Biomedical subjects

C D Marsden

Publications and source records attributed to C D Marsden.

At least 721 records · Page 40Linked to original sources

PubMed1984

Interpretation of changes in apomorphine-induced stereotyped behaviour in rats receiving continuous administration of trifluorperazine for 15 months.

Rats treated continuously with trifluoperazine dihydrochloride (4.4-4.9 mg/kg per day) for 15 months showed an exaggerated stereotyped response to large doses of apomorphine (1.0 mg/kg, s.c.), but inhibition of stereotyped behaviour by a small dose of apomorphine (0.125 mg/kg, s.c.) as compared to responses obtained in age-matched control animals. Apomorphine (0.03-1.0 mg/kg, s.c.) produced more hyperactivity in trifluoperazine-treated rats than in control animals. After withdrawal of the drug for a period of 2 weeks or more, the stereotyped responses to all doses of apomorphine (0.0625-0.5 mg/kg, s.c.) were exaggerated in animals treated with trifluoperazine compared with age-matched control rats. Acute administration of trifluoperazine (4.5 mg/kg, p.o., 3 hr previously) to animals withdrawn from trifluoperazine abolished the stereotyped behaviour induced by a small dose of apomorphine (0.125 mg/kg) but a maximal response still was obtained with large doses (1.0 mg/kg). In contrast, acute challenge with trifluoperazine (4.5 mg/kg, p.o.) in control animals inhibited the stereotyped behaviour at virtually all doses of apomorphine, as compared with the responses to apomorphine in both animals withdrawn from trifluoperazine, given the same treatment, and naive control rats. Administration of trifluoperazine (0.28 and 0.56 mg/kg, p.o.) inhibited stereotypy induced by small doses of apomorphine (0.125 mg/kg, s.c.) in control animals but the response in animals withdrawn from trifluoperazine was exaggerated. Larger doses of trifluoperazine (1.125-4.5 mg/kg) totally inhibited apomorphine-induced (0.125 mg/kg, s.c.) stereotypy in both groups. These findings do not support the concept of separate mechanisms controlling low grade and high grade stereotyped behaviour during chronic treatment with neuroleptics.

Animals↗

PubMed1984

Behavioural and biochemical alterations in the function of dopamine receptors following repeated administration of L-DOPA to rats.

Rats received L-DOPA (40 or 200 mg/kg, i.p.) for 14 days, followed by a 3 day withdrawal period. Spontaneous locomotor activity was not altered by repeated administration of L-DOPA. Rats treated with L-DOPA (200 mg/kg) showed identical locomotor hypoactivity in response to small doses of apomorphine when compared to saline-treated control animals. However, hyperactivity induced by large doses of apomorphine was reduced by prior treatment with L-DOPA (200 mg/kg). The smaller dose of L-DOPA (40 mg/kg) did not alter the locomotion induced by apomorphine. Stereotyped behaviour induced by apomorphine was enhanced by prior treatment with both 40 and 200 mg/kg of L-DOPA. The treatment regimes with L-DOPA had no effect on the concentrations of apomorphine in the striatum. Administration of L-DOPA (40 or 200 mg/kg) followed by withdrawal for 3 days, had no effect on the concentrations of dopamine, homovanillic acid (HVA) or 3,4-dihydroxyphenylacetic acid (DOPAC) in the striatum. The Bmax and KD for the binding of [3H]spiperone, [3H]N,n-propylnorapomorphine (NPA) and [3H] piflutixol in the striatum was not altered by drug treatment. Similarly, the formation of dopamine-stimulated cyclic AMP in homogenates of striatum was unaltered by repeated administration of L-DOPA. Repeated administration of L-DOPA for 14 days in the rat appears to result in altered behaviour mediated by dopamine in the absence of any apparent change in the function of dopamine receptors in the striatum.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1984

Alterations in different populations of striatal dopamine receptors produced by 18 months continuous administration of cis- or trans-flupenthixol to rats.

