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Biomedical subjects

B Costall

Publications and source records attributed to B Costall.

At least 145 records · Page 8Linked to original sources
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↗
PubMed1986

Biochemical changes caused by the infusion into the substantia nigra of the rat of MPTP and related compounds which antagonise dihydropteridine reductase.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), 1-methyl-4-phenylpyridinium bromide (MPP+), 1-methyl-4-(3', 4'-dihydroxyphenyl)pyridinium bromide, 4-(3',4'-dihydroxyphenyl)pyridine, 4-phenyl-1,2,3,6-tetrahydropyridine and 4-(3',4'-dimethoxyphenyl)1,2,3,6-tetrahydropyridine were infused bilaterally into the substantia nigra of the rat (10 micrograms/24 hr for 4 days). The ability to inhibit spontaneous locomotor activity and to reduce levels of neurotransmitters and metabolites in the nigrostriatal system (striatum, substantia nigra) was compared with activity to inhibit dihydropteridine reductase (DHPR) in vitro. The compound MPP+ was most effective to reduce motor responding and to decrease levels of dopamine, DOPAC and HVA (50-56%) in the striatum in addition to reducing levels of dopamine, DOPAC, noradrenaline, serotonin and 5-HIAA (42-86%) in the substantia nigra, yet MPP+ has been shown to have very weak ability to inhibit DHPR. In contrast, 4-(3',4'-dihydroxyphenyl)pyridine and 1-methyl-4-(3',4'-dihydroxyphenyl)pyridinium bromide were in the order of 10(4) and 2 X 10(5) times, respectively, more potent than MPP+ to inhibit DHPR in vitro, but these compounds failed to modify dopamine neuronal function when assessed in vivo. Therefore, there would not appear to be any correlation between the ability to modify dopamine neuronal function, as assessed behaviourally or biochemically, and ability to inhibit DHPR in synaptosomes from the striatum of the rat in vitro.

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

Modification of electrical field stimulation-induced contractions in the guinea-pig ileum by metoclopramide and ICS 205-930 depends on the integrity of the mucosa.

Contractions induced by electrical field stimulation of guinea-pig ileum longitudinal muscle strips were enhanced by metoclopramide and ICS 205-930 at concentrations similar to those required to antagonize at 5-hydroxytryptamine 'M' receptors. The enhancement of contraction was observed in intact ileum strips but was not recorded in the longitudinal muscle myenteric plexus preparation or from the ileum with the mucosal layer removed. It is concluded that an intact mucosal layer is required for metoclopramide and ICS 205-930 to enhance electrical field stimulation-induced contractions of the guinea-pig ileum.

Animals↗
PubMed1986

Evidence that 5-hydroxytryptamine may exert both facilitatory and inhibitory control of electrical field stimulation-evoked contractions in longitudinal muscle taken from the body of guinea-pig stomach.

Electrical field stimulation (FS) of guinea-pig stomach body longitudinal muscle strips caused frequency-related contractions mediated via cholinergic mechanisms. Metoclopramide (10(-8)-10(-5) M), MDL 72222 (10(-9)-10(-7) M) and 5-hydroxytryptophan (5-HTP) (3 X 10(-7)-2.4 X 10(-4) M) enhanced these contractions in all tissues, whereas 5-hydroxytryptamine (5-HT) (3 X 10(-8)-3 X 10(-5) M) enhanced the contractions, but only in approximately 15% of the tissues tested. FS-induced contractions were also enhanced in tissues treated in-vitro with p-chlorophenylalanine (2.5 X 10(-7)-2.5 X 10(-5) M) or monofluoromethyldopa (6 X 10(-7)-10(-4) M) or in tissues taken from animals having received p-chlorophenylalanine or monofluoromethyldopa. It is concluded that cholinergic-mediated contractions of stomach strips are subject to 5-HT modulation in two ways. The predominant action of endogenous 5-HT is to exert an inhibitory tone mediated via a metoclopramide and MDL 72222-sensitive 5-HT neuronal receptor. Exogenously applied 5-HT has little overt action to increase the essentially maximal inhibitory action of endogenous 5-HT, but acts on a 5-HT facilitatory receptor system to enhance contractions. Therefore, the actions of 5-HT agonists and antagonists to modify contractions in stomach strips will reflect the balance between 5-HT inhibitory and facilitatory influences, and the specificity of action of the compounds for the two 5-HT receptor systems.

