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Biomedical subjects

B Costall

Publications and source records attributed to B Costall.

At least 253 records · Page 14Linked to original sources
PubMed1976

A comparison of the abilities of typical neuroleptic agents and of thioridazine, clozapine, sulpiride and metoclopramide to antagonise the hyperactivity induced by dopamine applied intracerebrally to areas of the extrapyramidal and mesolimbic systems.

Dopamine injected directly into the caudate--putamen, nucleus accumbens or tuberculum olfactorium of rat brain, following a nialamide pretreatment, caused dose-dependent hyperactivity. The hyperactivity was more intense after injections into the nucleus accumbens, but was limited by the development of stereotyped biting when larger doses of dopamine were injected into the caudate--putamen or tuberculum olfactorium. Haloperidol, fluphenazine and pimozide were shown to antagonise, in a dose-dependent manner, the hyperactivity induced by dopamine from all 3 areas. Pimozide appeared equieffective against the 3 hyperactivity mediated from the mesolimbic areas, the nucleus accumbens and tuberculum olfactorium. Sulpiride, clozapine and thioridazine also caused dose-dependent reductions in the hyperactivity induced by dopamine injections into the caudata--putamen, nucleus accumbens and tuberculum olfactorium, although the doses required to effect this inhibition were notably larger than for the typical neuroleptics. Generally, these atypical agents were also least effective as antagonists of the hyperactivity following intrastriatal dopamine. Metoclopramide differed from all other agents tested in failing to antagonise the hyperactivity induced by dopamine injections into the nucleus accumbens. However, the responses to dopamine from the caudate-putamen and tuberculum olfactorium were both antagonised by metoclopramide, the striatal response being the least sensitive. The alpha- and beta-adrenergic blocking agents, aceperone and propranolol, failed to reduce the hyperactivity induced by dopamine injections into the caudate-putamen, nucleus accumbens or tuberculum olfactorium. The abilities of the agents tested to antagonise a hyperactivity induced by dopamine in the striatum or in the mesolimbic areas, the nucleus accumbens and tuberculum olfactorium, are compared with the potential of these agents to induce extrapyramidal side effects and to exert an antipsychotic action in man.

Animals↗
PubMed1975

Neuropharmacological studies on D145 (1,3-dimethyl-5-aminoadamantan).

The effects of D145 (1,3-dimethyl-5-aminoadamantan) and amantadine on dopaminergic mechanisms in the rat were investigated by use of pharmacological agents known to disrupt dopamine function, by placing electrolytic lesions in the dopamine-containing areas of the extrapyrimidal and mesolimbic systems and by the direct application to dopamine sensitive areas. Stereotypy and circling behaviour were used as behavioural indices of dopaminergic stimulation and apomorphine and d-amphetamine were used as standard dopaminergic agonists. In addition, the possible importance of 5-hydroxytryptamine to the dopamine effects was investigated using electrolytic lesions of the midbrain raphé nuclei. Both D145 and amantadine caused a stereotyped behaviour characterized by periodic sniffing, repetitive limb movements and biting, but the effect of amantadine was far more periodic. In addition D145, but not amantadine, caused marked hyperactivity. These behavioural effects were resistant to pretreatment with alpha-methylparatyrosine but not to combined alpha-methylparatyrosine/reserpine or low doses of haloperidol. Also, the prior administration of D145 or amantadine inhibited the development of the biting components of apomorphine and d-amphetamine stereotypy. Both D145 and amantadine caused circling behaviour in animals with asymmetric lesions of the medial raphé nucleus or unilateral lesions of the substantia nigra but the action of D145 was more intense. Bilateral electrolytic lesions placed in the extrapyrimidal (caudate-putamen, globus pallidus, substantia nigra), mesolimbic (nucleus accumbens septi, tuberculum olfactorium, nucleus interstitialis stria terminalis, nucleus amygdaloideus centralis) nuclei or the neuronal pathways supplying them showed D145 and amantadine to act in both areas although their action on the extrapyrimidal system was most marked. However, of particular note was the significantly greater involvement of the substantia nigra with the D145 effect, and the greater involvement of the D145 effect with mesolimbic function. Lesions placed in the medial and/or dorsal raphé nucleus indicated some involvement of 5-hydroxytryptamine with the actions of both D145 and amantadine. The bilateral intrastriatal application of D145 or amantadine in nialamide pretreated animals failed to induce stereotyped or hyperactive behaviour although contralateral asymmetries, which were abolished by lesions of the substantia nigra, were recorded following the unilateral intrastriatal application of D145 or amantadine in haloperidol pretreated animals.

Amantadine↗
PubMed1975

Detection of the nueroleptic properties of clozapine, sulpiride and thioridazine.