Administration of cis-flupenthixol (0.8-1.2 mg/kg per day) for 18 months enhanced stereotyped behaviour induced by apomorphine, bromocriptine and lergotrile, but not that induced by amphetamine or lisuride. Catalepsy induced by acute administration of haloperidol, trifluoperazine or cis-flupenthixol was reduced by continuous chronic intake of cis-flupenthixol. The number (Bmax) and dissociation constant (KD) of specific [3H]spiperone binding sites on striatal membranes was increased by chronic administration of cis-flupenthixol, but not trans-flupenthixol. In contrast, the Bmax and KD for specific binding of [3H]N,n-propylnorapomorphine were decreased by administration of cis-flupenthixol compared to the effect of the trans-isomer. Specific binding of [3H]piflutixol was unaffected by chronic administration of cis- or trans-flupenthixol, but chronic administration of cis-flupenthixol enhanced stimulation by dopamine of the activity of striatal adenylate cyclase. As a result of chronic continuous administration of cis-flupenthixol dopamine receptors in the striatum appeared to be supersensitive to most dopamine agonists but sub-sensitive to dopamine antagonists. This was reflected by increased numbers of D-2 antagonist receptor sites of decreased affinity, but by a decreased number of agonist sites of higher affinity. The D-1 recognition sites appeared to be unaltered, but activity of adenylate cyclase stimulated by dopamine was enhanced, suggesting post-junctional changes. The D-2 receptors appear to be primarily concerned with altered function of dopamine receptors.

Adenylyl Cyclases↗

PubMed1984

A comparison of the effects of acute and one year's continuous neuroleptic treatment on the release of [3H]glutamate and [3H]acetylcholine from rat striatal slices.

The effect of neuroleptic drugs administered acutely or continuously for 1 year on the release of [3H]glutamate and [3H]acetylcholine from striatal slices in vitro has been compared. Acute in vivo administration of haloperidol, trifluoperazine and clozapine increased the potassium-evoked release of [3H]acetylcholine from striatal slices in a dose-dependent fashion, whereas sulpiride was without effect. None of the neuroleptics given acutely had any effect on the potassium-evoked striatal release of [3H]glutamate. Potassium-evoked striatal release of [3H]acetylcholine in animals receiving 1 year's continuous administration of haloperidol, trifluoperazine or sulpiride was no different from that in age-matched control animals, but was less than controls in animals receiving clozapine for 1 year. All drugs caused a decrease in potassium-evoked striatal [3H]glutamate release following drug administration for 1 year compared to age-matched controls. The reversal of the acute action of neuroleptic drugs on striatal [3H]acetylcholine and [3H]glutamate release is consistent with a functional increase in striatal dopamine transmission following long-term neuroleptic treatment.

Acetylcholine↗

PubMed1984

Function of the basal ganglia as revealed by cognitive and motor disorders in Parkinson's disease.

Early Parkinson's disease is taken to be the best human model of disordered basal ganglia function. An experimental study in Parkinsonians with swings in motor response to drug treatment suggests that general cognition is not controlled by dopamine mediated striatal activity. The variety of motor disorders in Parkinson's disease cannot be explained by simple concepts. Although Parkinsonians cannot execute fast ballistic movements, an experimental study shows that they can adopt a predictive motor control strategy. It is argued that simple motor programs are not grossly disturbed in Parkinson's disease. It is concluded that Parkinsonians cannot automatically execute learned motor plans.

Basal Ganglia↗

PubMed1984

A double-blind trial of clonazepam in benign essential tremor.

Clonazepam has been reported to be of some value in the treatment of benign essential tremor in open trials. The efficacy of clonazepam was evaluated in a double-blind placebo-controlled study using up to 4 mg/day. By a variety of objective measures, clonazepam was not found to be an effective form of therapy.

Adult↗

PubMed1984

L-Dopa methyl ester--a candidate for chronic systemic delivery of L-Dopa in Parkinson's disease.