5-Hydroxytryptophan↗
PubMed1986

Neuropharmacological manipulations with MPTP.

Studies have been carried out in the rodent and marmoset to assess (i) the selectivity of MPTP action to the nigrostriatal system, (ii) the possibility that melanin pigmentation may influence the actions of MPTP, (iii) whether the metabolites of MPTP may contribute to its actions on dopamine cells, (iv) the site(s) of action of MPTP in the brain, (v) the mechanism(s) of action of MPTP and whether it is possible to prevent the damaging effects of MPTP/metabolites on the brain dopamine systems. The peripheral administration of MPTP in the mouse causes depletions of dopamine and its metabolites in both the striatal and limbic systems: this action is similar in both white and pigmented mice. The MAO-B inhibitor deprenyl was shown to antagonize the actions of MPTP, and its metabolite formed via oxidation through MAO, MPP+, was shown to disrupt striatal dopamine function as determined behaviorally (as motor impairment) or biochemically (as loss of dopamine and its metabolites) when injected into the cerebral ventricles of mouse or infused into the substantia nigra of rat brain. MPTP and MPP+ act in the midbrain to interfere with dopamine cell functioning, and studies in both the rodent and marmoset are presently analyzing possible additional actions in forebrain regions. It is therefore proposed that the neurotoxic action of MPTP, effected via its metabolite MPP+, may not be selective for the nigrostriatal system. Nevertheless, the nature and profile of neurotoxicity effected by MPTP and, in particular, MPP+ should ensure continuing analyses of the relevance of such action to an understanding of the etiology of, treatment of, and even the possible prevention of Parkinson's disease in man.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1985

A central site of dopamine agonist action to modify gastric secretion in the rat.

2-Di-n-propylamino-5,6-dihydroxytetralin (tetralin) administered subcutaneously (6.25-25 micrograms/kg s.c.) or into the cerebral ventricles (i.c.v. 0.5-10 micrograms) dose-dependently reduced the volume and acid concentration of gastric secretion collected from rats having chronically implanted gastric and intracerebral cannulas. Apomorphine or dopamine given i.c.v. also reduced gastric secretory volume and acid concentration. Tetralin-induced reductions (s.c. or i.c.v.) in gastric acid concentrations were antagonised by the dopamine antagonists metoclopramide, sulpiride or haloperidol and by the alpha 2-adrenoceptor antagonist yohimbine given systemically or i.c.v. The alpha 2-adrenoceptor antagonist idazoxan or the beta-adrenoceptor antagonist propranolol (i.c.v.) also antagonised the tetralin-induced (i.c.v.) reduction in gastric acid concentration. In contrast, the reduction in gastric secretory volume effected by centrally or peripherally administered tetralin could only be antagonised by propranolol. Previous observations that apomorphine can reduce gastric secretory volume and acid concentration are thus extended to 2-di-n-propylamino-5,6-dihydroxytetralin. Both agents reduce gastric secretory volume via an action on beta-adrenoceptors, and reduce gastric acid concentration via dopamine receptors, with alpha 2-adrenoceptor and, more speculatively, beta-adrenoceptor mechanisms contributing to the effect of the tetralin compound. These actions may be mediated, at least in part, via central mechanisms.

