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Biomedical subjects

C D Marsden

Publications and source records attributed to C D Marsden.

At least 847 records · Page 47Linked to original sources
PubMed1980

The role of D-1 and D-2 receptors.

Dopamine receptors in intracerebral motor and endocrine systems have been divided into two main types, D-1 and D-2, dependent on the presence or absence of adenylate cyclase linkage. Here we have investigated a number of dopamine agonist and antagonist drugs in man that have different actions on D-1 and D-2 receptors in animals. Motor and endocrine effects in parkinsonian subjects seem to depend on drug interaction with D-2, but not D-1, receptors. These results may have important implications for the design of anti-parkinsonian and antipsychotic agents.

Adenylyl Cyclases↗
PubMed1980

Changes in rat striatal dopamine turnover and receptor activity during one years neuroleptic administration.

Administration of trifluoperazine (2.5--3.5 mg/kg/day p.o.) or thioridazine (30--40 mg/kg/day) for up to 1 year initially increased homovanillic acid and 3,4-dihydroxyphenylacetic acid concentrations in striatum. However, by 1 month and thereafter metabolite levels returned almost to control values. Dopamine concentrations were elevated after 3 months administration of both drugs and also after 12 months administration of trifluoperazine. Trifluoperazine administration for 1 month produced a marked increase in the dissociation constant (KD) for striatal 3H-spiperone binding but a reduction in receptor numbers. Thereafter receptor numbers increased at 6 and 12 months in both trifluoperazine and thioridazine treated animals compared to control values. The KD for both drug treated groups returned to normal at 6 months; however, by 12 months drug treated animals again demonstrated high KD values. Dopamine stimulation of striatal adenylate cyclase was inhibited after administration of trifluoperazine or thioridazine for 1 week or 1 month. However, by 6 and 12 months this effect was replaced by an enhanced stimulation. Administration of lower doses of trifluoperazine (0.7--0.9 mg/kg/day p.o.) or thioridazine (6--9 mg/kg/day p.o.) for up to 1 year produced similar although generally less marked changes in these biochemical indices of dopamine function. This study provides evidence of biochemical changes which parallel the behavioural findings of enhanced dopamine receptor activity that occur during continuous long-term neuroleptic administration to rodents.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1980

Cerebral dopamine function in rats following withdrawal from one year of continuous neuroleptic administration.

Continuous administration of trifluoperazine (2.5--3.5 mg/kg/day) or thioridazine (30--40 mg/kg/day) to rats for 12 months enhanced the stereotyped response to apomorphine (0.5 mg/kg s.c.), increased dopamine 1--150 muM) stimulation of striatal adenylate cyclase, increased KD and Bmax for dopamine (10(-4) M) specific 3H-spiperone striatal binding and produced spontaneous mouthing movements. On drug withdrawal, spontaneous locomotor activity was enhanced after 2 weeks and the enhanced stereotyped response was maintained for up to 1 month. Spontaneous mouthing had disappeared 2 weeks after drug withdrawal. The increase in Bmax for 3H-spiperone binding was maintained for up to 3 months after drug removal, but KD reverted to control levels by 2 weeks. In contrast, the dopamine stimulation of striatal adenylate cyclase remained enhanced for the 6 month withdrawal period. Administration of trifluoperazine (0.7--0.9 mg/kg/day) or thioridazine (6--8 mg/kg/day) for 12 months produced a less marked effect than administration of the higher dose. No enhancement of effect was observed on drug withdrawal and the initial changes disappeared rapidly on removal of drug. Supersensitivity of striatal dopamine mechanisms produced by continuous long-term neuroleptic administration differs from that produced by shorter treatment periods since no enhancement of effect occurs on drug withdrawal. The behavioural and biochemical components of the supersensitivity show variable time courses and in particular the enhanced stimulation of striatal adenylate cyclase persists for at least 6 months. Such effects may be of relevance to tardive dyskinesias in man.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1980

A comparison of striatal and mesolimbic dopamine function in the rat during 6-month trifluoperazine administration.