Continuous intravenous infusions of L-Dopa as a treatment for response swings in Parkinson's disease are limited by the insolubility and acidity of L-Dopa. Its methyl ester is a soluble neutral derivative that might be of benefit to these patients, and is examined in the present study in behavioural and biochemical animal models. On intraperitoneal or subcutaneous administration to mice L-Dopa methyl ester was equivalent to L-Dopa in reversing reserpine-induced akinesia and producing contraversive circling behaviour in rats with a 6-hydroxydopamine lesion of the medial forebrain bundle. On oral administration the methyl ester was more active. The administration of L-Dopa or the methyl ester produced equivalent changes in striatal and mesolimbic dopamine, homovanillic acid, and 3,4-dihydroxyphenylacetic acid metabolite levels. We suggest that systemic or subcutaneous infusion of L-Dopa methyl ester to patients who experience response fluctuations may provide a means of maintaining mobility.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1984

Multiple dopamine receptors in brain and the pharmacological action of substituted benzamide drugs.

Neuroleptic drugs are believed to control schizophrenia by blocking brain dopamine receptors, although most act also on a number of other neuronal systems in brain. Substituted benzamide drugs in general, are more specific for the dopamine system. Brain dopamine receptors, however, are not a single entity. They can be divided on the basis of their linkage to adenylate cyclase. Substituted benzamide drugs are selective antagonists of the adenylate cyclase independent dopamine receptor population. They may be selective antagonists of one sub-population of these adenylate cyclase independent receptors, for unlike typical neuroleptics the receptor interaction of substituted benzamide drugs with brain dopamine receptors depends upon the presence of sodium ions. The specificity of substituted benzamide drugs for brain dopamine receptors is reflected in their behavioural profile. Typical substituted benzamide drugs do not cause catalepsy and, in general, only weakly inhibit motor phenomena. This inability to act in vivo cannot be entirely explained by the poor penetration of these drugs into brain. The unique properties of the substituted benzamide drugs might explain their clinical value in the treatment of schizophrenia and in the treatment of dyskinesias.

Adenylyl Cyclases↗

PubMed1984

Dopamine receptor binding sites in the rat superior colliculus.

Following intravenous administration of [3H]spiperone or [3H]N,n-propylnorapomorphine (NPA) to rats, radioactivity derived from the ligands accumulated in the striatum and superior colliculus when compared with cerebellar levels. The accumulation of [3H]spiperone in both areas was prevented by intraperitoneal administration of (+)-butaclamol, haloperidol and sulpiride but not by (-)-butaclamol, cinanserin, propranolol or prazosin. The accumulation of [3H]NPA was prevented by administration of (+)-butaclamol, haloperidol and apomorphine but not by (-)-butaclamol. In in-vitro experiments, membrane preparations from the superior colliculus showed a small number of specific binding sites for both [3H]spiperone and [3H]NPA. The dissociation constant (KD) for [3H]NPA was not different from that for striatal preparations but that for [3H]spiperone was 10-fold higher. We conclude that dopamine receptors may be present within the superior colliculus.

Animals↗

PubMed1984

Reciprocal inhibition between the muscles of the human forearm.