Animals↗
PubMed1985

The toxic actions of MPTP and its metabolite MPP+ are not mimicked by analogues of MPTP lacking an N-methyl moiety.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), its metabolite 1-methyl-4-phenylpyridine (MPP+) and three analogues of MPTP, lacking an N-methyl moiety, namely, 4-phenylpiperidine (I), 4-phenyl-1,2,3,6-tetrahydropyridine (II) and 4-phenylpyridine (III), were infused continuously for a period of 4 days into the rat substantia nigra. Within 12 h of commencing the bilateral infusion of MPTP or MPP+, rats showed marked motor deficits with reduction in locomotor activity, loss of ability to move the forelimbs and grip with forepaws and, following MPP+ infusions, similar loss of movement in the hindlimbs associated with the development of limb and body rigidity. These motor deficits were not induced by the 3 analogues of MPTP on infusion into the substantia nigra. After 4 days of infusion, the motor deficits caused by MPTP and, in particular, MPP+, were still marked, and for MPP+ these correlated with marked loss of striatal dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid. 4-Phenyl-1,2,3,6-tetrahydropyridine caused a small loss in striatal DA and DOPAC, but the other analogues failed to modify the striatal content of DA or its metabolites. Small alterations of chemical structures related to MPTP and its metabolite can critically alter ability to induce behavioural and neurochemical changes reflecting toxicity on the nigrostriatal DA system.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1985

Mechanism of action of apomorphine on rat gastric secretion.

The effects of apomorphine on the volume of gastric secretion and its content of H+, K+, Na+ and Cl- were determined in conscious rats having gastric cannulas. Apomorphine dose-dependently (0.25-0.5 mg/kg s.c.) decreased the volume of gastric secretion, its acid concentration and, at the highest dose, Cl- concentration. However, Na+ and K+ concentrations were unchanged. The alpha 1- and alpha 2-adrenoceptor antagonists prazosin (0.25-0.5 mg/kg i.p.) and yohimbine (5-10 mg/kg i.p.), the beta 1- and beta 2-adrenoceptor antagonist propranolol (5 mg/kg i.p.), the beta 2-adrenoceptor antagonist ICI 118551 (1 mg/kg i.p.) and the dopamine receptor antagonists haloperidol (0.25-2.5 mg/kg i.p.), metoclopramide (2.5-10 mg/kg i.p.) or domperidone (2.5 mg/kg i.p.), administered alone, had little or no effect on the volume, H+, Na+ or Cl- concentrations of gastric secretion. Propranolol prevented the action of apomorphine to reduce the volume of gastric secretion but failed to modify the reductions in H+ and Cl- concentrations. The action of propranolol was mimicked by ICI 118551 but not by the beta 1-adrenoceptor antagonist atenolol. Yohimbine, prazosin or domperidone had little or no effect on the actions of apomorphine. Haloperidol (0.5 mg/kg i.p.) and metoclopramide (10 mg/kg i.p.) antagonised apomorphine's action to reduce H+ and Cl- concentrations but significantly enhanced the action of apomorphine to reduce the volume of gastric secretion. The results suggest that the ability of apomorphine to reduce the volume of gastric secretion is mediated via beta 2-adrenoceptors whilst acid concentration is reduced via an action on neuroleptic sensitive receptors.

Adrenergic beta-Antagonists↗
PubMed1985

The neurotoxic actions of 1-methyl-4-phenylpyridine (MPP+) are not prevented by deprenyl treatment.

1-Methyl-4-phenylpyridine (MPP+) injected into the cerebral ventricles (ICV) of mouse caused depletions of striatal dopamine (DA)(-42%), 3,4-dihydroxyphenylacetic acid (DOPAC) (-34%) and homovanillic acid (HVA) (-16%) content without significant reductions in levels of noradrenaline (NA), serotonin (5-HT) or 5-hydroxyindoleacetic acid (5-HIAA). When deprenyl was administered before MPP+, striatal DA and its metabolites were further depleted, and striatal NA and 5-HT levels also were reduced. Further, whilst ICV MPP+ alone failed to influence the biochemistry of the limbic areas (nucleus accumbens plus tuberculum olfactorium), in the presence of deprenyl MPP+ caused 20-40% reductions in levels of limbic NA, DA, DOPAC, HVA, 5-HT and 5-HIAA. Therefore, deprenyl treatment does not prevent the neurotoxic actions of MPP+; indeed, a more extensive neurotoxicity for MPP+ is revealed in the presence of this monoamine oxidase inhibitor.

