Spasmodic dysphonia in Gilles de la Tourette's disease.
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Adult↗
Biomedical subjects
C D Marsden
Publications and source records attributed to C D Marsden.
Lesions of the globus pallidus, entopeduncular nucleus and substantia nigra alter dopamine mediated circling behaviour.
Unilateral kainic acid lesions of the globus pallidus in the rat caused weak spontaneous circling at 3 and 10 days after surgery. Unilateral kainic acid lesions of the entopeduncular nucleus caused no spontaneous circling at any time after surgery. Systemic administration of apomorphine to such lesioned animals caused ipsiversive circling in both groups. Pallidal lesions in animals with a prior ipsilateral 6-OHDA lesion of the medial forebrain bundle attenuated apomorphine-induced, but not amphetamine-induced, circling. Entopeduncular nucleus lesions in the 6-OHDA lesioned animal attenuated both apomorphine- and (+)-amphetamine-induced circling. Kainic acid lesions of the globus pallidus or entopeduncular nucleus did not alter nigral glutamic acid decarboxylase (GAD) activity. Unilateral electrolytic lesions of the globus pallidus or entopeduncular nucleus caused ipsiversive circling in response to apomorphine. An electrolytic lesion of the globus pallidus in animals with a prior 6-OHDA lesion did not alter (+)-amphetamine-induced circling but reversed the direction of apomorphine-induced circling. Electrolytic lesions of the entopeduncular nucleus enhanced (+)-amphetamine-induced circling and attenuated apomorphine-induced circling. Nigral GAD activity was reduced by electrolytic lesions of the globus pallidus but not by those of the entopeduncular nucleus. Large kainic acid lesions in the area of the substantia nigra caused weak spontaneous contraversive circling 3 days after surgery, and ipsiversive circling in response to the systemic administration of apomorphine. Similar lesions in animals with a prior ipsilateral 6-OHDA lesion of the medial forebrain bundle initially attenuated the response to (+)-amphetamine, but the response returned with time. The direction of apomorphine-induced circling was reversed in these animals. The strio-nigral pathway and nigral efferents are confirmed to be involved in circling induced by dopamine agonists in rats with a unilateral lesion of the medial forebrain bundle. Both the globus pallidus and the entopeduncular nucleus also appear to be involved in this dopamine-mediated circling behaviour.
Animals↗
Cholinergic manipulation of perioral behaviour induced by chronic neuroleptic administration to rats.
Rats treated continuously for 4 months with haloperidol (1.4-1.6 mg/kg/day), trifluoperazine (4.5-5.1 mg/kg/day), or sulpiride (102-110 mg/kg/day), but not clozapine (23-26 mg/kg/day), exhibited an increased frequency of chewing jaw movements. Chewing in both control and haloperidol-treated rats was increased by acute administration of the cholinergic agents pilocarpine or physostigmine. Physostigmine or pilocarpine also induced abnormal gaping jaw movements; physostigmine-induced gaping was more prevalent in haloperidol-treated rats than control rats receiving physostigmine alone. Acute administration of the anticholinergic agents scopolamine and atropine decreased chewing in control animals and reduced haloperidol-induced chewing to control values or below. The effects of these cholinergic manipulations suggest that neuroleptic-induced perioral responses in rats do not resemble tardive dyskinesia in man.
Animals↗
Basal ganglia outflow pathways and circling behaviour in the rat.
