Biomedical subjects
C D Marsden
Publications and source records attributed to C D Marsden.
Control of on/off phenomenon by continuous intravenous infusion of levodopa.
In 10 parkinsonian patients with severe, chaotic clinical response fluctuations, oral levodopa treatment was replaced by continuous intravenous infusion of levodopa (with orally administered benserazide). Four patients were also given levodopa infusions in addition to their usual oral treatment. All patients remained continuously mobile and ambulant during the infusions. Side effects were minimal, except in two patients with diphasic dyskinesias whose abnormal movements were consistently suppressed by a further increase in the rate of levodopa administration, only to return after an interval. If a soluble nonacidic dopamine replacement drug can be developed for continuous subcutaneous infusion, "brittle" parkinsonians may be chronically controlled by portable, minipump technology.
The pathophysiology of movement disorders.
This review concentrated on the more recent findings of investigations into the functional anatomy and pathophysiology of movement disorders. Attempts were made to provide explanations for rigidity, bradykinesia, and tremor. What little is known of the pathophysiology of chorea, tics, and dystonia is discussed. Greater information is available to allow pathophysiologic classification of different types of myoclonus.
Pergolide in the treatment of Parkinson's disease.
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Motor disorders in basal ganglia disease.
The clinical motor symptoms of basal ganglia disease are explored in relation to possible functions of this region of the human brain. It is concluded that Parkinsonian akinesia, and the dyskinesias of chorea, hemiballism and torsion dystonia are likely to represent the critical abnormalities of motor action in human basal ganglia lesions. These motor disorders involve most muscles, all classes of movement, and the individual sequential components of movement, but spare the overall motor plan. It is suggested that Parkinsonian akinesia is due to putaminal dysfunction disrupting the normal automatic execution of learned motor plans. The dyskinesias of chorea, hemiballism and torsion dystonia are conceived as being due to dysfunction of other strio-pallidal regions superimposed upon the normal function of the motor strio-pallidal system.
Changes in apomorphine-induced stereotypy as a result of subacute neuroleptic treatment correlates with increased D-2 receptors, but not with increases in D-1 receptors.
Administration of haloperidol (5 mg/kg i.p.), cis-flupenthixol (2.5 mg/kg i.p.) or sulpiride (2 X 100 mg/kg i.p.) daily for 21 days followed by a 3-day drug withdrawal period caused equivalent cerebral dopamine receptor supersensitivity as judged by enhanced apomorphine-induced stereotypy. These treatments also produced equivalent rises in the number of adenylate cyclase-independent dopamine receptors (D-2) in both striatal and mesolimbic tissue as assessed by specific [3H]spiperone and [3H]N,n-propylnorapomorphine (NPA) binding. No change in the dissociation constant (KD) was apparent in response to neuroleptic treatment. However, only repeated administration of cis-flupenthixol caused an increase in the number of adenylate cyclase-linked dopamine receptors (D-1) in striatum as assessed by enhanced [3H]piflutixol binding and increased dopamine-stimulated cyclic AMP formation. The dissociation constant for [3H]piflutixol binding was unchanged by cis-flupenthixol administration. No change in D-1 receptor numbers or dopamine stimulation of adenylate cyclase occurred in mesolimbic tissue. Repeated treatment with sulpiride or haloperidol was without effect on either [3H]piflutixol binding to D-1 receptors or cyclic AMP formation. In conclusion, increased apomorphine-induced stereotypy following subacute neuroleptic treatment correlates with changes in D-2 receptor numbers, but not with changes in D-1 receptors.
Turnover of specific [3H]spiperone and [3H]N,n-propylnorapomorphine binding sites in rat striatum following phenoxybenzamine administration.
Inclusion of phenoxybenzamine into incubates containing rat striatal preparations equipotently displaced specific striatal [3H]spiperone and [3H]NPA binding. Pre-incubation of striatal membranes with phenoxybenzamine followed by extensive washing equipotently inhibited the subsequent specific [3H]spiperone or [3H]NPA binding. In both displacement and pre-incubation experiments phenoxybenzamine caused complete inhibition of specific [3H]spiperone binding to rat striatal membranes, but only partially inhibited specific [3H]NPA binding. Following parenteral administration to rats, phenoxybenzamine caused a marked inhibition of ex vivo specific [3H]spiperone binding in striatal tissue preparations from these animals which lasted approximately 24 hr following in vivo drug administration. In contrast, administration of phenoxybenzamine caused only a transient change in ex vivo specific [3H]NPA binding. Phenoxybenzamine causes irreversible inhibition of [3H]spiperone and [3H]NPA binding in vitro. In vivo administration of phenoxybenzamine discriminates between [3H]spiperone and [3H]NPA in ex vivo studies suggesting that these binding sites have different turnover rates.