1-Methyl-4-phenylpyridinium↗
PubMed1985

Dopamine agonist action in mesolimbic, cortical and extrapyramidal areas to modify spontaneous climbing behaviour of the mouse.

Dopamine and apomorphine were injected directly into limbic, extrapyramidal and cortical areas of mouse brain to determine relative sensitivities to the inhibitory effects of these agents on mouse spontaneous climbing behaviour. Injections of 0.06-2 micrograms apomorphine or dopamine into the nucleus accumbens, central area of the amygdala, septum or ventral tegmental nucleus caused dose-dependent motor inhibition with maximal reductions in the order of 60-70% of control value. In the extrapyramidal nuclei, caudate-putamen and globus pallidus, apomorphine and dopamine were required at 0.5-2.5 micrograms to produce inhibition, but the degree of inhibition never achieved 50% of control. Apomorphine and dopamine (0.001-10 micrograms) failed to cause any inhibition of mouse spontaneous climbing behaviour when injected into the anteromedial, supragenual or suprarhinal cortex. The higher doses of dopamine or apomorphine could effect stimulation of climbing behaviour from the limbic, extrapyramidal and cortical areas. Bilateral injections of haloperidol or (-)sulpiride (0.001-1 microgram) into the selected limbic and extrapyramidal areas caused dose-related depression of mouse spontaneous climbing, the limbic areas, particularly the nucleus accumbens, being the most sensitive. Doses of these neuroleptics selected as having minimal effect in their own right were shown to antagonise the marked motor inhibition effected by dopamine and apomorphine from the limbic areas, and the modest inhibition effected from the extrapyramidal areas. In contrast, intracerebral pretreatments with prazosin or yohimbine failed to antagonise the motor inhibitory effects of dopamine or apomorphine from any brain area.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1985

An analysis of the hypothalamic sites at which substituted benzamide drugs act to facilitate gastric emptying in the guinea-pig.

An analysis of the hypothalamic sites at which the substituted benzamides, metoclopramide and clebopride, act to facilitate gastric emptying was undertaken in the guinea-pig. Standard stereotaxic techniques for intracerebral injection via chronically indwelling intracerebral guides were combined with measurement of gastric emptying by fluoroscopic following of the passage of barium sulphate spheroids from the stomach. Injections were made at 7 different locations within the hypothalamus at Ant. 8.0, 8.9 and 9.6, Lat. +/- 1.0, +/- 1.6, +/- 2.2 (relative to the stereotaxic frame) and at 7.0, 8.0 and 9.0 mm below guide tips in the cortex. The most sensitive sites for gastric facilitation by the substituted benzamides were located at Ant. 8.9, Lat. +/- 1.6, Vert. -8.0, -9.0, the "perifornical area". As the distance of the injection site from the area of the fornix increased, so the facilitatory gastric action diminished, with marked delays or loss in response occurring when injection sites were moved 1 mm above, 0.6 mm lateral, 0.4 mm medial, 0.9 mm posterior or 0.7 mm anterior. The facilitatory gastric actions of metoclopramide and clebopride in the perifornical area of the hypothalamus were not mimicked by haloperidol, domperidone or sulpiride. Atropine, injected into the hypothalamus, markedly reduced gastric emptying; hexamethonium was less effective, and phentolamine, propranolol and methysergide were inactive. Atropine (but not hexamethonium, phentolamine, propranolol or methysergide), injected into the hypothalamus, dose-dependently antagonised the facilitatory gastric action of metoclopramide injected at the same site. Carbachol (but not serotonin, noradrenaline, dopamine or apomorphine), injected into the perifornical area, caused marked facilitation of gastric emptying.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1985

The continuity of dopamine receptor antagonism can dictate the long-term behavioural consequences of a mesolimbic infusion of dopamine.