The role of efferents in substantia nigra pars reticulata in the mediation of circling behaviour in the rat has been studied by means of lesions designed to interrupt these pathways or to damage nigral projection areas. The behavioural model used was the circling rodent with a prior 6-hydroxydopamine lesion of the left nigro-striatal pathway in which amphetamine induced ipsiversive rotation and apomorphine induced contraversive rotation. Removal of the left fronto-parietal cortex caused only a transient decrease in drug-induced rotation. An electrolytic lesion of the left, right or both parafascicular thalamic nuclei did not alter circling behaviour. Electrolytic lesioning of the left ventromedial thalamus decreased apomorphine-induced contraversive circling whereas a lesion of the right ventromedial thalamus decreased amphetamine-induced ipsiversive rotation. Bilateral electrolytic lesions of the ventromedial thalamus did not alter drug-induced circling. Unilateral or bilateral electrolytic lesioning of the medial superior colliculus did not alter the rotational response to apomorphine or amphetamine. However, an electrolytic lesion interrupting the dorsal tegmental decussation reduced apomorphine-induced circling but not amphetamine-induced circling. That a critical role for the nigro-thalamic and nigro-tectal pathways is not involved in the mediation of circling behaviour was confirmed by placing knife cuts so as to separate these structures from the substantia nigra; such lesions failed to alter the contraversive rotation induced by the ipsilateral injection of muscimol into substantia nigra pars reticulata. Electrolytic lesions of the ipsilateral nucleus reticularis gigantocellularis or kainic acid lesions of the ipsilateral nucleus tegmenti pedunculopontinus did not alter drug-induced circling in animals with a prior 6-hydroxydopamine nigral lesion. In contrast, an ipsilateral lesion of the midbrain periaqueductal grey matter and adjacent midbrain reticular formation (the angular complex) decreased apomorphine-induced contraversive rotation in such animals, while bilateral lesions reduced both apomorphine-and amphetamine-induced circling; in each case the postural component of rotation was abolished. Unilateral kainic acid lesions of the angular complex in naive animals caused ipsiversive rotation which was enhanced by apomorphine. Unilateral kainic acid lesions of the angular complex with an ipsilateral 6-hydroxydopamine nigral lesion caused reversal of the previous contraversive rotation to apomorphine, and enhanced amphetamine-induced ipsiversive rotation.(ABSTRACT TRUNCATED AT 400 WORDS)
Animals↗
Alterations in cerebral dopamine function caused by administration of cis- or trans-flupenthixol for up to 18 months.
Rats received either cis-flupenthixol (0.8-1.2 mg/kg per day) or trans-flupenthixol (0.9-1.2 mg/kg per day) continuously in drinking water for periods up to 18 months. cis-Flupenthixol, but not trans-flupenthixol, initially inhibited apomorphine-induced stereotyped behaviour but by 6 months and thereafter the stereotyped response was enhanced compared to age-matched control animals. Striatal and mesolimbic homovanillic acid and 3,4-dihydroxyphenylacetic acid concentrations were elevated for up to 3 months after starting cis-, but not trans-flupenthixol intake, but thereafter levels generally fell below those for age-matched control animals. Dopamine concentrations were not altered by cis- or trans-flupenthixol administration. The number of striatal [3H]spiperone binding sites (Bmax) was decreased by 40% after 1 months' administration of cis-flupenthixol but this gradually reversed, such that by 18 months a 40% increase in Bmax was apparent. Administration of trans-flupenthixol decreased Bmax up to 3 months but thereafter values were not different from those found in age-matched control animals. The dissociation constant (KD) for [3H]spiperone binding in striatum was not altered by 6 months cis-flupenthixol intake, but then increased as drug administration continued. trans-Flupenthixol administration did not alter striatal KD values. Bmax for [3H]spiperone binding to mesolimbic preparations was not altered by up to 12 months cis-flupenthixol intake, but was decreased after 18 months drug administration. cis-Flupenthixol administration had no effect on mesolimbic KD values. Administration of trans-flupenthixol for up to 18 months did not alter mesolimbic Bmax or KD values for [3H]spiperone binding.(ABSTRACT TRUNCATED AT 250 WORDS)
3,4-Dihydroxyphenylacetic Acid↗
Noradrenaline and 5-hydroxytryptamine modulation of brain dopamine function: implications for the treatment of Parkinson's disease.