Elevation of circulating prolactin concentrations may not cause striatal dopamine receptor supersensitivity.
Neuroleptic drugs, on repeated administration, increase plasma prolactin levels and induce behavioural and biochemical changes suggesting supersensitivity of striatal dopamine receptors. It has been suggested that the increase in plasma prolactin is responsible for the change in striatal dopamine receptors. We now find that repeated administration of haloperidol (5 mg/kg i.p.) for 21 days, followed by a 3 day drug-washout period, caused a 12-fold increase in circulating prolactin concentration in samples taken 1 h after the last injection. Haloperidol treated animals also exhibited an exaggerated stereotyped response to apomorphine 0.0625-0.5 mg/kg s.c.) and an increase in striatal dopamine receptor numbers labelled by [3H]spiperone. Administration of the same dose of domperidone or sulpiride (5 mg/kg i.p., 21 days), compounds which penetrate poorly into brain, also elevated plasma prolactin levels, but failed to alter cerebral dopamine function. Our findings indicate that neuroleptic-induced elevations in plasma prolactin levels are not responsible for the induction of cerebral dopaminergic supersensitivity.
Persistent increase in striatal dopamine stimulated adenylate cyclase activity persists for more than 6 months but disappears after 1 year following withdrawal from 18 months cis-flupenthixol intake.
Administration of cis-flupenthixol to rats for 18 months enhanced apomorphine-induced stereotyped behaviour, increased the number of specific [3H]spiperone binding sites in striatum and potentiated striatal dopamine stimulated cyclic AMP formation, but did not alter specific [3H]piflutixol binding. Following withdrawal of cis-flupenthixol intake, apomorphine-induced stereotypy returned to control values after 1 month and Bmax for [3H]spiperone binding returned to normal after 3 months. In contrast, the increased dopamine stimulated adenylate cyclase activity remained elevated 6 months after drug removal, but was normal 1 year after drug withdrawal.
Transmission in the spinal reciprocal Ia inhibitory pathway preceding willed movements of the human wrist.
Transmission in the Ia inhibitory pathway from wrist extensor muscles onto flexor motoneurones was investigated in the 160 ms period prior to a willed movement in 6 human subjects. H-reflexes were evoked in flexor muscles at various times before the onset of electromyographic activity. Disynaptic inhibition of the H-reflex was produced by low intensity stimulation of the antagonist radial nerve. Prior to a wrist flexion movement, transmission in the inhibitory pathway was diminished. Prior to an extension movement it was facilitated. The findings are consistent with the notion that the command to the agonist motoneurones acts also on a specific population of Ia inhibitory interneurones.
Interaction between the long-latency stretch reflex and voluntary electromyographic activity prior to a rapid voluntary motor reaction.
The size of the long-latency component of the stretch reflex has been examined in the time interval between a signal to move and the required rapid voluntary contraction of triceps and flexor pollicis longus in 8 normal subjects. Bilateral movements of the elbow and thumb were made following an auditory signal. In 50% of the trials a torque pulse was applied unilaterally in order to elicit a stretch reflex response in one arm. The voluntary response in the contralateral arm was uncorrupted by a stretch reflex response, so was used as an indicator of voluntary reaction time. Control experiments, using an electrical stimulus to the fingers rather than muscle stretch, verified that both arms reacted almost simultaneously to the auditory cue, even when the reaction time was shortened by the presence of a unilateral electrical stimulus. Similarly, an interposed muscle stretch stimulus considerably reduced the reaction time to the audio signal. Because of this, the start of the voluntary EMG response frequently 'over-lapped' the end of the long-latency stretch reflex. Failure to take this shortening of voluntary reaction time into consideration can lead to the erroneous conclusion that reflex gain is increased prior to a rapid movement. If the 'overlap' of EMG responses is accounted for, very little change in the size of the long-latency stretch reflex is evident prior to activation of the muscles responsible for the movement of either the elbow or the thumb.
Alterations in brain 5HT and tryptamine content during indoleamine-induced myoclonus in guinea pigs.