Peripheral and central mechanisms of reciprocal inhibition between antagonist muscles in the forearm have been studied in ten human subjects. H reflexes were evoked in flexor muscles by stimulating the median nerve with single shocks at around motor threshold intensity. Peripheral inhibition of the flexor H reflex was produced by motor threshold stimulation with a single shock of the radial nerve supplying the extensor muscles. The conditioning radial nerve stimulus produced inhibition of the flexor H reflex consisting of three phases. In some individuals, an H reflex could be evoked in extensor muscles of the forearm. Stimulation of the median nerve produced inhibition of the extensor H reflex with a similar time course to that from extensors to flexors. The first phase of inhibition was apparent when the test median nerve shock was given from 1 ms before to 3 ms after the conditioning radial nerve shock. It was abrupt in onset and short in duration and could be evoked with a conditioning stimulus intensity as low as 0.75 X motor threshold. The second and third phases of inhibition were evident when the conditioning radial nerve stimulus preceded the median nerve test shock by 5 to 50, and 50 to 500 ms respectively. The characteristics of these later phases of inhibition are to be the subject of a separate report. The difference in timing of the peak initial short-latency inhibition from extensor to flexor and from flexor to extensor muscles enabled an estimate to be made of the central synaptic delay of the inhibitory process. This method yielded a central delay of 0.95 ms in excess of that of the H reflex. We conclude that the first phase of inhibition is mediated via large group I afferents acting through a single inhibitory interneurone . Central inhibition of the flexor H reflex was demonstrated with the radial nerve anaesthetized by injection of local anaesthetic at the elbow. Subjects were asked to try to contract the paralysed extensor muscles. Under this condition, attempted voluntary wrist extension inhibited the flexor H reflex even though no movement occurred. A shock was delivered to the radial nerve at a site proximal to the anaesthetic block. When the shock was applied in conjunction with an attempted voluntary contraction of the paralysed extensor muscles, the depth of inhibition was greater than that predicted from the effect of either a shock or a willed contraction acting independently.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗

PubMed1984

On the significance of giant somatosensory evoked potentials in cortical myoclonus.

Four patients with cortical myoclonus were studied. All had reflex muscle jerking and grossly enlarged somatosensory evoked responses (SEPs) following electrical stimulation of the digital nerves. In addition, three of the patients had spontaneous or action-induced myoclonus. Back-averaging the EEG from these spontaneous muscle jerks showed a large positive wave over the contralateral somatomotor cortex which preceded the jerk by about 20 ms. Administration of lisuride (0.1 mg iv) reduced the severity of the reflex and spontaneous myoclonus, but had no effect on, or increased the size of the SEP. Two of the patients also received 1 mg clonazepam iv. As with lisuride, the severity of myoclonic jerking was reduced although the size of the SEP was increased. It is concluded that the usual association between giant SEPs and reflex muscle jerking can be abolished by acute administration of lisuride and clonazepam in patients with cortical myoclonus.

Adult↗

PubMed1984

The treatment of severe dystonia in children and adults.

Twenty-three children (aged less than 18 years) and 17 adults with severe widespread dystonia were treated with high doses of benzhexol (up to 130 mg daily introduced slowly over many weeks). Children tolerated higher doses (median 30 mg/day) than adults (median 20 mg/day). 52% of the children gained useful benefit, many (43%) without unwanted side effects. Such an approach was less successful in adults; 41% gained benefit, but only 35% had no side effects. Twelve adults with severe axial dystonia, and two children with life-threatening generalised dystonia were treated with a combination of a low constant dose of tetrabenazine to which were added pimozide and benzhexol as necessary. The dose of tetrabenazine was aimed at 75 mg daily; pimozide was increased (6 to 25 mg/day) until the dystonia was relieved or Parkinsonism and other side-effects prevented further increments; if necessary benzhexol (6 to 30 mg/day) then was added to control side-effects and to provide additional benefit. 75% of the adults with severe axial dystonia, and one of the two children with life threatening generalised dystonia gained useful benefit from this regime. It is concluded that high dose benzhexol is the present first treatment of choice for children with severe dystonia, and is worth a try in adults but with less expectation of success. When benzhexol treatment alone fails in adults with severe disabling axial dystonia, or in children with life-threatening generalised dystonia, combined therapy with tetrabenazine, pimozide and benzhexol may give valuable symptomatic relief.

Adolescent↗

PubMed1984

Patients with Parkinson's disease can employ a predictive motor strategy.