The cataleptic and antistereotypic abilities of clozapine, sulpiride and thioridazine were determined in the rat and compared with the responses of typical neuroleptic agents, haloperidol, fluphenazine and pimozide. Haloperidol and fluphenazine caused a dose-dependent cataleptic state which attained maximum intensity: the effects of pimozide were also dose-dependent but, although the catalepsy was marked, maximum intensity was not attained. In contrast, thioridazine, clozapine and sulpiride each caused a very weak, but definite, cataleptic response although a dose-dependency could not be demonstrated. Pretreatment of animals with alpha-methylparatyrosine was shown to significantly potentiate the cataleptic actions of haloperidol, fluphenazine, pimozide, thioridazine and sulpiride but failed to modify the action of clozapine, Threshold cataleptic doses of all agents markedly synergised in the production of catalepsy with threshold doses of the cholinergic drug RS86. Similarly, all "neuroleptic" agents tested were shown to reduce the intensity of the stereotyped behaviour induced by amphetamine, apomorphine and nomifensine in a dose-dependent manner but only haloperidol, fluphenazine and pimozide were shown to be capable of 100% inhibition. The antistereotypic abilities of haloperidol, fluphenazine and pimozide were most marked against amphetamine, but this was not a consistent observation for thioridazine, clozapine and sulpiride. Threshold, or even subthreshold, doses of both the typical and atypical neuroleptic agents combined with threshold doses of RS86 markedly synergised in the antagonism of the stereotypic actions of amphetamine, apomorphine and nomifensine.

Animals↗
PubMed1975

Nomifensine: a potent dopaminergic agonist of antiparkinson potential.

Nomifensine was shown to be a potent stereotypic agent in rat. Its effect was resistant to a-methylparatyrosine pretreatment but was abolished by combined reserpine/alpha-methylparatyrosine and by haloperidol. Electrolytic lesions placed in dopamine-containing areas of the extra-pyramidal, mesolimbic and amygdaloid systems indicated an effect in all areas, but the globus pallidus and substantianigra were shown to be most important for its action. Also the effect of nomifensine was reduced by lesions of the medial and/or dorsal raphé nuclei. A circling behaviour was recorded following nomifensine administration to animals with unilateral electrolytic lesions of the substantia nigra or asymmetric lesions of the medial raphé nucleus. These effects were resistant to alpha-methylparatyrosine and inhibited by haloperidol. Nomifensine reduced the intensity of harmine-induced tremor. The M2-metabolic of nomifensine mimicked the effects of the parent compound on peripheral administration bu the onset of action was more rapid and the duration shorter. The M2-metabolite was active on intrastriatal injection to induce stereotyped/hyperactive behaviour and contralateral asymmetries. In all experimental situations nomifensine was compared with apomorphine and d-amphetamine (dopamine and L-Dopa where appropriate). Nomifensine/metabolite was shown to be a potent dopaminergic agonist with an action mainly dependent upon functioning of the extrapyramidal system and partly independent of presynaptic mechanisms.

Animals↗
PubMed1975

A comparison of circling models for the detection of antiparkinson activity.

Apomorphine, d-amphetamine, methylphenidate, nomifensine, ET495 and amantadine each induced a dose-dependent stereotyped behaviour in the rat. L-Dopa was inactive in the absence of any pretreatment. The behaviour induced by apomorphine, methylphenidate, nomifensine and amantadine persisted following pretreatment with a-methylparatyrosine. However, only the effect of apomorphine developed following combined pretreatment with reserpine/a-methylparatyrosine. The effects of all stereotypic agents were inhibited by haloperidol, apomorphine, methylphenidate and nomifensine being most resistant. All agents, including L-Dopa, induced a dose-dependent contralateral circling behaviour in animals with asymmetric lesion of the medial raphé nucleus and a dose-dependent ipsilateral circling after unilateral lesion of the substantia nigra. Following unilateral lesions in the ventromedial area of the medial forebrain bundle (medial to the substantia nigra and carrying 5-hydroxytryptamine neurones) amphetamine caused an ipsilateral circling behaviour, amantadine a behaviour which was characterised by definite bursts in either direction, and all other agents caused contralateral circling.

Amantadine↗
PubMed1975

Differences in the nature of the stereotyped behaviour induced by aporphine derivatives in the rat and in their actions in extrapyramidal and mesolimbic brain areas.