L-5-Hydroxytryptophan (5HTP) (with or without carbidopa pretreatment), L-tryptophan (plus pargyline pretreatment), or tryptamine (plus pargyline pretreatment) all induced dose-dependent myoclonus in guinea pigs. At the time of maximal behavioural response animals were killed for determination of brain indoleamine content. Administration of 5HTP (50-200 mg/kg) to naive guinea pigs, or of 5HTP (20-80 mg/kg) to carbidopa- (25 mg/kg 1 hr previously) pretreated animals, markedly elevated brain 5-hydroxytryptamine (5HT) concentrations but depressed whole brain tryptamine content. L-Tryptophan (50-200 mg/kg) administration to pargyline- (75 mg/kg 30 min previously) pretreated animals also increased cerebral 5HT levels. L-Tryptophan (200 mg/kg plus pargyline), elevated whole brain tryptamine content. Administration of tryptamine (40 mg/kg) to pargyline-pretreated guinea pigs caused a small increase in brain 5HT levels, but markedly elevated cerebral tryptamine content. 5HT appears to be the indoleamine mainly responsible for 5HTP-induced myoclonus but tryptamine predominates in tryptamine-induced myoclonus. Both 5HT and tryptamine may contribute to myoclonus induced by L-tryptophan.
The effect of chronic neuroleptic administration on cerebral dopamine receptor function.
Acute administration of neuroleptic drugs causes blockade of cerebral dopamine receptors. It has been discovered that chronic administration of neuroleptic drugs may have different effects on cerebral dopamine systems. Initial antagonism of dopamine mediated behaviour, such as stereotypy, disappears and may be replaced by supersensitivity to dopamine agonists. Changes also occur in biochemical indices of dopamine receptors, such as in the number and affinity of specific binding sites identified by 3H-ligands labelling D-2 receptors, and in dopamine-stimulated adenylate cyclase activity. All these changes occur obviously in the striatum in response to chronic administration of a range of neuroleptic drugs. Lesser changes take place in the mesolimbic dopamine system. What happens in the mesocortical dopamine pathways is unknown. The consequence of such adaptive responses to chronic neuroleptic therapy may be of importance to understanding of tardive dyskinesia and schizophrenia.
Chronic clozapine treatment of rats down-regulates cortical 5-HT2 receptors.
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Cation specificity of 3H-sulpiride binding involves alteration in the number of striatal binding sites.
Specific 3H-sulpiride binding to rat striatal membranes shows an absolute requirement for the presence of sodium ions in the incubation buffer. Potassium, rubidium and caesium ions were unable to initiate specific 3H-sulpiride binding in a sodium free buffer, and lithium ions could only partially replace sodium ions. Specific 3H-spiperone binding was unaffected by variation of the cation content of the incubation buffer. The alteration in 3H-sulpiride binding caused by sodium and lithium ions was due predominantly to an increase in the number of available binding sites, rather than to altered receptor affinity. Sodium ions may be essential for the accessability of 3H-sulpiride to a single site labelled also by 3H-spiperone. However, the Ki value for sulpiride displacement of 3H-spiperone in the presence of sodium ions was 20 times greater than the KD value for 3H-sulpiride binding. So, 3H-sulpiride may interact with a highly sodium dependent binding site distinct from that labelled by 3H-spiperone.
Differentiation of dopamine agonists using drug-induced rotation in rats with unilateral or bilateral 6-hydroxydopamine destruction of ascending dopamine pathways.
Eighteen compounds with dopamine agonist properties were examined in two rat rotational models. In the classical Ungerstedt model, a unilateral 6-hydroxydopamine (60HDA) lesion destroyed nigrostriatal and mesolimbic dopamine pathways on one side. Indirectly acting compounds, amphetamine, amantadine, methylphenidate and S1694, produced ipsiversive rotation, which was inhibited by pretreatment with alpha-methyl-p-tyrosine (AMPT). All other compounds produced contraversive rotation, but the rotation caused by CM 29-712, bromocriptine and ET 495 was reduced by AMPT. In animals with a bilateral 60HDA lesion removing both dopaminergic inputs to nucleus accumbens and the dopaminergic input into one striatum, indirectly acting drugs caused ipsiversive posturing prevented by AMPT, but little rotation. All other compounds produced contraversive rotation, but the effects of CM 29-712, bromocriptine and ET 495 were reduced by AMPT pretreatment. Inhibition of monooxygenase drug metabolising activity utilising SKF-525A inhibited contraversive turning induced by bromocriptine and ET 495 in the unilateral lesion model, but had no effect on rotation caused by apomorphine or CM 29-712. We conclude that, in addition to indirect pre-synaptically acting agonists and direct post-synaptic receptor agonists, there are a small group of compounds which produce rotation associated with direct receptor activation, which is inhibited by disruption of pre-synaptic dopamine function. The mechanism of action of this latter group is not understood, but cannot be attributed solely to active metabolite formation.
Differential labelling of dopamine receptors in rat brain in vivo: comparison of [3H]piribedil, [3H]S 3608 and [3H]N,n-propylnorapomorphine.
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