C. D. Marsden

L-dopa withdrawal in Parkinson's disease selectively impairs cognitive performance in tests sensitive to frontal lobe dysfunction

A group of ten patients with idiopathic Parkinsons disease (PD) was tested on a series of automated tests of learning, memory, planning and attention whilst either on or offl-dopa medication. Controlled with-drawal ofl-dopa interfered with aspects of performance on three of the tests that had previously been shown to be sensitive to frontal lobe dysfunction; a spatial working memory task, the Tower of London planning test, and a visual discrimination paradigm that also included intra- and extra-dimensional shift tests of selective attention. More specifically, errors were increased in the spatial working memory test, and both the accuracy and latency of thinking were impaired. Thinking time was significantly slowed followingl-dopa withdrawal, even though the possible contaminating effects on motor slowing were fully controlled by a yoked control procedure. Nine out of ten patients reached a further stage of the visual discrimination, set-shifting paradigm when on, rather than off,l-dopa medication. Spatial span was also impaired off medication, but there were no effects ofl-dopa withdrawal on tests of pattern and spatial recognition memory, simultaneous and delayed matching to sample or visuospatial conditional associative learning. Comparisons with a large control group confirmed previous findings that PD is associated with deficits on the majority of these tests. The results are discussed in terms of the fronto-striatal, dopamine dependent nature of some of the cognitive deficits found in PD, but the apparent dopamine-independent nature of deficits in other aspects of cognitive functioning, notably in tests of visual recognition memory and associative learning.

Synergism of the AMPA-antagonist NBQX and the NMDA-antagonist CPP with L-Dopa in models of Parkinson's disease

SummaryDegeneration of dopaminergic nigrostriatal neurons in Parkinsons disease results in an overactivity of excitatory glutamatergic projections from the subthalamic nucleus to the output nuclei of the basal ganglia resulting in rigidity and akinesia. In theory pharmacological blockade of these overactive systems should improve parkinsonian symptomatology. The selective AMPA-antagonist NBQX and the competitive NMDA-antagonist CPP are not effective in animal models of Parkinsons disease when given alone but ameliorate parkinsonian symptomatology and stimulate locomotor activity when co-administered with a threshold dose of L-Dopa. These synergistic effects are seen in the MPTP-treated (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) common marmoset and the rat with unilateral 6-hydroxydopamine (6-OHDA) lesions of the substantia nigra. Therefore competitive NMDA and non-NMDA antagonists may offer a new therapeutic strategy for the treatment of Parkinsons disease.

Altered muscarinic and nicotinic receptor densities in cortical and subcortical brain regions in Parkinson's disease

Abstract: Muscarinic and nicotinic cholinergic receptors and choline acetyltransferase activity were studied in postmortem brain tissue from patients with histopathologically confirmed Parkinsons disease and matched control subjects. Using washed membrane homogenates from the frontal cortex, hippocampus, caudate nucleus, and putamen, saturation analysis of specific receptor binding was performed for the total number of muscarinic receptors with [3H]quinuclidinyl benzilate, for muscarinic M1 receptors with [3H]pirenzepine, for muscarinic M2 receptors with [3H]oxotremorine‐M, and for nicotinic receptors with (–)‐[3H]nicotine. In comparison with control tissues, choline acetyltransferase activity was reduced in the frontal cortex and hippocampus and unchanged in the caudate nucleus and putamen of parkinsonian patients. In Parkinsons disease the maximal binding site density for [3H]quinuclidinyl benzilate was increased in the frontal cortex and unaltered in the hippocampus, caudate nucleus, and putamen. Specific [3H]pirenzepine binding was increased in the frontal cortex, unaltered in the hippocampus, and decreased in the caudate nucleus and putamen. In parkinsonian patients Bmax values for specific [3H]oxotremorine‐M binding were reduced in the cortex and unchanged in the hippocampus and striatum compared with controls. Maximal (–)‐[3H]nicotine binding was reduced in both the cortex and hippocampus and unaltered in both the caudate nucleus and putamen. Alterations of the equilibrium dissociation constant were not observed for any ligand in any of the brain areas examined. The present results suggest that both the innominatocortical and the septohippocampal cholinergic systems degenerate in Parkinsons disease. The reduction of cortical [3H]oxotremorine‐M and (–)‐[3H]nicotine binding is compatible with the concept that significant numbers of the binding sites labelled by these ligands are located on presynaptic cholinergic nerve terminals, whereas the increased [3H]pirenzepine binding in the cortex may reflect postsynaptic denervation supersensitivity.