Previous work has shown that 6---12 months continuous trifluoperazine (TFP) administration to rats causes striatal dopamine receptor supersensitivity. We have now replicated our original findings in the striatum and report concurrent changes in mesolimbic dopamine function during chronic TFP (2.8---4.0 mg/kg/day) administration for 6 months. Initial inhibition of apomorphine-induced stereotyped behaviour, which lasted for 2 weeks after the beginning of drug administration, was replaced by an exaggerated response to apomorphine (0.5 mg/kg SC) after 6 months drug intake. Striatal dopamine sensitive adenylate cyclase activity was inhibited at 1 and 3 months, but y 6 months was enhanced compared to control values. Mesolimbic adenylate cyclase activity was inhibited after 2 weeks and thereafter returned to control levels. Dopamine-identified 3H-spiperone binding sites (Bmax) in the striatum were increased by 2 weeks, reduced at 1 month and increased again at 6 months. In mesolimbic areas Bmax was increased at 2 weeks and 1 month but thereafter returned to control levels. The dissociation constant (kD) of specific 3H-spiperone binding was increased in the striatum and mesolimbic areas at 1 month and 2 weeks respectively. The results show differential changes in dopamine function in striatal and mesolimbic brain areas during 6 months continuous TFP administration to rats.

Adenylyl Cyclases↗
PubMed1980

Failure of lithium treatment in established tardive dyskinesia.

Eleven patients with tardive dyskinesia were treated with lithium carbonate in a placebo-controlled double-blind crossover study. No significant effect of lithium on either tardive dyskinesia or blood prolactin concentrations was demonstrated, but 5 patients developed pseudo-Parkinsonian features.

Aged↗
PubMed1980

Anticipatory postural reflexes in Parkinson's disease and other akinetic-rigid syndromes and in cerebellar ataxia.

We have examined anticipatory postural responses in calf muscles (triceps surae) in response to a small pull to the arm in standing subjects. This stimulus normally evokes a brisk automatic compensatory contraction of the calf muscles. This is not due to calf muscle stretch, for leg movement occurs after the response has appeared. It appears to be driven centrally by input produced by the pull to the arm. Such anticipatory postural responses were present in every one of the 50 normal subjects studied, but were absent or greatly reduced in many patients with Parkinson's disease when compared to age-matched normal subjects, particularly in those exhibiting postural instability. However, a normal anticipatory postural response was elicited in four patients with progressive supranuclear palsy and in a single patient with an akinetic rigid syndrome due to cerebrovascular disease. Cerebellar truncal ataxia only depressed the response in severe cases. We conclude that although these responses may not be necessary to maintain balance, they may be employed in fine adjustment of posture.

Cerebellar Ataxia↗
PubMed1980

A grab reflex in the human hand.

The effect of stretching or unloading flexor pollicis longus indirectly has been investigated by altering the force on the wrist while the subject tracked a moving spot on a cathode ray oscilloscope by flexing the top joint of the thumb against a fixed stiff lever. A radialward pull on the wrist, which lifted the thumb off the lever, thereby indirectly unloading flexor pollicis longus, caused a burst of EMG activity about 50 to 60 ms later, rather than the silent period seen at the same latency when the muscle was unloaded directly. A similar burst of activity occurred in the long finger flexors. Letting the wrist go, which caused the thumb to hit against the lever thereby indirectly stretching flexor pollicis longus, produced an initial burst of EMG activity about 50 ms later, as occurred when the thumb was stretched directly; but this was terminated prematurely after about 10 ms by a paradoxical silent period. The response of flexor pollicis longus to indirect unloading was not altered by anaesthetizing the skin of the wrist under the chain pulling it, nor by anaesthesia of the thumb, so was not due to cutaneous stimuli. Nor was it affected by motor point anaesthesia of flexor pollicis longus, so it was unlikely to be due to changes in spindle input from that muscle. However, it was reduced considerably by bracing the arm, suggesting that it arose as a result of movement proximally at the shoulder. The response to indirect unloading of flexor pollicis longus by a pull on the wrist did not occur if the subject held the lever free in his hand, indicating that it was dependent on and adapted to the task. A similar response to a pull on the wrist occurred if the subject was asked merely to hold his thumb and fingers adjacent to a full sherry glass. In these circumstances wrist release also caused a thumb flexion. Such an automatic flexion response or 'grab reflex' helps the subject to maintain contact of his digits with an object when his hand is displaced from it, provided that is his intent. Although the response occurs too early to be voluntary, it depends on the nature of the task and the subject's prior instruction.

Electromyography↗
PubMed1980

Observations on chloralose-induced myoclonus in guinea-pigs.

