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Biomedical subjects

R J Naylor

Publications and source records attributed to R J Naylor.

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

Characterisation of the mechanisms for hyperactivity induction from the nucleus accumbens by phenylethylamine derivatives.

A wide variety of phenylethylamine derivatives were injected bilaterally into the nucleus accumbens of rat following a nialamide pretreatment and hyperactivity was recorded. 2-Phenylethylamine was shown to induce a low intensity hyperactivity but the introduction of hydroxyl functions on to the phenyl ring at the 3- and/or 4-positions enhanced activity and m- and p-tyramine and dopamine each caused marked hyperactivity in the 3.4-25 mug dosage range. Methylation of one hydroxyl function reduced activity (3-methoxy-4-hydroxy- and 3-hydroxy-4-methoxy-phenylethylamine); 2(3,4-methylenedioxyphenyl) ethylamine was inactive. Agents with substitution of the side chain, such as noradreline, d-amphetamine and alpha-methyldopamine, were all shown to induce marked hyperactivity at doses of 1.6-25 mug. Alterations in the chain length markedly reduced activity (4-(3,4-dihydroxyphenyl) butylamine, 3,4-dihydroxybenzylamine). A variety of N-substituted compounds were shown to be potent inducers of hyperactivity from the nucleus accumbens (adrenaline, epinine, N-ethyldopamine, N-isopropyl-dopamine, isoprenaline) (0.2-25 mug). However, N-methyl-N-isopropyldopamine showed only weak activity and N,N-dimethyldopamine was inactive. All hyperactivity effects were shown to be dose-dependent. The hyperactivities induced by dopamine, noradrenaline and isoprenaline were each inhibited in a dose-dependent manner by subsequent injections of fluphenazine (1.25-25 mug) into the nucleus accumbens, although no reductions were recorded following similar injections of saline, solvent, 2% procaine, 50 mug propranolol or 50 mug piperoxan.

Animals↗
PubMed1976

Dissociation of stereotyped biting responses and oro-bucco-lingual dyskinesias.

A comparison was made of the doses of neuroleptic and related agents required to inhibit the stereotyped biting/gnawing/licking response induced in the guinea pig by systemically administered apomorphine and d-amphetamine or by dopamine administered bilaterally into the striatum. Haloperidol. lenperone, fluphenazine (0.5-8 mg/kg i.p.) and fluspirilene (0.125-8 mg/kg i.p.) each inhibited the stereotyped behaviour induced by apomorphine and amphetamine but doses up to 16 mg/kg i.p. failed to modify the dyskinesias induced by intrastriatal dopamine. Pimozide similarly abolished the stereotypies (0.125-8 mg/kg i.p.) but a larger dose (16 mg/kg i.p.) also abolished the dopamine-induced dyskinesias. However, oxiperomide and spiroxatrine were both shown to possess marked anti-dyskinetic (1-2 mg/kg i.p.) as well as anti-stereotypic (0.25-5 mg/kg i.p.) properties. Thioridazine, clothiapine, clozapine, sulpiride and metoclopramide were generally inactive against the stereotypies and dyskinesias although 1.25-5 mg/kg s.c. morphine effectively abolished stereotyped behaviour and the dopamine-induced dyskinesias were inhibited in a small proportion of animals. It is suggested that the dopamine mechanisms involved with stereotypy induction differ from those activated by intrastriatally administered dopamine to induce abnormal oro-facial movements, and that, since only the effects of intrastriatal dopamine showed the same relative degree of resistance to neuroleptic inhibition as clinical dyskinesias, that this may be more applicable to the clinical situation than the stereotypy model.

Animals↗
PubMed1976

Hyperactivity induced by tetrahydroisoquinoline derivatives injected into the nucleus accumbens.

Several derivatives of tetrahydroisoquinoline were injected bilaterally into the nucleus accumbens of rat 2 h after a nialamide pretreatment and activity recorded in cages fitted with photocells. 1,2,3,4-Tetrahydroisoquinoline, 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline, 1,2,3,4-tetrahydro-6,7-dihydroxy-1-(3,4-dihydroxybenzyl)-isoquinoline (tetrahydropapaveroline) and 6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline caused virtually no change in locomotor activity and 2-methyl-1,2,3,4-tetrahydroisoquinoline and 2-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline caused only modest hyperactivity responses. However, 3-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline and 3-methyl-6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinoline were both shown to markedly increase activity in a dose-dependent manner. Of these two compounds, the 3-methyl-6,7-methylenedioxyderivatives was most active and equalled the effectiveness of dopamine. The responses to dopamine and to 3-methyl-6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinoline were both threshold at 3.125 mug and maximum at 50 mug. Both effects developed within 1-2 h and persisted for at least 6 h. The hyperactivity induced by dopamine was antagonised in a dose-dependent manner by haloperidol: propranolol and aceperone were without effect. Similar results were obtained for these blocking agents against the responses to 3-methyl-6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinoline and 2-methyl-1,2,3,4-tetrahydroisoquinoline but aceperone and propranolol, in addition to haloperidol, were shown to inhibit the hyperactivity induced by 3-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline.