Apomorphine, (minus)-N-n-propylnorapomorphine [ (minus)-NPA ] and (plus or minus)-N-n-propylnorapomorphine [ (plus or minus)-NPA ] each caused stereotyped behaviour patterns in the rat which could be differentiated into two components, sniffing and repetitive head and limb movements (low intensity component) and gnawing, biting and licking (high intensity component). Low intensity components occurred at low doses of apomorphine and high intensity components at larger doses but the two components never occurred independently for (minus)-NPA or (plus or minus) NPA. Biting was the predominant effect of these agents which were shown to be at least twenty times more potent than apomorphine. The (minus)-isomer of NPA was the more potent. The two components of stereotypy were differentiated both pharmacologically (using amantadine, reserpine plus alpha-methyl-p-tyrosine and haloperidol) and by lesions placed in areas of the extrapyramidal (caudate--putamen, globus pallidus, substantia nigra) and mesolimbic (nucleus accumbens septi, tuberculum olfactorium, nucleus amygdaloideus centralis) systems. However, both sniffing and biting responses were reduced by lesions of the serotonergic raphe nuclei. The two stereotypic components were differentially induced by intracerebral injections of apomorphine and (minus)-NPA into the caudate--putamen, nucleus accumbens septi and tuberculum olfactorium. Injections into the central nucleus of the amygdala were ineffective. The degree of involvement of the different areas was shown to differ for apomorphine and (minus)-NPA, in particular the nucleus accumbens septi appeared more important for the action of (minus)-NPA and the tuberculum olfactorium for apomorphine. Intracaudate (minus)-NPA was less active than apomorphine but, generally, intracerebrally applied (minus)-NPA was twice as potent as apomorphine. Both (minus)-NPA and apomorphine caused circling behaviour in animals with asymmetric medial raphe nucleus lesions (contralateral) or unilateral lesions of the substantia nigra (ipsilateral). In these experiments (minus)-NPA was ten times more potent than apomorphine.

Amantadine↗
PubMed1975

Dyskinetic phenomena caused by the intrastriatal injection of phenylethylamine, phenylpiperazine, tetrahydroisoquinoline and tetrahydronaphthalene derivatives in the guinea pig.

The intrastriatal injection of dopamine-like compounds in the guinea pig caused the development of abnormal involuntary movements (dyskinesias) which were observed as facial grimacing, biting/gnawing/licking, severe hear and neck twisting, limb movements, whole body rocking, head and neck rocking and marked locomotor hyperactivity. With the exception of the whole body and head and neck rocking movements the dyskinesias were specifically induced by dopamine-like agents. The most conspicuous dyskinesias which followed the administration of phenylethylamine derivatives were the movements of biting/gnawing/licking and the development of marked locomotor hyperactivity. This effect was shown to be highly specific for dopamine. Tetrahydroisoquinohydroxy-1,2,3,4-tetrahydronaphthalene (ADTN) caused locomotor hyperactivity and gnawing/biting/licking dyskinesias. Of all compounds investigated 1-(3,4-dihydroxyphenyl)pierazine (DHPP) induced the most marked dyskinetic disturbances upon intrastriatal injection: intense facial grimacing, biting/gnawing/licking, head and neck twisting and limb movements were observed although the locomotor hyperactivity was absent. Of the 1-phenylpiperazine derivatives examined, dyskinetic activity was only demonstrated using compounds with a hydroxyphenyl substitution. Results are discussed in terms of the structure--activity relationships for the stimulation of different types of dopamine receptive structures within the neostriatum.

Animals↗
PubMed1975

The behavioural effects of dopamine applied intracerebrally to areas of the mesolimbic system.

The intracerebral injection technique was used to apply dopamine directly into dopamine-containing areas of the mesolimbic system, the nucleus accumbens septi, tuberculum olfactorium and nucleus amygdaloideus centralis. 200 mug dopamine injected bilaterally into the nucleus accumbens septi caused a stereotyped sniffing behaviour and hyperactivity but only a periodic hyperactivity developed after similar injections into the tuberculum olfactorium and no change in behaviour was observed following injections into the nucleus amygdaloideus centralis. After pretreatment with nialamide, the effects of intracerebral dopamine were enhanced, doses of 1-50 mug dopamine causing consistent stereotyped sniffing and a dose-dependent hyperactivity on injection into the nucleus accumbens septi or tuberculum olfactorium. The effects initiated from the nucleus accumbens septi were most marked. In addition, 50-100 mug dopamine injected into the tuberculum olfactorium caused a periodic biting behaviour. Biting was not observed after injections into the nucleus accumbens septi and, even in the presence of nialamide, injections of dopamine into the nucleus amygdaloideus centralis failed to cause any change in motor behaviour.

Animals↗
PubMed1975

N-Isopropyl derivatives of dopamine and 5,6-dihydroxy-2-aminotetralin.

Secondary and tertiary amino homologs of the title compounds have been prepared, bearing an N-isopropyl group. In peripheral evaluation, certain members of the series exhibited beta-adrenergic agonist effects of lower activity than isoproterenol. N-Methyl-N-isopropyl-5,6-dihydroxytetralin exhibited marked properties consistent with its being an alpha agonist, and it is concluded that introduction of considerable bulk about the nitrogen of a catecholamine does not a priori destroy alpha-agonist effects. The compounds qualitatively paralleled the effects of dopamine in assays based upon direct intrastriatal administration in rats, although they were less potent than dopamine.

2-Naphthylamine↗