An infusion of dopamine for 13 days into the nucleus accumbens of rat caused biphasic peaks of hyperactivity responding during infusion and an enhanced locomotor responsiveness to the dopamine agonist (-)N-n-propylnorapomorphine [(-)NPA] after the infusion when rats where initially preselected as low activity responders to (-)NPA. Antagonism of the response to dopamine during the infusion by sulpiride, given every 8 hr (three daily doses provided 30 mg/kg, i.p., daily), could both facilitate spontaneous locomotor activity after the infusion, and potentiate the consequence of enhanced hyperactivity responding to (-)NPA, for at least 11 weeks. In contrast, when sulpiride was administered in a daily dose of 30 mg/kg but by continuous intraperitoneal infusion, not only were the events during the infusion prevented, without subsequent change in spontaneous locomotion after the infusion, but also the long-term consequences for responding to (-)NPA were prevented and the rats remained at their preselected low activity response levels. The repeated treatment with (-)NPA or the repeated/continuous treatment with sulpiride alone were not responsible for the changes observed. It is concluded that the consequence of intervention with sulpiride during a period of infusion of dopamine into the mesolimbic region depends on the degree and/or continuity of antagonism of dopamine receptors such that fluctuating antagonism (daily injections) can exacerbate, whilst a continuous and constant receptor antagonism (effected by infusion), can prevent the long-term consequences of increased sensitivity to challenge with a dopamine agonist.

Animals↗
PubMed1985

Biochemical correlates of motor changes caused by the manipulation of dopamine function in the substantia nigra of the mouse.

2-Di-n-propylamino-5,6-dihydroxytetralin, injected bilaterally into the substantia nigra of the mouse, caused dose-dependent motor inhibition which was associated with decreased levels of DOPAC and increased levels of dopamine in the striatum. (-)Sulpiride, injected into the substantia nigra, antagonised the locomotor depression although the partial antagonism of the elevation in the level of dopamine in the striatum and of the reduction in levels of DOPAC did not achieve significance. The specificity of the action of tetralin on dopamine receptors was shown by the failure of prazosin and yohimbine to antagonise the locomotor depression induced by tetralin and the reduction in levels of DOPAC. The selectivity of the action of tetralin for the dopamine system was shown by its failure to affect levels of noradrenaline, serotonin and 5-hydroxyindoleacetic acid in the striatum. The injection of tetralin into the substantia nigra also caused biochemical changes in limbic areas (nucleus accumbens and tuberculum olfactorium), where the levels of dopamine and DOPAC were elevated, and in the frontal cortex where the levels of DOPAC were reduced. These changes were antagonised by a concomitant injection of (-)sulpiride into the substantia nigra. It is concluded that the action of dopamine agonists in the midbrain can decrease the functional activity in the ascending dopaminergic pathways.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1985

Laterality of dopamine function and neuroleptic action in the amygdala in the rat.

Rats selected according to turn preference in an open field were categorised as showing left or right hemispheric dominance (turning to right or left respectively). Dopamine was persistently infused into the central area of the left or right amygdala of animals showing left or right hemispheric dominance. Infusion was effected for 9 days by Alzet osmotic minipumps, implanted subcutaneously, which delivered 25 micrograms/24 hr of dopamine via chronically-indwelling, stereotaxically-located injection units. Dopamine caused marked and consistent hyperactivity only when infused into the left amygdala when the right hemisphere was dominant. This hyperactivity developed during the first day of infusion and persisted throughout the 9-day infusion period. Both (-)sulpiride and fluphenazine, injected unilaterally into the amygdala, antagonised the hyperactivity caused by infusion of dopamine into the left amygdala in animals with right hemispheric dominance. This antagonism could be effected both from the infused amygdala [5-50 pg (-)sulpiride, 25-100 pg fluphenazine] and from the contralateral amygdala [100-250 pg (-)sulpiride, 25-100 pg fluphenazine]. Thus, a laterality was shown for the action of dopamine in the amygdala of the rat. In contrast, neuroleptic agents failed to show an exclusive laterality of action, but were able to act in either hemisphere to antagonise the effects of dopamine injected into the left amygdala. Interhemispheric biochemical differences "within-animals" could not be shown, although differences were seen between rats having right or left hemispheric dominance.(ABSTRACT TRUNCATED AT 250 WORDS)

Amygdala↗
PubMed1985

Modification of dyskinesias following the intrastriatal injection of prostaglandins in the rodent.

