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Biomedical subjects

P Jenner

Publications and source records attributed to P Jenner.

At least 487 records · Page 27Linked to original sources
PubMed1976

Modification of the L-DOPA reversal of reserpine akinesia by inhibitors of dopamine-beta-hydroxylase.

The effect of the dopamine-beta-hydroxylase inhibitors (DBHI) FLA-63 and U10,157 on the reversal of reserpine akinesia by L-DOPA in mice was investigated both behaviourally and by measurement of the cerebral amines dopamine and noradrenaline. Pretreatment of reserpinised animals with intraperitoneal, but not oral, FLA-63 produced hypermotility in the first hour after L-DOPA administration, compared to animals receiving L-DOPA alone. This enhanced activity was associated with an increase in dopamine, but no significant change in the noradrenaline content of whole brain. Pretreatment with both oral and intraperitoneal FLA-63 caused dose-dependent suppression of locomotor activity in the second and third hours after L-DOPA. This suppression was associated with a significant decrease in brain noradrenaline in the presence of a significant elevation in brain dopamine. Pretreatment of animals with U10,157 produced similar but less marked behavioural responses. The results do not appear to be due to stressful effects of DBHI's, causing release of corticosteroids; neither corticosterone nor beta-methasone had any significant effect on L-DOPA-induced locomotor activity in reserpinised animals, although they did increase spontaneous motor activity in normal animals. The data presented support the concept that both noradrenaline and dopamine are responsible for the gross motor activity induced by L-DOPA in the reserpinised mouse.

Adrenal Cortex Hormones↗
PubMed1976

Noradrenaline synthesis from L-DOPA in rodents and its relationship to motor activity.

Evidence has been obtained for an increase in noradrenaline (NA) turnover after administration of L0DOPA to rodents. Normal mice, and those pre-treated with either reserpine or alpha-methyl-p-tyrosine (AMPT) were given L-DOPA (200 mg/kg) plus MK 486 (alpha-methyldopahydrazine; 25 mg/kg). In all cases L-DOPA produced a rise in cerebral dopamine (DA) levels. Cerebral NA levels were increased by L-DOPA in reserpinised and AMPT-treated mice. The same dose of L-DOPA produced no change in NA in normal mice, although pre-treatment with the monoamine oxidase inhibitor pargyline (200 mg/kg) resulted in a greater rise in NA 1 hr after L-DOPA compared to animals receiving pargyline alone. This evidence suggests that NA is synthesized from- L-DOPA in all these situations. But whole brain 3-methoxy-4-hydroxyphenylglocol sulphate (MOPEG-SO4), a major metabolite of NA, measured after administration of the same dose of L-DOPA plus MK 486, was unaltered in normal and AMPT-treated rats, and was significantly decreased in reserpinised rats. However, an elevation of whole brain MOPEG-SO4 was found in reserpinised and AMPT-treated rats after a lower dose of L-DOPA (50 mg/kg). This discrepancy may be explained by high doses of L-DOPA causing inhibiton of catechol-O-methyl transferase (COMT), which is suggested by the observation that the forebrain homovanillic acid (HVA): 3,4-dihydroxyphenylacetic acid (DOPAC) ratio was significantly lower after the high dose of L-DOPA than in untreated mice. Such an inhibition would prevent formation of MOPEG-SO4. Pretreatment with dopamine-beta-hydroxylase inhibitor FLA (63(bis-(1-methyl-4-monopiperazinyl-thiocarbonyl)disulphide) prevented the increase in NA And MOPEG-SO4 formation observed following L-DOPA induced motor activity in these groups of animals suggesting the involvement of NA in the production of such behaviour.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1976

The relative importance of dopamine and noradrenaline receptor stimulation for the restoration of motor activity in reserpine or alpha-methyl-p-tyrosine pre-treated mice.

