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Biomedical subjects

C D Marsden

Publications and source records attributed to C D Marsden.

At least 505 records · Page 28Linked to original sources
PubMed1988

The D1 agonist SKF 38393 inhibits the antiparkinsonian activity of the D2 agonist LY 171555 in the MPTP-treated marmoset.

Administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to common marmosets induced persistent motor deficits. Administration of the D1 agonist SKF 38393 (2.5-20 mg/kg, i.p.) caused a dose-dependent increase of this akinesia. Administration of the D2 agonist LY 171555 (0.3 mg/kg, i.p.) reversed the motor deficits induced by MPTP treatment. Pretreatment of animals with SKF 38393 (2.5-20 mg/kg, i.p.) caused dose-dependent inhibition of the anti-parkinsonian action of LY 171555 (0.3 mg/kg i.p.). In primates SKF 38393 does not reverse motor deficits induced by MPTP and inhibits the actions of a D2-agonist.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1988

The D-1 dopamine receptor partial agonist, CY 208-243, exhibits antiparkinsonian activity in the MPTP-treated marmoset.

Administration of L-DOPA plus carbidopa, or the D-2 agonist (+)-PHNO, to MPTP-treated common marmosets caused motor hyperactivity and a reversal of the parkinsonian syndrome. In contrast, administration of the putative D-1 agonist SKF 38393 was without effect on movement or motor disability. The subsequent administration of another putative selective D-1 partial agonist CY 208-243 produced a dose-related improvement in motor activity and reversal of parkinsonian motor deficits in MPTP-treated animals. The effect of CY 208-243 was inhibited by pretreatment with the D-1 antagonist SCH 23390 and, to a lesser extent, by the D-2 antagonist sulpiride. In another group of normal drug naive marmosets, the administration of CY 208-243 produced only a small increase in motor activity. Following treatment with MPTP and without other drug administration, administration of CY 208-243 produced a marked reversal of motor deficits and locomotor hyperactivity. Thus, CY 208-243, suggested to be a partial D-1 agonist exhibits antiparkinsonian activity in MPTP-treated marmosets which does not require prior or concurrent exposure to D-2 agonists.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1988

Monoamine oxidase activity and distribution in marmoset brain: implications for MPTP toxicity.

This study describes the histochemical localisation of monoamine oxidase (MAO) in marmoset brain. No MAO A staining was observed but MAO B was found in many areas, with medium intensity of staining in the substantia nigra, and high intensity staining in the striatum and nucleus accumbens, among other regions. The high activity in the nigrostriatal tract, compared with the rat, may partially explain the greater sensitivity of the marmoset to MPTP toxicity. As in the rat, high activity was present in the raphe nuclei. However, unlike the rat, no enrichment of MAO B was observed in blood vessels or ventricular linings.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1988

Bladder hyperreflexia induced in marmosets by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.

In marmosets, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) causes degeneration of the cell bodies of the substantia nigra and the animals subsequently develop parkinsonian symptoms. Cystometrograms obtained from such animals while under pentobarbitone anaesthesia, showed their bladders to be hyperreflexic when compared to those of normal animals of the same age (less than 2 years). Bladder hyperreflexia is present in many parkinsonian patients and is difficult to treat, partly because it is made worse by dopaminergic agents. This is the first demonstration of an effect of MPTP on this type of peripheral function. It suggests the suitability of MPTP-treated marmosets for studying the mechanisms by which a loss of nigrostriatal dopamine leads to bladder hyperreflexia and for devising pharmacological strategies which may be of therapeutic value in the clinic.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1988

The effect of carbidopa on plasma and muscle levels of L-dopa, dopamine, and their metabolites following L-dopa administration to rats.

Administration of L-dopa (L-3,4-dihydroxyphenylalanine) (200 mg/kg p.o.) to rats produced elevated plasma and muscle concentrations of both L-dopa and 3-O-methyldopa (3-OMD). This effect was potentiated by simultaneous administration of carbidopa (25 mg/kg p.o.). Both L-dopa and 3-OMD accumulated in muscle after administration of L-dopa with or without carbidopa. Elevated dopamine levels were detected in both muscle and plasma after treatment with L-dopa alone. Concurrent administration of carbidopa only diminished dopamine levels in plasma, and the duration of raised dopamine levels in muscle was increased. Carbidopa administration had no effect on the elevated plasma concentrations of 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) caused by L-dopa administration. In muscle, carbidopa treatment tended to prolong the duration of raised metabolite levels. Muscle appears to accumulate L-dopa at a site where decarboxylation is not totally prevented by concurrent carbidopa administration, and where dopamine is not degraded as actively as in other tissues. The muscle sink for L-dopa may influence the plasma profile of the amino acid, which has implications for the therapeutic response to L-dopa in Parkinson's disease.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1988

An investigation of the phenomenon of "set" in Parkinson's disease.

