour was compared to the effects of diazepam in the light/dark exploration test in the mouse, the elevated plus maze and social interaction test in the rat, and in anxiety-related behaviours induced by human threat in the marmoset. In the four tests the acute administration of captopril, SQ29,852 and diazepam had the same profiles of action to reduce aversive responding. This was also observed during chronic administration with the three agents in the mouse. However, withdrawal from a chronic treatment with diazepam precipitated a syndrome of increased aversion, whereas withdrawal from treatment with captopril and SQ29,852 was uneventful, values waning to control levels. Withdrawal from treatment with ethanol, nicotine and cocaine also enhanced aversive responding. Treatment with captopril and SQ29,852 antagonised the behavioural consequences of withdrawal from treatment with diazepam and nicotine and SQ29,852 also blocked the consequences of withdrawal from ethanol and cocaine. It is concluded that captopril and SQ29,852 have an anxiolytic profile of action in 3 species, that cessation of treatment is not associated with a withdrawal syndrome, that the ACE inhibitors cross tolerate with diazepam and can antagonise the behavioural consequences of withdrawal from treatment with drugs of abuse.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1990

Sites of action of ondansetron to inhibit withdrawal from drugs of abuse.

The cerebral site of action of the selective 5-HT3 receptor antagonist ondansetron to influence the behavioural consequences of withdrawal from subchronic treatment with diazepam, ethanol, nicotine or cocaine was studied in the light/dark exploration test in the mouse. The aversive response to the light compartment of the test box was reduced during a subchronic treatment with peripherally administered diazepam, ethanol, nicotine and cocaine, but was exacerbated following withdrawal from the 4 treatments. The behavioural consequences of withdrawal from diazepam (10 mg/kg IP b.i.d. 14 days), ethanol (8%/w/v drinking water for 14 days), nicotine (0.1 mg/kg IP b.i.d. 14 days) or cocaine (1.0 mg/kg IP b.i.d. 14 days) were antagonised by ondansetron injected into the amygdala and dorsal raphe nucleus (1-10 ng); injections of ondansetron (10 ng) into the median raphe nucleus, the nucleus accumbens and striatum were ineffective. It is concluded that the amygdala and dorsal raphe nucleus may be sites of action for ondansetron to antagonise the aversive behaviour caused by withdrawal from 4 common drugs of abuse in a mouse model, and that 5-HT projections from the dorsal raphe nucleus may be involved in aversive behaviour.

Amygdala↗
PubMed1990

Actions of ORG 5222 as a novel psychotropic agent.

ORG 5222 is a tetracyclic compound with high affinity for dopamine and 5-HT2 receptors. ORG 5222 was compared to fluphenazine in behavioural tests and was shown to be less potent to cause catalepsy on peripheral administration or to induce asymmetric body posturing following intrastriatal injection. On injection into the nucleus accumbens, ORG 5222 antagonised spontaneous and amphetamine-induced hyperactivity. The peripheral administration of ORG 5222 antagonised the hyperactivity induced by infusion of dopamine into the nucleus accumbens of rat or ventral striatum of the marmoset and, unlike the use of fluphenazine, there was no evidence of a 'rebound' hyperactivity after discontinuation of treatment. Furthermore, ORG 5222 prevented changes in responsiveness to dopamine agonist challenge following dopamine infusion. In a mouse black and white test box and the rat elevated plus maze ORG 5222 released exploratory behaviour suppressed by the aversive white or elevated environments. It is concluded that ORG 5222 is effective to antagonise mesolimbic dopamine function in the rodent and primate and an aversive behaviour in rodent tests. Such effects reveal a novel profile of action of ORG 5222 in behavioural paradigms predictive of antipsychotic and anxiolytic potential and may relate to a dopamine and 5-HT receptor antagonism.

Amphetamines↗
PubMed1990

The effects of ondansetron, a 5-HT3 receptor antagonist, on cognition in rodents and primates.

The selective 5-HT3 receptor antagonist, onansetron, has been assessed in three tests of cognition in the mouse, rat and marmoset. In a habituation test in the mouse, ondansetron facilitated performance in young adult and aged animals, and inhibited an impairment in habituation induced by scopolamine, electrolesions or ibotenic acid lesions of the nucleus basalis magnocellularis. Arecoline failed to improve basal performance in young adult mice but inhibited the impairment caused by scopolamine and lesions of the nucleus basalis magnocellularis. In the T-maze reinforced alternation task in rats, ondansetron and arecoline antagonised a scopolamine-induced impairment. In an object discrimination and reversal learning task in the marmoset, assessed using a Wisconsin General Test Apparatus, ondansetron improved performance in a reversal learning task. We conclude that ondansetron potently improves basal performance in rodent and primate tests of cognition and inhibits the impairments in performance caused by cholinergic deficits.