Animals↗
PubMed1976

Non-specific supersensitivity of striatal dopamine receptors after 6-hydroxydopamine lesion of the nigrostriatal pathway.

6-Hydroxydopamine (6-OHDA) was injected unilaterally into the area of the ascending dopamine pathways in the lateral hypothalamus. Rats immediately developed spontaneous ipsilateral circling which was enhanced by d-amphetamine (0.63-2.5 mg/kg i.p.) and reversed to a contralateral response by apomorphine (0.015-0.5 mg/kg s.c.). These effects were maximal by the 8th postoperative day. At a time when circling responses were established and biochemical determinations showed striatal dopamine levels to be reduced by at least 80% (limbic dopamine depleted by 60%, telencephalic noradrenaline by 35% but no reductions in 5-hydroxytryptamine), the injection of dopamine (50, 100 mug) and apomorphine (12.5, 25 mug) into the striatum ipsilateral to the 6-OHDA lesion induced contralateral circling/asymmetries. These effects were of lower intensity or absent in non-lesioned rats but a consistent increase in potency of dopamine after 6-OHDA could not be demonstrated. However, similar injections of 5-hydroxytryptamine and noradrenaline, which are completely inactive in normal rats, caused more marked contralateral asymmetries/circling at lower intrastriatal doses than dopamine (5-hydroxytryptamine 25-100 mug, noradrenaline 6.25-100 mug). Dyskinesias of the contralateral forelimb were induced by unilateral intrastriatal dopamine (100 mug) in a small proportion of non-lesioned rats: the effects were enhanced when dopamine (50-100 mug) was injected into the striatum ipsilateral to a 6-OHDA lesion. Both potency and intensity of effect were enhanced. Noradrenaline (25-100 mug) also induced contralateral dyskinesias in the 6-OHDA-lesioned rats although similar injections were inactive in non-lesioned rats. 5-Hydroxytryptamine was inactive in this effect in both groups of rats. It is suggested that after 6-OHDA lesion of the nigrostriatal pathway striatal dopamine receptors may change both their sensitivity and specificity.

Animals↗
PubMed1976

The importance of 5-hydroxytryptamine for the induction of harmine tremor and its antagonism by dopaminergic agonists assessed by lesions of the midbrain raphe nuclei.

The brain lesion technique was used to destroy the ascending 5-hydroxytryptamine (5-HT) system at its cell bodies in the dorsal and medial raphe nuclei in order to assess the importance of 5-HT for the induction of harmine tremor and its antagonism by the dopaminergic agonists, L-DOPA, apomorphine and d-amphetamine. Lesions of the medial or dorsal raphe nucleus reduced the intensity of harmine tremor. The remaining tremor was generally resistant to further reduction by the dopaminergic agonists. 5-hydroxytryptophan was shown to enhance tremor: this effect was reduced both by the raphe lesions and by treatment with L-DOPA. The data are discussed in terms of the possible relationship between 5-HT and dopamine.

Alkaloids↗
PubMed1976

Antagonism of the hyperactivity induced by dopamine applied intracerebrally to the nucleus accumbens septi by typical neuroleptics and by clozapine, sulpiride and thioridazine.

Dopamine administered intracerebrally to the nucleus accumbens septi was shown to induce a dose-dependent hyperactivity following pretreatment with nialamide. This effect was optimum following the injection of 50 mug dopamine. The hyperactivity induced by this dose of dopamine was inhibited by the i.p. injection of both the typical neuroleptic agents, haloperidol, fluphenazine, pimozide and clothiapine (0.05--0.5 mg/kg i.p.), and the atypical neuroleptics clozapine, sulpiride and thioridazine (0.5--20 mg/kg i.p.) although, generally, the doses required ot the latter were in the order of 20--100 times those of the typical agents to produce an equivalent effect. In contrast, cataleptic doses of metoclopramide (10--30 mg/kg i.p.) failed to reduce the dopamine-induced hyperactivity: aceperone and propranolol were similarly ineffective. However, inhibition of hyperactivity was recorded following the peripheral administration of the antimanic drug, IB503. It is suggested that the ability of a drug to antagonise the hyperactivity induced by the injection of dopamine into the nucleus accumbens septi may be of value in the detection of antipsychotic activity.

Animals↗
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↗