It has been suggested that patients with Parkinson's disease have a basic deficit in shifting "set." Previous authors have used this hypothesis as an explanation for deficits on a range of cognitive tasks. An experiment was conducted to investigate this phenomenon. A reaction time paradigm was used in which the subject had to make left-right decisions under two stimulus conditions. Both patients and controls showed a facilitation in performance with repetition within each block of trials, followed by a deterioration in performance when the stimulus type switched. Furthermore, the shapes of the reaction-time functions were equivalent in both groups, suggesting that the patients had no deficit in either switching or establishing set in this task. In contrast, they were impaired on the Wisconsin Card Sorting Test. This dissociation suggests that patients with Parkinson's disease do not have a generalized deficit in switching set. It is suggested that patients with Parkinson's disease are impaired on tasks where they have to rely upon internal control for the regulation of behaviour, but are relatively unimpaired on tasks where external cues are available.

Aged↗
PubMed1988

Writer's cramp: not associated with anxiety.

Many authors have commented on an association between writer's cramp and anxiety and some view it as a form of anxiety disorder. This study describes 22 patients with writer's cramp who were recruited from a neurology clinic. Clinical examination found little evidence of generalized anxiety or of anxiety specific to the writing situation. Additionally, the subjects' scores on the Crown-Crisp Experiential Index, which contains several anxiety subscales, did not differ significantly from those of a matched normal control group. Writer's cramp differs from the anxiety disorders in two other respects: it has a later onset (mean in the 30s) and the male preponderance is much greater than in any anxiety disorder, even social phobia.

Adolescent↗
PubMed1988

Pathological report of four patients presenting with cranial dystonias.

Secondary dystonias and experimental models of dystonia suggest that mechanisms responsible for primary dystonias may lie in the basal ganglia or brainstem. A histological study has been done in three patients with cranial dystonia (blepharospasm with oromandibular dystonia in two, blepharospasm alone in one), and one patient with craniocervical dystonia (oromandibular dystonia with retrocollis). In the patient with blepharospasm alone, an angioma, 0.5 mm in diameter, was found in the dorsal pons at the site of the central tegmental tract, confirming that some patients presenting with primary dystonias may have longstanding lesions in the brainstem. In the three other cases, the striatum, pallidum, thalamus, and brainstem were examined and cell populations in the putamen, substantia nigra, and inferior olives were compared with age-matched controls, but no significant abnormality was found.

Aged↗
PubMed1988

Receptor changes during chronic dopaminergic stimulation.

The underlying cause of the long term complications of L-DOPA or dopamine agonist therapy in Parkinson's disease remains unknown. Previous studies of repeated administration of L-DOPA or bromocriptine to rodents have shown increases, decreases or no change in brain dopaminergic activity. For this reason we have re-examined the effects of chronic L-DOPA or dopamine agonist administration on brain dopamine receptor function in rats. Repeated intraperitoneal administration of L-DOPA to rats for 21 days followed by 3 days drug withdrawal caused an enhancement of apomorphine-induced stereotypy but no apparent alteration in striatal dopamine receptor numbers or affinity (as judged by 3H-spiperone; 3H-NPA and 3H-piflutixol binding). Chronic oral administration of L-DOPA plus carbidopa to rats for one year was without effect on apomorphine-induced stereotypy or striatal D-2 dopamine receptors. Similarly, no effects were observed on striatal dopamine function following one year's administration of bromocriptine. Pergolide produced an enhancement of apomorphine-induced stereotypy but a decrease in D-2 receptor density as judged by 3H-spiperone binding. In rats with a unilateral 6-OHDA lesion of the medial forebrain bundle the oral administration of L-DOPA plus carbidopa for 4 weeks, followed by 4 days withdrawal, enhanced the rate of apomorphine-induced contraversive rotation. It appears difficult, at least in rats, to manipulate striatal dopamine receptors with L-DOPA or dopamine agonist drugs. An enhancement of motor behaviour can occur in the presence of no change or a decrease in dopamine receptor numbers identified by in vitro ligand binding to tissue homogenates.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1988

Continuous subcutaneous lisuride infusions in Parkinson's disease.