Two animal models of Parkinsonism have been employed to investigate the role of noradrenaline in the motor effects of levodopa. Pretreatment with reserpine or alpha-methyl-p-tyrosine (AMPT) causes cerebral amine depletion and reduction of motor activity, which can be reversed by levodopa. The effect of inhibitors of noradrenaline (NA) synthesis and antagonists of NA and dopamine (DA) receptors on the action of levodopa have been studied. For comparison, the effects of such treatments on apomorphine action has been investigated. Reversal of reserpine (10 mg/kg) induced akinesia in mice by levodopa (200 mg/kg) plus the peripheral decarboxylase inhibitor MK 486 (L-alpha-methyl-dopahydrazine; 25 mg/kg) was inhibited by prior administration of phenoxybenzamine (20 mg/kg), haloperidol (1 mg/kg), pimozide (1 mg/kg) or the dopamine-beta-hydroxylase inhibitor FLA-63 (bis [4-methyl-l-homopiperazinylthiocarbonyl] disulphide; 15 or 25 mg/kg). Apomorphine (2 mg/kg) reversal of reserpine akinesia was similarly inhibited by haloperidol (1 mg/kg) and pimozide (2 mg/kg) but not by phenoxybenzamine (20 mg/kg) or FLA-63 (25 mg/kg). Apomorphine (5 mg/kg) reversal of reserpine akinesia was enhanced by simultaneous administration of the noradrenergic agonist clonidine (1 mg/kg) and this effect was not significantly altered by prior administration of FLA-63. Clonidine, however, reversed the FLA-63 induced inhibition of the levodopa effect on reserpine akinesia. Levodopa reversal of akinesia induced by AMPT (200 mg/kg) was also inhibited by FLA-63, pimozide and haloperidol. Phenoxybenzamine, however, was without effect, but produced a different pattern of behaviour. Similarly, pimozide and haloperidol blocked apomorphine reversal of AMPT induced akinesia; FLA-63 was without effect but phenoxybenzamine produced marked inhibition. The results suggest that full restoration of motor activity in reserpine or AMPT pretreated animals requires stimulation of both DA and NA receptors.

Animals↗
PubMed1976

The involvement of noradrenaline in motor activity as shown by rotational behaviour after unilateral lesions of the locus coeruleus.

Unilateral electrolytic lesions in the region of the locus coeruleus in rats result in contraversive circling behaviour following the administration of systemic apomorphine or dexamphetamine. In a large group of such animals there was a very good correlation between histological damage to the locus coeruleus and the presence of such rotation. There was a progressive increase in the percentage of rats showing this drug-induced behaviour as ipsilateral cerebral cortical noradrenaline content decreased. Unilateral injections of 6-OHDA produce more selective damage to the noradrenergic locus coeruleus and result in a similar, although less marked, apomorphine- and dexamphetamine-induced rotation. Unlike the rats with electrolytic lesions of the locus coeruleus, those with 6-OHDA injections did not show an increase in ipsilateral striatal dopamine content. It seems likely that the motor asymmetry seen with lesions which involve the locus coeruleus is due to damage to its noradrenergic cells. A possible explanation of the differences between electrolytic and 6-OHDA induced lesion is that the 6-OHDA produces damage to the ventral noradrenergic bundle as well as the locus coeruleus and results in an increase in ipsilateral cerebral cortical 5-hydroxytryptamine.

Animals↗
PubMed1976

A reappraisal of the stereoselective metabolism of nicotine to nicotine-1'-N-oxide.

1. The cis and trans 1'-N-oxide metabolites of (2'R)-(+)-nicotine have the absolute configuration (1'S; 2'R) and (1'R; 2'R), respectively, and not the reverse as previously published. 2. Reinterpretation of metabolic data in the light of this reassignment reveals that N-oxidation of nicotine leads preferentially to the (1'R)-N-oxide, with little dependence on the configuration of the 2'-centre. 3. It is proposed that (2'S)-(-)-nicotine and (2'R)-(+)-nicotine bind to the same enzymic site by two distinct modes of binding; each of these modes involves the more basic centre (in this case the pyrrolidine ring) as the governing binding moiety.

Animals↗
PubMed1975

Manipulation of brain serotonin in the treatment of myoclonus.