Motor activity following the administration of selective D-1 and D-2 dopaminergic drugs to normal common marmosets

In normal common marmosets administration of the D-1/D-2 agonist apomorphine or the selective D-2 agonist quinpirole caused a dose-dependent increase in motor activity and induced stereotyped behaviour. Both the selective D-2 antagonist raclopride and the selective D-1 antagonist SCH 23390 inhibited normal locomotor activity and induced catalepsy. Quinpirole- and apomorphine-induced motor activity were potently inhibited by pretreatment with raclopride. The effects of quinpirole, but not apomorphine, were weakly inhibited by SCH 23390. The selective D-1 partial agonist SKF 38393 decreased motor activity and did not induce grooming, oral movements or other behaviours. SKF 38393 inhibited motor activity induced by the administration of quinpirole but did not alter apomorphine-induced motor behaviour. Locomotor activity in normal common marmosets appears to be mediated mainly via D-2 systems. In contrast to rodents, administration of SKF 38393 does not induce behavioural activation and there does not appear to be a facilitating effect of D-1 systems on D-2 function in the normal common marmoset. However, the ability of both SKF 38393 and SCH 23390 to inhibit quinpirole locomotor activity suggests some interaction between D-1 and D-2 systems to occur in this species.

Alien hand sign in association with Alzheimer's histopathology.

A 68 year old man is described with an alien left hand, cortical myoclonus, bilateral parietal lobe dysfunction and memory impairment but preserved language skills. The clinical diagnosis was of corticobasal degeneration but at necropsy, four years after the onset of symptoms, the pathology was of Alzheimers disease together with some scattered chromatolytic pale neurons in the cerebral cortex. The alien hand sign has not previously been described in Alzheimers dementia and is an illustration of the clinical heterogeneity that may occur in association with Alzheimer histopathology.

Drugs acting at D-1 and D-2 dopamine receptors induce identical purposeless chewing in rats which can be differentiated by cholinergic manipulation

Purposeless chewing in rats was dose dependently increased by acute administration of the dopamine D-1 receptor agonist SKF 38393 (5–20 mg/kg), the D-2 receptor antagonist sulpiride (10–100 mg/kg) and the D-2 receptor agonist quinpirole (0.05–0.25 mg/kg). Only high doses of the D-1 receptor antagonist SCH 23390 (1 and 5 mg/kg) induced purposeless chewing. SCH 23390 (0.05 mg/kg) blocked SKF 38393 (20 mg/kg)-induced purposeless chewing, but had no effect on the purposeless chewing induced by sulpiride (100 mg/kg) or quinpirole (0.1 mg/kg). A dose of SKF 38393 (5 mg/kg) which did not itself induce chewing, potentiated the increase in purposeless chewing observed after administration of sulpiride (100 mg/kg). Administration of SKF 38393 (20 mg/kg) and quinpirole (0.1 mg/kg) did not induce purposeless chewing but stereotyped licking was observed. Administration of sulpiride (100 mg/kg) with quinpirole (0.1 mg/kg) produced an incidence of purposeless chewing not different from that observed when either compound was administered alone. Acute administration of the cholinergic agonist pilocarpine (0.5–4.0 mg/kg) or the cholinesterase inhibitor physostigmine (0.05–0.2 mg/kg) increased the frequency of purposeless chewing in rats. Co-administration of pilocarpine (0.5 mg/kg) with sulpiride (100 mg/kg) increased the frequency of purposeless chewing above that seen when either compound was administered alone. Co-administration of pilocarpine (0.5 mg/kg) with SKF 38393 (20 mg/kg) increased the frequency of purposeless chewing in an additive manner. Co-administration of physostigmine (0.1 mg/kg) with sulpiride (100 mg/kg) but not SKF 38393 (20 mg/kg), increased the frequency of purposeless chewing above that observed when either compound was administered alone. Quinpirole (0.1 mg/kg)-induced purposeless chewing was not affected by co-administration with either pilocarpine (0.5 mg/kg) or physostigmine (0.1 mg/kg). The anticholinergic agent scopolamine (0.1 mg/kg) blocked the purposeless chewing induced by either SKF 38393 (20 mg/kg) or sulpiride (100 mg/kg), but had no effect on the purposeless chewing induced by quinpirole (0.1 mg/kg). Contrary to previous reports, acute manipulation of D-1 or D-2 receptor function can both enhance purposeless chewing behaviour in rats. These apparently identical behaviours can be differentiated by the response to cholinergic manipulation.

Actions of the D1 agonists A-77636 and A-86929 on locomotion and dyskinesia in MPTP-treated L-dopa-primed common marmosets