1 Dopamine deficiency in the brain is the prime biochemical deficit in Parkinson's disease, but loss of noradrenaline and 5HT also may contribute. 2 In rats, 5HT-containing neurones originating from the dorsal and median raphe nuclei innervate forebrain dopamine-containing areas so as to impose an inhibitory regulatory tone on dopamine function. However, this interaction between brain dopamine and 5HT-containing neuronal systems is complex, and the effect produced appears dependent on the relative activity of each system. 3 Anatomical evidence for innervation of dopamine-containing brain regions by noradrenaline fibres in the rat is scanty, but functional studies suggest the existence of inputs which facilitate dopamine function. 4 Drug therapy designed to increase or decrease brain 5HT function has had no consistent effect in Parkinson's disease. 5 Manipulation of brain noradrenergic activity in Parkinson's disease had little effect, although the noradrenaline precursor L-threo-DOPS may reduce freezing attacks. 6 Until more specific drug molecules are available the role of brain noradrenergic and 5HT mechanisms in Parkinson's disease remains uncertain.
Brain↗
Differential anatomical location of [3H]-N,n-propylnorapomorphine and [3H]-spiperone binding sites in the striatum and substantia nigra of the rat.
Specific [3H]-spiperone and [3H]-N,n-propylnorapomorphine (NPA) binding was measured in striatum and substantia nigra of the rat following unilateral 6-hydroxydopamine (6-OHDA) lesions of the medial forebrain bundle, kainic acid lesions of the substantia nigra or striatum, and following decortication. Binding sites labelled by [3H]-spiperone in striatum were found to lie on striatal cell bodies and on the terminals of cortico-striate glutamate fibres, but not on presynaptic dopamine terminals. In contrast, binding sites labelled by [3H]-NPA were demonstrated on striatal cell bodies and on the terminals of nigro-striata dopamine fibres, but not on cortical afferents. In substantia nigra, specific [3H]-spiperone binding sites were found only on non-dopamine cell bodies. No clear evidence was found for their existence on dopamine cell bodies, the terminals of strio-nigral fibres or the terminals of cortico-nigral fibres. In contrast, specific binding sites for [3H]-NPA were found on dopamine cell bodies and the terminals of strio-nigral fibres. Localization on non-dopamine cell bodies or on cortico-nigral fibres was not demonstrated. These studies support the concept of differential localization of agonist and antagonist binding sites.
Animals↗
Potent lipophilic substituted benzamide drugs are not selective D-1 dopamine receptor antagonists in the rat.
The substituted benzamide drugs YM 09151-2 and clebopride potently inhibited apomorphine-induced stereotyped behaviour in the rat and caused displacement of the specific binding of [3H]spiperone to D-2 binding sites on striatal membranes in low nanomolar concentrations. Other substituted benzamide drugs including metoclopramide, sultopride and flubepride also inhibited stereotyped behaviour to a greater or lesser degree, but were less potent in displacing [3H]spiperone from D-2 sites. YM 09151-2 and clebopride only weakly displaced specific binding of [3H]piflutixol to D-1 sites on rat striatal membranes, and only weakly inhibited striatal dopamine stimulated adenylate cyclase activity, when compared with cis-flupenthixol. The other substituted benzamide drugs did not displace [3H]piflutixol or inhibit dopamine stimulation of adenylate cyclase activity in the concentration range used. Clebopride and YM 09151-2 were highly lipophilic with apparent partition coefficient (log P') values equivalent to those of classical neuroleptic compounds, such as cis-flupenthixol. In contrast, the other substituted benzamide drugs were markedly less lipophilic. A log P' value of approximately 2 was required before inhibition of adenylate cyclase activity or displacement of [3H]piflutixol binding occurred. However, in excess of this value there was no correlation between either inhibition of adenylate cyclase activity or displacement of [3H]piflutixol binding and the lipophilicity of the various compounds. We conclude that potent lipophilic substituted benzamide drugs, like other members of the substituted benzamide series, are selective D-2 receptor antagonists. Inherent steric factors within the drug series would appear to dictate activity at D-1 and D-2 sites, although lipophilicity may contribute to actions in these environments.
Adenylyl Cyclases↗
Hypophysectomy does not prevent increased cerebral dopamine turnover following sulpiride administration.
