S C Cheetham

Publications (3)8.33 Total impact

• Article: Does contraversive circling in the 6-OHDA-lesioned rat indicate an ability to induce motor complications as well as therapeutic effects in Parkinson's disease?

  E L Lane, S C Cheetham, P Jenner
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  ABSTRACT: Circling behaviour in unilateral 6-OHDA-lesioned rats is interpreted as being opposite in direction to the side of the brain with highest striatal dopaminergic activation. Ipsiversive rotation indicates an action on the intact striatum, while contraversive rotation demonstrates an effect on dopamine receptors in the denervated striatum and is taken as predictive of symptomatic benefit in Parkinson's disease. But does an equivalent behavioural outcome result from stimulating the intact and denervated striatum to the same degree? We report on the behavioural responses produced by administration of L-dopa and the monoamine uptake inhibitor BTS 74,398. These were given alone, or in combination, at doses equivalent to their ED(25), ED(50) and ED(75) for inducing circling in unilateral 6-OHDA-lesioned rats. L-dopa administered alone induced dose-dependent contraversive circling while BTS 74,398 produced ipsiversive rotation. However, L-dopa and BTS 74,398 in combination, produced the same contraversive circling response as when L-dopa was administered alone. Little or no ipsiversive rotation occurred, irrespective of the combination of doses employed. This surprising finding suggests that there are major differences in the outcome of stimulating the intact and denervated striatum with the latter dominating the behavioural response. Since repeated administration of L-dopa but not BTS 74,398, sensitises rotational responses and induces abnormal movements, it may be that contraversive rotation is predictive of both clinical response in PD and the ability to induce motor complications.
  Experimental Neurology 03/2006; 197(2):284-90. · 4.70 Impact Factor
• Article: Repeated administration of the monoamine reuptake inhibitor BTS 74 398 induces ipsilateral circling in the 6-hydroxydopamine lesioned rat without sensitizing motor behaviours.

  E L Lane, S C Cheetham, P Jenner
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  ABSTRACT: BTS 74 398 (1-[1-(3,4-dichlorophenyl)cyclobutyl]-2-(3-diaminethylaminopropylthio)ethanone monocitrate) is a monoamine reuptake inhibitor that reverses motor deficits in MPTP-treated (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) common marmosets without provoking established dyskinesia. However, it is not known whether BTS 74 398 primes the basal ganglia for dyskinesia induction. In this study, the ability of BTS 74 398 to sensitize 6-hydroxydopamine (6-OHDA)-lesioned rats for the production of abnormal motor behaviours and the induction of striatal DeltaFosB were determined in comparison with l-3,4-dihydroxyphenylalanine methyl ester (L-dopa). Acute administration of BTS 74 398 induced a dose-dependent ipsilateral circling response in unilaterally 6-OHDA-lesioned rats whereas L-dopa produced dose-dependent contraversive rotation. The ipsilateral circling response to BTS 74 398 did not alter during 21 days of administration. In contrast, L-dopa treatment for 21 days caused a marked increase in rotational response. Repeated administration of both L-dopa and BTS 74 398 increased general motor activity and stereotypic behaviour. In L-dopa-treated rats, orolingual, locomotive, forelimb and axial abnormal movements developed whereas BTS 74 398 produced only locomotion with a side bias but no other abnormal movements. Sensitization of circling responses and the development of abnormal movements in 6-OHDA-lesioned rats have been associated with the potential of dopaminergic drugs to induce dyskinesia. Furthermore, striatal DeltaFosB immunoreactivity, shown to correlate with dyskinesia induction, was increased by L-dopa but was unaffected by repeated BTS 74 398 administration. The lack of such changes following repeated BTS 74 398 treatment suggests that it may be an effective antiparkinsonian therapy that is unlikely to produce involuntary movements.
  European Journal of Neuroscience 02/2005; 21(1):179-86. · 3.63 Impact Factor
• Article: Does contraversive circling in the 6-OHDA-lesioned rat indicate an ability to induce motor complications as well as therapeutic effects in Parkinson's disease?

  E.L. Lane, S.C. Cheetham, P. Jenner
  [show abstract] [hide abstract]
  ABSTRACT: Circling behaviour in unilateral 6-OHDA-lesioned rats is interpreted as being opposite in direction to the side of the brain with highest striatal dopaminergic activation. Ipsiversive rotation indicates an action on the intact striatum, while contraversive rotation demonstrates an effect on dopamine receptors in the denervated striatum and is taken as predictive of symptomatic benefit in Parkinson's disease. But does an equivalent behavioural outcome result from stimulating the intact and denervated striatum to the same degree? We report on the behavioural responses produced by administration of l-dopa and the monoamine uptake inhibitor BTS 74 398. These were given alone, or in combination, at doses equivalent to their ED25, ED50 and ED75 for inducing circling in unilateral 6-OHDA-lesioned rats. l-dopa administered alone induced dose-dependent contraversive circling while BTS 74 398 produced ipsiversive rotation. However, l-dopa and BTS 74 398 in combination, produced the same contraversive circling response as when l-dopa was administered alone. Little or no ipsiversive rotation occurred, irrespective of the combination of doses employed. This surprising finding suggests that there are major differences in the outcome of stimulating the intact and denervated striatum with the latter dominating the behavioural response. Since repeated administration of l-dopa but not BTS 74 398, sensitises rotational responses and induces abnormal movements, it may be that contraversive rotation is predictive of both clinical response in PD and the ability to induce motor complications.
  Experimental Neurology.