Aging↗
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

The psychopharmacology of 5-HT3 receptors.

The review presents evidence that 5-HT3 receptors within the brain may contribute to the control of behavior. 5-HT3 receptor antagonists GR38032F, zacopride, ICS 205-930 and other agents are very potent in reducing mesolimbic dopamine hyperactivity caused by the injection of amphetamine or infusion of dopamine into the rat nucleus accumbens and amygdala, and the ventral striatum of the marmoset. Such actions are distinguished from those of neuroleptic agents by a failure to reduce normal levels of activity or to induce a rebound hyperactivity after discontinuation of treatment. Indeed, the 5-HT3 receptor antagonists can prevent the neuroleptic-induced rebound hyperactivity. Further evidence that 5-HT3 receptors moderate limbic dopamine function is shown by their ability to reduce both the behavioral hyperactivity and changes in limbic dopamine metabolism caused by DiMe-C7 injection into the ventral tegmental area. The 5-HT3 receptor antagonists also have an anxiolytic profile in the social interaction test in the rat, the light/dark exploration test in the mouse, the marmoset human threat test and behavioral observations in the cynomolgus monkey. They differ from the benzodiazepines by an absence of effect in the rat water lick conflict test and a withdrawal syndrome. Importantly, the 5-HT3 receptor antagonists are highly effective to prevent the behavioral syndrome following withdrawal from treatment with diazepam, nicotine, cocaine and alcohol. Intracerebral injection techniques in the mouse indicate that the dorsal raphe nucleus and amygdala may be important sites of 5-HT3 receptor antagonist action to inhibit aversive behavior. Studies with GR38032F indicate an additional effect in reducing alcohol consumption in the marmoset. The identification and distribution of 5-HT3 receptors in the brain using a number of 5-HT3 receptor ligands, [3H]65630, [3H]zacopride and [3H]ICS 205-930 correlates between studies, and the 5-HT3 recognition sites in cortical, limbic and other areas meet the criteria for 5-HT3 receptors to mediate the above behavioral effects. Thus the use of 5-HT3 receptor antagonists reveals an important role for 5-hydroxytryptamine in the control of disturbed behavior in the absence of effect on normal behavior. The profile of action of the 5-HT3 receptor antagonists has generated a major clinical interest in their potential use for schizophrenia, anxiety and in the control of drug abuse.

Animals↗
PubMed1990

The ACE inhibitor [3H]SQ29,852 identifies a high affinity recognition site located in the human temporal cortex.

The angiotensin converting enzyme (ACE) inhibitor [3H]SQ29,852 identified a single high affinity recognition site (defined by 10.0 microM captopril) in the human temporal cortex (pKD 8.62 +/- 0.03; Bmax 248 +/- 24 fmol mg-1 protein, mean +/- S.E.M., n = 4). ACE inhibitors and thiorphan competed to a similar level for the [3H]SQ29,852 binding site in the human temporal cortex with a rank order of affinity (pKi values mean +/- S.E.M., n = 3), lisinopril (9.49 +/- 0.02), captopril (9.16 +/- 0.08), SQ29,852 (8.58 +/- 0.04), epicaptopril (7.09 +/- 0.08), fosinopril (7.08 +/- 0.05) and thiorphan (6.40 +/- 0.04). Since this rank order of affinity is similar to the affinity of these compounds to inhibit brain ACE activity it is concluded that [3H]SQ29,852 selectively labels the inhibitor recognition site of ACE in the human temporal cortex.

Adult↗
PubMed1990

Biochemical models for cognition enhancers.

Although the etiology of Alzheimer's disease includes a wide range of dysfunction, the most essential dysfunction is probably in the mesolimbic acetylcholine (ACh) system. Three novel approaches to modulating ACh function were considered, somatostatin, serotonin (5-HT) and modulation of cortical ACh tone through angiotension II. Concerning somatostatin there is no correlation between the decrease in somatostatin binding sites in brain and choline-acetyl-transferase activity suggesting that modulating somatostatin is not a promising therapeutic approach to Alzheimer's disease. With 5-HT, evidence suggests that 5-HT receptors (in particular 5HT1A) are located on cholinergic projections and behavioral evidence suggests 5-HT modulation of memory function. This area could therefore develop rapidly, particularly in view of the recent discovery of numerous subtypes of 5-HT receptor. Concerning the third approach, recent evidence has shown that angiotensin converting enzyme (ACE) inhibitors can facilitate ACh release and also possess cognition enhancing activity. The possibility was also evoked that drugs such as piracetam might prevent age-related decreases in ACh receptor density. Concerning trophic factors (e.g. glutamate-induced neuronal sprouting) most approaches have induced amnesia but the search for partial glutamate agonists may have potential. Finally, a neuronal transplant approach was considered but was thought to be very difficult in view of the global brain shrinkage associated with aging and Alzheimer's disease.