Thirteen patients with idiopathic Parkinson's disease and "on-off" fluctuations on oral levodopa plus dopa decarboxylase inhibitor (DDI) were treated with continuous (24 hour) subcutaneous lisuride infusions together with a reduced dose of levodopa (plus DDI). An improvement in motor performance was seen in 10 patients, with a mean increase in percentage of waking time spent "on" of 32 per cent (range 13-59 percent). However, adverse effects were common, especially psychiatric effects, leading to treatment withdrawal in 11 of 13 subjects after a mean of 40 days' treatment. Continuous lisuride infusion together with a small dose of levodopa (plus DDI) are effective treatment for "on-off" fluctuations in Parkinson's disease, but the frequency of adverse effects limits the number of patients who can be treated successfully with this technique.

Adult↗
PubMed1988

The pharmacological characterisation of pilocarpine-induced purposeless chewing behaviour in the rat.

Purposeless chewing in rats was induced by the acute administration of the cholinergic agonist pilocarpine or by physostigmine. Pilocarpine-induced chewing was antagonised by the centrally acting anticholinergic drugs scopolamine, benzhexol and secoverine, but not by the peripherally acting anticholinergic drug methylscopolamine. Both benzhexol and secoverine caused dose-dependent inhibition of pilocarpine-induced chewing. The D-2 antagonist sulpiride and the D-1 antagonist SCH 23390 did not inhibit pilocarpine-induced chewing. The non-selective neuroleptics pimozide, trifluoperazine and thioridazine also were inactive. In contrast, clozapine caused a dose-related inhibition of pilocarpine-induced chewing. The alpha-1 antagonist prazosin, the alpha-2 antagonist idazoxan, the beta-antagonists propranolol and metoprolol and the H-1 antagonist mepyramine did not reduce pilocarpine-induced chewing. Purposeless chewing behaviour induced by pilocarpine was reduced in a dose-related manner by the administration of the 5-HT antagonists methiothepin and mianserin, but not by spiperone or ketanserin. These data confirm that pilocarpine-induced chewing behaviour in the rat is a model of central cholinergic activity, but suggest that a serotonergic component may be involved in the mediation of this behaviour.

Adrenergic alpha-Antagonists↗
PubMed1988

The effect of long-term treatment with amine-depleting drugs or chlorpromazine on alpha-adrenoreceptors and 5-HT2 receptors in the brain of the rat.

The effect of chlorpromazine, oxypertine, tetrabenazine or reserpine on alpha-adrenoreceptors and 5-HT2 receptors in the brain of the rat was studied both in vitro and after the administration to animals for up to 12 months. In vitro, chlorpromazine and oxypertine potently displaced the specific binding of [3H]WB 4101 to alpha 1 adrenoreceptors in the cortex and of [3H]ketanserin to 5-HT2 receptors in the frontal cortex. Both drugs were moderately effective in displacing the specific binding of [3H]clonidine from cortical alpha 2-adrenoreceptors. Tetrabenazine only weakly displaced the specific binding of [3H]WB 4101, [3H] clonidine and [3H]ketanserin. The incorporation of reserpine into tissue incubates had little effect on the binding of any of these ligands. Administration of chlorpromazine (33-36 mg/kg/day) to rats for up to 12 months reduced the number of specific binding sites (Bmax) for [3H]ketanserin in the frontal cortex, but did not alter the specific binding of [3H]WB 4101 or specific [3H]clonidine to cortical membranes. In contrast, treatment with oxypertine (6.3-7.3 mg/kg/day), tetrabenazine (6.0-6.7 mg/kg/day) or reserpine (0.28-0.30 mg/kg/day) increased the Bmax for the specific binding of [3H]WB 4101, but did not alter the specific binding of [3H]clonidine or [3H]ketanserin. Oxypertine resembles chlorpromazine in its ability to interact with alpha-adrenoreceptors and 5-HT2 receptors in brain. Tetrabenazine and reserpine have few direct actions on post-synaptic monoamine receptors. However, on long-term administration, oxypertine, like tetrabenazine and reserpine, predominantly altered alpha 1-adrenoreceptors, whereas chlorpromazine influenced the population of 5-HT2 receptors.

Animals↗