Hypophysectomy is claimed to prevent increased forebrain dopamine turnover produced by administration of sulpiride. We have measured the increase in dopamine metabolite concentrations caused by sulpiride following surgical removal of the pituitary. In saline-treated control animals and in hypophysectomized rats 1 week or 1 month following surgery, administration of sulpiride caused marked elevations of striatal, nucleus accumbens and tuberculum olfactorium, homovanillic acid (HVA) and 3,4-dihydroxyphenylacetic acid (DOPAC) concentrations which were maximal 4-8 h following drug administration. The maximal increases in nucleus accumbens and tuberculum olfactorium were generally comparable in control and hypophysectomized animals, except for a greater increase in HVA levels in the nucleus accumbens 1 month following hypophysectomy. However, maximal increases in HVA and DOPAC in striatum were more pronounced in hypophysectomized rats 1 week or 1 month following surgery compared with control animals. At 30 min following sulpiride administration only inconsistent changes in dopamine turnover were observed in both control and hypophysectomized rats. Hypophysectomy does not prevent sulpiride from increasing forebrain dopamine turnover suggesting this is due to a direct interaction with cerebral dopamine receptors.
3,4-Dihydroxyphenylacetic Acid↗
The function of the antagonist muscle during fast limb movements in man.
We have examined fast flexion movements of the human thumb and fast extension movements of the elbow over three different distances at a variety of speeds in order to elucidate the function of the antagonist muscle in these circumstances. All movements were of such a velocity that they showed the typical bi- or triphasic pattern of muscle activation in agonist and antagonist. Slower movements, with continuous agonist activity, were not analysed. For movements made through the same angle at different velocities, there was a linear relationship between the amount of antagonist activity needed to halt the movement and the peak velocity. However, the slope of this relationship was a function of the distance moved. Movements made through large angles showed less antagonist activity than those made through small angles at the same speed. The timing of the antagonist activity also changed as a function of both distance and speed. Fast, small movements showed earlier onset of antagonist activity than slow, large ones. Movements which were halted mechanically with the subject's prior knowledge had little or no antagonist activity, since it was no longer necessary in these conditions. The complexity of these relations indicates that the triphasic pattern of muscle activity underlying these movements can no longer be regarded as a simple immutable 'programme'. The size and timing of the bursts of muscle activity are subtly adjusted to the precise nature of the task.
Action Potentials↗
The behaviour of the long-latency stretch reflex in patients with Parkinson's disease.
The size of the long-latency stretch reflex was measured in a proximal (triceps) and distal (flexor pollicis longus) muscle in 47 patients with Parkinson's disease, and was compared with that seen in a group of 12 age-matched normal control subjects. The patients were classified clinically into four groups according to the degree of rigidity at the elbow or tremor. Stretch reflexes were evaluated while the subject was exerting a small force against a constant preload supplied by a torque motor, and the size of the reflex response was measured as fractional increase over basal levels of activity. When stretches were given at random intervals by increasing the force exerted by the motor by a factor of 2 or 3, there was a clear trend for the more severely affected patients to have larger long latency responses in the triceps muscle, although there was no change in the size of the short-latency, spinal component of the response. In contrast, there was no change in the size of the long-latency response of the flexor pollicis longus in any group of patients with Parkinson's disease. Despite any differences in reflex size, the inherent muscle stiffness of both muscles appeared to be normal in all groups of patients with Parkinson's disease, since the displacement trajectory of the limb following the force increase was the same as control values in the short (25 ms) period before reflex compensation could intervene. In 20 of the patients and in seven of the control subjects, servo-controlled, ramp positional disturbances were given to the thumb. Up to a velocity of 300°/s, the size of the long-latency stretch reflex was proportional to the log velocity of stretch. This technique revealed, in both moderately and severely rigid patients, increases in the reflex sensitivity of the flexor pollicis longus, which had not been clear using step torque stretches alone. However, whether using ramp or step displacements, long latency stretch reflex gain was not closely related to rigidity; reflex size was within the normal range in many patients with severe rigidity. Enhanced long latency stretch reflexes thus contribute to, but may not be solely responsible for, rigidity in Parkinson's disease.
Electromyography↗
Beta-adrenoreceptor mechanisms in essential tremor; a double-blind placebo controlled trial of metoprolol, sotalol and atenolol.