Alzheimer Disease↗
PubMed1990

Development of a class of selective cholecystokinin type B receptor antagonists having potent anxiolytic activity.

PD134308 and PD135158 are potent and selective antagonists at the cholecystokinin type B (CCK-B) receptors with IC50 values of 1.6 nM and 3.5 nM, respectively, in the radioligand binding assay and Ke values of 7.82 and 12.9 nM, respectively, in their blocking action on CCK responses in the rat lateral hypothalamic slice. PD134308 and PD135158 produced potent anxiolytic effects in the mouse black/white box test after either subcutaneous or oral administration. There was no evidence of the development of tolerance to the anxiolytic action of either PD134308 or PD135158 in mice treated twice daily for 7 days, nor was there any sign of withdrawal anxiogenesis after abrupt termination of this treatment. Both CCK-B antagonists were able to suppress the withdrawal anxiogenesis and produce an anxiolytic effect in mice previously made tolerant to diazepam. PD134308 and PD135158 produced potent anxiolytic effects in the rat elevated plus maze test and the rat social interaction test. The effects were comparable in magnitude to those seen with diazepam. However, unlike diazepam, PD134308 and PD135158 did not produce sedation. The CCK-B antagonists also showed powerful anxiolytic activity in the "marmoset human threat test." These results provide evidence of a selective role for CCK-B receptors in the control of anxiety. PD134308 and PD135158 are members of a class of anxiolytic agents that have a greatly improved profile compared with benzodiazepines or serotonin-related anxiolytics.

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↗
PubMed1990

5-HT3 receptor antagonists attenuate dopamine-induced hyperactivity in the rat.

The 5-HT3 receptor antagonists, ICS205-930, granisetron and zacopride, at low doses, inhibited the hyperactivity caused by a 13 day mesolimbic dopamine infusion in the rat. The antagonism decreased with the use of higher doses of the 5-HT3 receptor antagonists. The ability of low doses of the 5-HT3 receptor antagonists to inhibit dopamine-induced behavioural changes is similar to the inhibitory profile of known antipsychotic agents. It is suggested that 5-HT3 receptor antagonists may represent a new class of atypical antipsychotic agents.

Animals↗
PubMed1990

Angiotensin II inhibits cortical cholinergic function: implications for cognition.

In the present studies we have shown that angiotensin II (AT II), in a concentration-dependent manner in rat tissue (10(-9)-10(-5) M) or at a single concentration in human tissue (10(-6) M), can inhibit potassium-stimulated release of [3H]acetylcholine ( [3H]Ach) from slices of rat entorhinal cortex and human temporal cortex preloaded with [3H]choline for the biochemical analyses. The inhibitory effects of AT II (10(-6) M) were antagonised by the specific AT II receptor antagonist [1-sarcosine, 8-threonine]AT II in a concentration-dependent manner in rat tissue (10(-11)-10(-8) M) and at the single concentration employed in the human studies (10(-7) M). Also demonstrated were other components of the angiotensin system in the human temporal cortex; ACE activity was present (1.03 nmol min-1 mg-1 protein), as were AT II recognition sites (Bmax = 8.6 fmol mg-1 protein). It is hypothesised that the potential cognitive enhancing properties of ACE inhibitors may reflect their action to prevent the formation of AT II and so remove an inhibitory modulator of cholinergic function.

Acetylcholine↗
PubMed1990

The actions of fenfluramine and interaction with 5-HT3 receptor-antagonists to inhibit emesis in the ferret.

The racemate and (+)- and (-)-isomers of fenfluramine (5 mg kg-1 i.p., 1 h pretreatment) antagonized cisplatin-induced retching and vomiting in the ferret. The intravenous injection of (+/-)-fenfluramine administered on an established cisplatin-induced emesis antagonized the response within minutes of injection. The administration of a lower dose of (+/-)-fenfluramine (1.0 mg kg-1 i.p., 1 h pretreatment) failed to antagonize cisplatin-induced emesis when administered alone but enhanced the antiemetic effects of metoclopramide and ICS 205-930. This pretreatment with (+/-)-fenfluramine failed to enhance the antiemetic effects of zacopride. It is considered that an action of the racemate on presynaptic 5-HT/catecholaminergic systems to reduce neurotransmitter release may enhance the action of certain 5-HT3 receptor antagonists in controlling emesis induced by cisplatin.

Animals↗