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

Löschmann, P.-A.; Smith, Lance A.; Lange, Klaus W.; Jähnig, Peter; Jenner, Peter; Marsden, C. D.

doi:10.1007/bf02245479

Cited by 46 publications

(14 citation statements)

References 27 publications

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“…Locomotor and behavioural deficits were induced by subcutaneous administration of MPTP (1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine hydrochloride; Research Biochemical International, Natick, MA) 2.0 mg/kg daily for 5 consecutive days dissolved in sterile 0.9% saline solution 34, 35. Over the following 6 to 8 weeks, animals were hand fed on a daily basis with Mazuri marmoset jelly until the animals had recovered from the acute motor effects of MPTP treatment.…”

Section: Methodsmentioning

confidence: 99%

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Effect of pulsatile administration of levodopa on dyskinesia induction in drug‐naïve MPTP‐treated common marmosets: Effect of dose, frequency of administration, and brain exposure

et al. 2003

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Levodopa (L-dopa) consistently primes basal ganglia for the appearance of dyskinesia in parkinsonian patients and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP) -treated primates. This finding may reflect its relatively short duration of effects resulting in pulsatile stimulation of postsynaptic dopamine receptors in the striatum. We have compared the relationship between L-dopa dose and frequency of administration on dyskinesia initiation in drug-naïve, MPTP-treated common marmosets. We have also studied the effect of increased brain exposure to pulsatile administration by combining a low-dose of L-dopa with the peripheral catechol-O-methyltransferase inhibitor (COMT-I), entacapone. Pulsatile administration of a low (dose range, 5.0-7.5 mg/kg p.o.) or a high (12.5 mg/kg) dose of L-dopa plus carbidopa b.i.d. produced a dose-related reversal of motor deficits. Repeated administration of low and high doses of L-dopa for 26 days to drug-naïve, MPTP-treated animals also caused a dose-related induction of peak-dose dyskinesia. Repeated administration of high-dose L-dopa b.i.d. compared to once daily caused a frequency-related improvement of motor symptoms, resulting in a more rapid and initially more intense appearance of peak-dose dyskinesia. Administration of low-dose L-dopa b.i.d. for 26 days in combination with entacapone enhanced the increase in locomotor activity and reversal of disability produced by L-dopa alone, but with no obvious change in duration of L-dopa's effect. However, combining entacapone with L-dopa resulted in the more rapid appearance of dyskinesia, which was initially more severe than occurred with L-dopa alone. Importantly, increasing pulsatile exposure of brain to L-dopa by preventing its peripheral breakdown also increases dyskinesia induction.

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Section: Methodsmentioning

confidence: 99%

“…Interruptions of an infrared beam, by movement were automatically recorded as a single locomotor count. Locomotor counts were accumulated over 30‐minute periods for the 8‐hour duration of experimentation 35. Throughout the study, animals had ad libitum access to Mazuri marmoset food pellets and fresh water.…”

Section: Methodsmentioning

confidence: 99%

Effect of pulsatile administration of levodopa on dyskinesia induction in drug‐naïve MPTP‐treated common marmosets: Effect of dose, frequency of administration, and brain exposure

et al. 2003

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“…Baseline motility counts were measured approximately 2 weeks before administration of piribedil or L ‐dopa, and animals were subsequently allocated to treatment groups such that basal motility counts in each group was equivalent. The monitor was started immediately after drug administration and motility counts were accumulated over 30‐minute periods for 8 hours 13, 64, 65…”

Section: Methodsmentioning

confidence: 99%

“…Behavior was rated qualitatively to determine the presence or absence of grooming, stereotyped activity, retching/vomiting, oral movements, or other unusual motor activities. Assessments were undertaken by skilled behavioural pharmacologists (not blinded to drug treatments) with many years of experience in this field 13, 45–47, 64–67…”

Section: Methodsmentioning

confidence: 99%

Repeated administration of piribedil induces less dyskinesia than L‐dopa in MPTP‐treated common marmosets: A behavioural and biochemical investigation

et al. 2002

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Piribedil ([1-(3,4-methylenedioxybenzyl)-4-(2-pyrimidinyl)piperazine]; S 4200) is a dopamine agonist with equal affinity for D(2)/D(3) dopamine receptors effective in treating Parkinson's disease as monotherapy or as an adjunct to levodopa (L-dopa). However, its ability to prime basal ganglia for the appearance of dyskinesia is unknown. We now report on the ability of repeated administration of piribedil to induce dyskinesia in drug naïve 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) -lesioned common marmosets compared with L-dopa and its actions on the direct and indirect striatal outflow pathways. Administration of piribedil (4.0-5.0 mg/kg orally) or L-dopa (12.5 mg/kg orally plus carbidopa 12.5 mg/kg orally twice daily) produced equivalent increases in locomotor activity and reversal of motor deficits over a 28-day study period. Administration of L-dopa resulted in the progressive development of marked dyskinesia over the period of study. In contrast, administration of piribedil produced a significantly lower degree and intensity of dyskinesia. Surprisingly, piribedil caused an increase in vigilance and alertness compared to L-dopa, which may relate to the recently discovered alpha(2)-noradrenergic antagonist properties of piribedil. The behavioural differences between piribedil and L-dopa are reflected in the biochemical changes associated with the direct striatal output pathway. Administration of L-dopa or piribedil did not reverse the MPTP-induced up-regulation of preproenkephalin A mRNA in rostral or caudal areas of the putamen or caudate nucleus. In contrast, administration of either piribedil or L-dopa reversed the downregulation of preprotachykinin mRNA induced by MPTP in rostral and caudal striatum. L-dopa, but not Piribedil, reversed the decrease in preproenkephalin B mRNA produced by MPTP treatment.

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“…The MPTP-treated common marmoset exhibits stable parkinsonian deÞcits which are reversed by administration of L-dopa and other D 1 /D 2 agents, and by selective D 2 and D 1 -acting compounds (Jenner et al 1984;Temlett et al 1989;Kebabian et al 1992;Löschmann et al 1992). Recently, we have shown that the common marmoset, in common with other MPTPlesioned primate species, develops dyskinesias after chronic L-dopa administration and that repeated administration of the selective D 1 agonist A-77636 to L-dopa-primed MPTP-lesioned marmosets resulted in a gradual reduction in the intensity of dyskinesia with a retained antiparkinsonian e¤ect (Pearce et al 1995).…”

Section: Introductionmentioning

confidence: 98%

Actions of the D 1 agonists A-77636 and A-86929 on locomotion and dyskinesia in MPTP-treated L -dopa-primed common marmosets

et al. 1999

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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 micromol/kg and then at 1.0 micromol/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 micromol/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.

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

Cited by 46 publications

References 27 publications

Effect of pulsatile administration of levodopa on dyskinesia induction in drug‐naïve MPTP‐treated common marmosets: Effect of dose, frequency of administration, and brain exposure

Effect of pulsatile administration of levodopa on dyskinesia induction in drug‐naïve MPTP‐treated common marmosets: Effect of dose, frequency of administration, and brain exposure

Repeated administration of piribedil induces less dyskinesia than L‐dopa in MPTP‐treated common marmosets: A behavioural and biochemical investigation

Actions of the D 1 agonists A-77636 and A-86929 on locomotion and dyskinesia in MPTP-treated L -dopa-primed common marmosets

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