The abilities of prostaglandin E1 (PGE1), PGE2, PGD2 and PGF2 alpha to antagonize striatal dopamine function were assessed following bilateral and unilateral injections into the striata of the rat and guinea-pig. Three tests were used to assess the effects of the bilateral injections, ability to antagonize dyskinetic biting induced by 2-di-n-propylamino-5,6-dihydroxytetralin (0.025 mg kg-1 s.c.), ability to antagonize stereotyped behaviour induced by apomorphine (0.5 or 2 mg kg-1 s.c.) and ability to induce catalepsy. Asymmetry/circling behaviour revealed on challenge with apomorphine (0.25 mg kg-1 s.c.) was measured following unilateral injection into the striatum. In the rat, dyskinetic biting induced by 2-di-n-propylamino-5,6-dihydroxytetralin was antagonized by PGE1 (0.001-1 micrograms) and PGE2 (0.00001-1 micrograms) but not by PGD2 or PGF2 alpha (1 microgram). Stereotyped behaviour induced by apomorphine was not antagonized by any of the prostaglandins. A weak catalepsy was induced by PGE1 (1 microgram only), PGE2 (0.001-1 micrograms) and PGD2 (0.001-1 micrograms) but not by PGF2 alpha. Asymmetry and circling behaviour was only observed following the unilateral injection into the striatum of PGE1 and PGD2 (0.01-1 microgram) and challenge with apomorphine. In the guinea-pig the actions of PGE1 and E2 were compared with those of PGF2 alpha. Dyskinetic biting induced by 2-di-n-propylamino-5,6-dihydroxytetralin was antagonized by bilateral injections into the striatum of PGE2 (0.001-1 microgram), but not PGE1 (0.5 micrograms) and PGF2 alpha (1 microgram) but not PGE, (0.5 micrograms) and PGF2 alpha (1 microgram). Similar injections of PGE1, E2 and F2 alpha, all failed to antagonize apomorphine-induced stereotyped behaviour, or to induce catalepsy. PGE, (0.01-0.5 fig) and PGE2 (0.002-1 pg), but not PGF2 alpha, caused asymmetry following unilateral injection into the striatum and peripheral challenge with apomorphine. 5 It is concluded that the major effect in the striatum of the prostaglandins of the E series is to antagonize dyskinetic biting; this action is not shared by other prostaglandins tested, and does not reflect a generalised ability to antagonize striatal dopamine function. It is suggested that the actions of the prostaglandins to modify differentially dopamine-dependent behaviours from the striatum may reflect activity at a site subsequent to the dopamine receptor.

Alprostadil↗
PubMed1985

5-Hydroxytryptamine receptor antagonism by metoclopramide and ICS 205-930 in the guinea-pig leads to enhancement of contractions of stomach muscle strips induced by electrical field stimulation and facilitation of gastric emptying in-vivo.

Contractions induced by electrical field stimulation of isolated circular muscle strips, taken from the guinea-pig stomach, were enhanced by metoclopramide, ICS 205-930 and MDL 72222 at concentrations similar to those shown to antagonize at neuronal 5-hydroxytryptamine receptor sites in a variety of preparations. Metoclopramide, MDL 72222 and ICS 205-930 also facilitated gastric emptying in-vivo. The abilities of metoclopramide, MDL 72222 and ICS 205-930 to enhance stomach muscle contraction processes and to facilitate gastric emptying may be the consequence of 5-hydroxytryptamine receptor antagonism.

Animals↗