We have tested the hypothesis that predictive motor behaviour is abnormal in Parkinson's disease. In the first experiment elbow movements were performed to track a moving spot on an oscilloscope screen. The performance of 12 patients with Parkinson's disease and eight age-matched control subjects was measured when tracking a repeated pattern under two conditions. In the first condition subjects were not aware of the repetitive nature of the tracking task whilst in the second condition they were. For both groups tracking error and tracking lag were less when aware of the repetition. In the second experiment wrist movements were studied. Five age-matched controls were compared with five patients, studied on and off drugs. In this experiment the performance tracking a repeated pattern was compared to that tracking unpredictable patterns. Tracking lags were reduced to very low values (less than 20 ms) in response to the repeated pattern for both groups. This was true even when the patients were relatively immobile off drugs. We conclude that patients with Parkinson's disease are capable of predictive motor behaviour although such a strategy does not always confer as great an advantage in reducing tracking error in patients compared with control subjects.

Adult↗

PubMed1984

Familial paroxysmal dystonia induced by exercise.

A mother and daughter are described with paroxysmal dystonia induced by exercise. As has been reported in one previous family, the attacks were provoked in the lower limbs by prolonged exertion but not by sudden movements. It was also found that involuntary movements could be induced focally in any limb either by local exercise or by sensory stimulation restricted to that limb.

Adolescent↗

PubMed1984

Alterations in cognitive performance and affect-arousal state during fluctuations in motor function in Parkinson's disease.

Sixteen patients with idiopathic Parkinson's disease were selected who were all showing severe fluctuations in motor function ("on-off" phenomenon). Measures of cognitive function and of subjective affect/arousal state were taken on two occasions, once when "on" and once when "off". Twenty-five matched normal controls were also assessed on the same measures. Results revealed, on the average, a drop in cognitive function plus an adverse swing in affect/arousal state, in the patient group in the "off" condition, compared to the levels when "on". Analysis of the data suggested that the main factor associated with cognitive function when "off" was not the severity of disability but the level of affect/arousal. The fluctuations in cognitive function found tended to be mild relative to the severe changes in motor ability, and were present in only a proportion of patients.

Adult↗

PubMed1984

Mini-mental state examination in neurological patients.

The Mini-Mental State examination has been found to be a quick and valuable test for simple bedside screening, and for serial assessment of cognitive function in a population of 126 neurological patients. Amongst those with cognitive impairment, there was a close relation between the Mini-Mental State examination and the conventional Weschler Adult Intelligence Scale (WAIS). However, the Mini-Mental test was not a sensitive indicator of focal versus diffuse hemisphere disease. Further refinement in the areas of language and visuo-spatial function may improve its value.

Adolescent↗

PubMed1984

Hemi-dystonia secondary to localised basal ganglia tumour.

An 8-year-old boy with an 18 month history of left limb hemi-dystonia due to a right lenticular nucleus astrocytoma originating in the putamen is reported. Subsequent neuropathological study demonstrated that the tumour was mainly localised to the right lenticular nucleus, with cystic necrosis in the infero-lateral putamen. Solid tumour also infiltrated the right hypothalamus, the anterior commisure and the optic chiasm, and there was perivascular spread into the globus pallidus, internal capsule and roof of the right lateral ventricle. This case, and the few other published reports of symptomatic dystonia due to focal brain lesions verified pathologically, indicate that damage to the lenticular nucleus, and to the putamen in particular, can cause limb dystonia in man.

Astrocytoma↗

PubMed1984

A double blind trial of sulpiride in Huntington's disease and tardive dyskinesia.

Eleven patients with Huntington's disease and nine patients with tardive dyskinesia participated in a randomised double-blind crossover trial of sulpiride (as sole antidopaminergic therapy) versus placebo. Although functional improvement was not seen in Huntington's disease patients, sulpiride reduced movement count and total dyskinesia score in both conditions. Sulpiride differs pharmacologically in several respects from conventional neuroleptics, and has not been convincingly shown to cause tardive dyskinesia. Among currently available treatments, it may therefore be considered a drug of choice for treatment of tardive dyskinesia.

Adult↗