The response of myoclonus to oral and intravenous L-5-hydroxytryptophan (5-H.T.P.) in combination with a peripheral decarboxylase inhibitor (carbidopa) and to clonazepam has been examined in 9 patients. Moderate improvement or complete cessation of myoclonus followed treatment with one or both of these regimens in 5 patients, 1 of whom also responded to the concurrent administration of L-tryptophan and a monoamineoxidase inhibitor. The remaining 4 patients were at best only slightly improved by either 5-H.T.P. or clonazepam. The responsive group consisted of 3 patients with a history of anoxia, 1 patient with non-history of severe head injury, and 1 patient with non-progressive focal myoclonus and epilepsy. This group had low levels of 5-hydroxyindole acetic acid in the lumbar cerebrospinal fluid. It is suggested that 5-H.T.P. plus carbidopa, L-tryptophan plus a monoamine-oxidase inhibitor, and clonazepam may all act by elevating brain levels of serotonin (5-H.T.) and that some human myoclonic syndromes may be specifically related to a cerebral deficiency of 5-H.T.

5-Hydroxytryptophan↗
PubMed1975

Amines, anticonvulsants, and epilepsy.

Concentrations of 5-hydroxyindoleacetic acid (5-H.I.A.T.) in cerebrospinal fluid (C.S.F.) were significantly raised in twenty-seven anticonvulsant-treated epileptic patients compared with fifteen untreated epileptics and twenty-two neurological controls. This rise was not seen until therapeutic blood-levels of phenobarbitone and diphenylhydantoin had been achieved, and was most striking in clinically intoxicated patients. Similar trends were seen in C.S.F. homovanillic acid (H.V.A). There was a close correlation between C.S.F. 5-H.I.A.A. and H.V.A., especially in the treated epileptics. These findings have implications for the antiepileptic and toxic effects of anticonvulsant drugs.

Adolescent↗
PubMed1975

Pharmacological evidence for cerebral dopamine receptor blockade by metoclopramide in rodents.

Metoclopramide antagonises apomorphine-induced stereotypy in rats (ED50 1.5 mg/kg), apomorphine reversal of reserpine-induced locomotor suppression in mice (50% inhibition produced by 17 mg/kg), and apomorphine- or amphetamine-induced turning behaviour in mice with unilateral lesions of the striatal dopaminergic nerve terminals (ED505.0 and 4.0 mg/kg respectively). Metoclopramide resembles pimozide in all these respects and appears to be a relatively potent antagonist of striatal dopamine receptors. Yet metoclopramide, in anti-emetic doses, has no effect on disability in Parkinson's disease or on the therapeutic benefit of L-Dopa and L-Dopa dyskinesias.

Animals↗
PubMed1975

The influence of piribedil (ET495) on components of locomotor activity.

Recent evidence suggests piribedil affects both cerebral NA neurones and DA neurones and receptors since it increases brain MOPEG-SO4, an observation confirmed presently. In the reserpinised mouse piribedil and apomorphine caused a reversal of akinesia, which was significantly enhanced by concurrent administration of clonidine. However, piribedil neither reduced nor increased the motor effects of apomorphine or L-DOPA in the reserpinised mouse, but slightly enhanced that of amphetamine. Phenoxybenzamine reduced the motor action of L-DOPA but had no effect on that of apomorphine or amphetamine. These results suggest piribedil has no significant NA receptor blocking or stimulating action in the reserpinised animal. They confirm the view that piribedil increases cerebral NA turnover due to a presynaptic action on NA neurones.

Amphetamine↗
PubMed1975

Folate and monoamine metabolism in epilepsy.

In 27 drug-treated epileptics there was a significant fall in serum, red cell and CSF folate levels compared with 15 untreated epileptics and 22 neurological controls. The 3 folate parameters were positively correlated with each other and negatively correlated with serum phenobarbitone, diphenylhydantoin and primidone. There was also a significant elevation of CSF 5-hydroxyindoleacetic acid (5HIAA) in the drug-treated epileptics; but this was not seen until "therapeutic" serum levels of phenobarbitone and diphenylhydantoin had been achieved and was most marked in clinically intoxicated patients. Similar trends were observed in CSF homovanillic acid (HVA). CSF 5HIAA and HVA were positively correlated with each other, especially in the drug-treated patients, in whom both amine metabolites were also negatively correlated with CSF folate. A possible relationship between folate and monoamine metabolism is discussed with particular reference to the antiepileptic and toxic effects of phenobarbitone, diphenylhydantoin and primidone.

Adolescent↗