Abstract Common marmosets show parkinsonian motor deficits following 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration and develop dyskinesias during chronic L-dopa exposure. The D1 agonists A-77636 [(1R, 3S) 3-(1’-adamantyl)-1-aminomethyl-3, 4-dihydro-5, 6-dihydroxy-1H-2-benzopyran HCl] and A-86929 [(−)-trans 9, 10-hydroxy-2-propyl-4, 5, 5a, 6, 7, 11b-hexahydro-3-thia-5-azacyclopent-1-ena[c]phenanthrene hydrochloride] possess potent antiparkinsonian activity in the MPTP-treated marmoset and we now assess their influence on L-dopa-induced dyskinesias. MPTP-treated marmosets with stable motor deficits were treated with L-dopa plus carbidopa for 28 days to induce dyskinesias. Subsequently, they received A-86929 for 10 days, initially at 0.5 μmol/kg and then at 1.0 μmol/kg for a further 5 days. Several months later, L-dopa 12.5 mg/kg plus carbidopa 12.5 mg/kg was given orally twice daily for 7 days, followed by A-77636 1 μmol/kg for 10 days, and then both A-77636 and L-dopa plus carbidopa were given concurrently for 3 further days. In these L-dopa-primed animals, A-86929 effectively reversed akinesia and produced dose-dependent dyskinesias which were significantly less intense than those produced by L-dopa administration. A degree of behavioral tolerance was encountered, but antiparkinsonian activity was preserved and elicited behaviour was free of hyperkinesis and stereotypy and more naturalistic than that seen with L-dopa. After a week of twice-daily L-dopa dosing, administration of the long-acting D1 agonist A-77636 initially dramatically enhanced locomotion and reproduced dyskinesia with prominent dystonia, but after repeated administration of A-77636, dyskinesia and in particular chorea, gradually disappeared. Tolerance to locomotor stimulation greater than with A-86929 occurred, although activity remained significantly above baseline levels. There was a marked reduction in L-dopa-induced climbing, stereotypy and hyperkinesis and behaviour more closely resembled that of normal unlesioned marmosets. Upon reintroduction of L-dopa concurrently with continued A-77636 administration, dystonic, but virtually no choreic dyskinesias appeared and behaviour was once again free of stereotypy and hyperkinesis, contrasting dramatically with the presence of these behaviours along with abundant chorea when L-dopa is given alone. These results show a lesser liability of A-86929 and A-77636 to reproduce dyskinesia in L-dopa-primed MPTP-lesioned subjects while maintaining effective antiparkinsonian activity and producing a more naturalistic motor response. The differential effects of A-77636 on chorea and dystonia, with suppression of chorea and stereotypy on co-administration with L-dopa, may reflect an altered balance of activity in the direct and indirect striatofugal pathways. These results suggest a possible role for D1 agonists in the treatment of Parkinson’s disease.

Brain muscarinic cholinergic receptors in Huntington's disease

SummaryMuscarinic cholinergic receptors and choline acetyltransferase (ChAT) activity were studied in postmortem brain tissue from patients with Huntingtons disease and matched control subjects. In comparison with controls, reductions in ChAT activity were found in the hippocampus, but not in the temporal cortex in Huntingtons disease. Patients with Huntingtons disease showed reduced densities of the total number of muscarinic receptors and of M-2 receptors in the hippocampus while the density of M-1 receptors was unaltered. Muscarinic receptor binding was unchanged in the temporal cortex. These results indicate a degeneration in Huntingtons disease of the septo-hippocampul cholinergic pathway, but no impairment of the innominato-cortical cholinergic system.

Electromyographical differentiation of the components of perioral movements induced by SKF 38393 and physostigmine in the rat.

Facial electromyography (EMG) coupled with visual observation was used to investigate spontaneous and drug induced perioral movements in freely moving rats. Four separate perioral behaviours were identified; facial tremor, purposeless chewing, gaping and yawning. Facial tremor, yawning and gaping but not purposeless chewing produced characteristic EMG signals. Normal rats displayed a low level of purposeless chewing, occasional bursts of facial tremor but not gaping or yawning. Each burst of facial tremor was accompanied by a transient increase in purposeless chewing. Administration of the D1 agonist SKF 38393 induced a dose related increase in bursts of facial tremors and consequently an increase in the total number of purposeless chews. Gaping and yawning were not induced by SKF 38393 administration. Administration of the cholinesterase inhibitor physostigmine (0.1–0.4 mg/kg) induced a dose related increase in the total number of purposeless chews, but primarily these were not associated with facial tremor. Administration of physostigmine also increased gaping and yawning. Administration of the D1 antagonist SCH 23390 almost abolished facial tremor in normal treated rats but only partially reduced that induced by SKF 38393 and physostigmine. SCH 23390 reduced purposeless chewing in SKF 38393 treated rats but not in normal or physostigmine treated animals. Administration of the cholinergic antagonist atropine almost abolished facial tremor in normal and physostigmine treated rats, but only reduced by 46% that induced by SKF 38393. Atropine reduced purposeless chewing in normal, physostigmine and SKF 38393 treated animals. Physostigmine induced gaping and yawning were abolished by atropine administration. Combined administration of SKF 38393 and physostigmine did not alter the total number of facial tremor bursts and purposeless chews compared to those observed in rats treated with physostigmine alone. Administration of SKF 38393 with physostigmine reduced physostigmine-induced yawning. The EMG technique described allows assessment of the different profiles of perioral movement induced by SKF 38393 and physostigmine, and the relationship that exists between the different components. The results suggest that it is necessary to individually assess each individual perioral behaviour. Assessment of only one component in isolation, or of an amalgamation of several behaviours will add to the confusion that exists over the origins of perioral movement.

Cortical nicotinic receptors in Alzheimer's disease and Parkinson's disease.

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