In order to elucidate the mode of action of beta-adrenoreceptor antagonists in essential tremor, the efficacy of chronic oral administration of metoprolol, atenolol and sotalol was compared in a randomised, double-blind placebo controlled trial in twenty-four patients. Only sotalol proved superior to placebo on both subjective and "objective" assessments. Metoprolol and sotalol produced comparable degrees of beta-adrenoreceptor antagonism as judged by the blockade of standing tachycardia. Atenolol, in the dose used, produced a trend towards a greater cardiac chronotropic effect. These findings provide no support for the concept that central or peripheral beta 1-adrenoreceptor mechanisms are important in essential tremor. The beneficial effect of beta-adrenoreceptor antagonists may be mediated predominantly through peripheral beta 2-adrenoreceptor mechanisms.
Adult↗
Dopa dose-dependent sexual deviation.
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Antiparkinson Agents↗
Postanoxic symptomatic oscillatory myoclonus.
Two young patients with a history of birth anoxia and cerebral palsy developed paroxysmal irregularly oscillating muscle jerks at rest and during voluntary movement. Electrophysiologic studies revealed short bursts of alternating activity at 4 to 6 Hz in antagonist muscles. The absence of time-locked EEG discharges suggests a subcortical origin for this unusual form of myoclonus. A comparison is made between this and previously reported conditions with a similar paroxysmal burstlike nature.
Child↗
Myoclonic dystonia.
We studied 14 patients who had a combination of idiopathic torsion dystonia and myoclonic jerks. In many cases, the same muscles were involved in both the myoclonus and the dystonia. This made observation of the crucial dystonic postures difficult and led to misdiagnosis of other dyskinesias. The jerks usually were brief (50 to 200 msec) and occurred irregularly, often showing cocontraction in antagonist muscles. Frequently, they were superimposed upon sustained dystonic contractions in the same or distant muscles. We found no time-locked EEG event before the jerks. The myoclonus probably arises from a subcortical focus, and the visible jerks probably are part of the spectrum of involuntary movements that accompany torsion dystonia.
Adolescent↗
Pharmacology of cranial dystonia.
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Dystonia↗
Acute anticholinergic action in focal dystonia.
We have investigated the effects of the intravenous administration of three anticholinergic drugs (atropine, benztropine, and chlorpheniramine) with variable antihistaminic properties in comparison with saline in adult-onset focal dystonias. In many patients, the severity of the involuntary movements varied from one observation to the next. Patients with spasmodic torticollis, writer's cramp, and segmental dystonia showed little change with any of the active drugs. The occasional individual who improved by more than 20% did so at the expense of drug-induced drowsiness. We conclude that cholinergic mechanisms are not of general importance in the pathogenesis of these conditions. However, the beneficial response to benztropine and chlorpheniramine in two of 20 patients emphasizes the continuing need for a trial-and -error approach in the therapy of these focal dystonias.
Acute Disease↗
Long-term adaptive changes in striatal dopamine function in response to chronic neuroleptic intake in rats.
Chronic neuroleptic drug administration to rats reverses initial dopamine receptor blockade so that animals exhibit striatal dopamine receptor supersensitivity. This effect may be of functional significance in the whole animal for it is accompanied by increased striatal acetylcholine content and by reversal of the acute increase in striatal acetylcholine release. Continuous drug intake may increase the number of striatal 3H-spiperone binding sites while decreasing the number of 3H-N, n-propylnorapomorphine binding sites. While D-2 adenylate cyclase independent dopamine receptor binding sites increase in number, no change occurs in the number of D-1 sites labelled by 3H-piflutixol despite increased adenylate cyclase activity. Haloperidol and sulpiride differentially alter striatal 3H-acetylcholine and 3H-glutamate release in a manner suggesting selective changes in dopamine receptors lying on striatal cell bodies and on the terminals of corticostriate glutamate terminals. In summary, neuroleptic drugs induce a series of adaptive changes on chronic administration consistent with the development of functional striatal dopamine receptor supersensitivity.
Acetylcholine↗