1 The physiological, biochemical and pharmacological features of alpha-chloralose-induced myoclonus in the guinea-pig have been studied. 2 EMG bursts in muscles jerking in chloralose-induced myoclonus are long, and are not time-locked to any cortical event recorded in the EEG, although they are evoked by auditory or peripheral nerve stimuli. 3 The efferent conduction velocity down the spinal cord of the signals generating the EMG bursts is fast but the afferent conduction velocity up the cord for stimulus-evoked jerks is slow, in distinction to the reverse characteristics of the spino-bulbo-spinal relfex arc. 4 alpha-Choralose did not cause any consistent change in 5-hydroxytryptamine (5-HT) or 5-hydroxyindoleacetic acid levels in any brain area, nor did it alter 5-HT turnover as judged by the depletion of 5-HT after p-chlorophenylalanine pretreatment. 5 Pretreatment of animals with drugs that increase brain 5-HT action (L-tryptophan with a monoamine oxidase inhibitor, or 5-hydroxytryptophan), or antagonize the action of 5-HT (cyproheptadine) did not abolish or obviously increase chloralose-induced myoclonus. 6 Chloralose-induced myoclonus is not similar to 5-HT-sensitive reticular reflex myoclonus in man.

Animals↗
PubMed1980

Behavioural changes induced by N,N-dimethyl-tryptamine in rodents.

1 N,N-Dimethyltryptamine (DMT) in pargyline pretreated rodents induced a dose-dependent behavioural syndrome consisting of hyperactivity, prostration and hindlimb abduction, mild tremor, Straub tail, retropulsion and jerking. 2 In rats pretreated with pargyline, the behavioural syndrome induced by DMT differed from that induced by L-tryptophan or quipazine, in the lack of forepaw treading and head-weaving and in the presence of only mild tremor. 3 The hyperactivity component of the DMT-induced behavioural syndrome in pargyline-pretreated mice was potentiated by cyproheptadine, methergoline, and mianserin, inhibited by cinanserin, haloperidol, pimozide, methiothepin and propranolol, and not affected by 501C67-sulphate and methysergide. 4 The maximal behavioural changes induced by DMT in rats, other than hyperactivity, were unaffected by pretreatment with cyproheptadine, methysergide, and cinanserin. However, propranolol reduced the intensity of all behavioural effects apart from body jerking, and methergoline decreased the duration of prostration. Phenoxybenzamine and haloperidol, in contrast, enhanced prostration. 5 DMT plus pargyline did not induce circling behaviour in mice with a unilateral 6-hydroxy-dopamine lesion of the nigro-striatal pathway. 6 The DMT-induced behavioural syndrome appears to consist of two components, (a) hyperactivity and (b) other behavioural changes. They differ in their response to drugs affecting brain monoamines. The hyperactivity component may be expressed via dopamine mechanisms, but the other behavioural changes are not. The two behaviours do not respond consistently to drugs believed to alter brain 5-hydroxytryptamine function.

Animals↗
PubMed1980

Lisuride in the treatment of Parkinsonism.

Lisuride 1.2-4.8 mg daily was given to 10 patients with severe Parkinsonism for up to 9 months. All had been taking bromocriptine and eight had been taking levodopa combined with carbidopa. Total replacement of bromocriptine by lisuride was achieved in every case, but partial or total levodopa replacement was possible only in five patients. Lisuride 1 mg has approximately the same antiparkinsonian activity as bromocriptine 15 mg or levodopa 250-500 mg combined with carbidopa, but the duration of action of each dose is short, and gastro-intestinal and neuropsychiatric side effects are common. However, lisuride i.v. may be of considerable value in the emergency treatment of severe Parkinsonism.

Administration, Oral↗
PubMed1980

Metabolite involvement in bromocriptine-induced circling behaviour in rodents.

Bromocriptine and apomorphine produced identical circling responses in rodents with medial forebrain bundle lesions. Rotation induced by bromocriptine, but not by apomorphine, was inhibited by prior treatment with reserpine or alpha-methyl-p-tyrosine suggesting a requirement for intact presynpatic events. Bromocriptine-induced circling also was inhibited by the catecholamine re-uptake blockers nomifensine and desmethylimipramine, supporting the role of presynaptic mechanisms. Bromocriptine-induced circling, but not apomorphine circling, was reduced by pre-treatment with SKF 525A, an inhibitor of monooxygenase enzymes, suggesting metabolite involvement in the turning response. This compound prolonged hexobarbitone sleeping times and zoxazolamine paralysis times in mice. These indices of drug metabolizing activity also were prolonged by pre-treatment with desmethylimipramine while nomifensine prolonged only hexobarbitone sleeping times and alpha-methyl-p-tyrosine had no effect on either index. The data suggest that a metabolite of bromocriptine may be of importance in causing circling and that uptake of bromocriptine (or a metabolite) into presynaptic catecholamine terminals may be necessary.

Amphetamine↗