Concluding Remarks

The Parkinson's-Reversing Breakthrough

Parkinson Disease Cure

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Thanks to the efforts of many investigators, a wide repertoire of behavioral testing methods have now been devised and characterized to permit a preclinical screening of anti-Parkinsonian treatments in the rat. Our laboratory has contributed to the characterization and validation of the first testing method that specifically rates L-dopa-induced abnormal involuntary movements (dyskinesia) in the rat. Since new treatments for PD will be successful to the extent that they can alleviate akinesia without producing abnormal movements and postures, the availability of a dyskinesia model in the rat represents a considerable methodological and conceptual advance. As we have illustrated in this chapter, different behavioral tests evaluate different aspects of a rat's motor function, they show different relationships to the degree of brain DA depletion, and exhibit different sensitivities to the anti-akinetic effect of L-dopa and to the disrupting effect of L-dopa-induced dyskinesia. Thus, the power and predictive validity of the 6-OHDA lesion model will be considerably increased by implementing different testing methods in the same study, or series of studies. A clear example of this concept is provided in the field of intra-cerebral transplantation. The first studies of fetal nigral grafts in the rat 6-OHDA model reported complete restoration of drug-induced rotational asymmetries. Later implementation of more articulate testing routines, however, showed that intra-cerebral grafts have a limited capacity to restore complex and physiologically more relevant behaviors (Herman et al. 1986; Mandel et al. 1990; Abrous et al. 1993). The need for articulate behavioral testing is further highlighted by the necessity to differentiate anti-akinetic treatments that restore normal motor patterns from those that also induce abnormal movements and postures. Moreover, if investigators specifically design aim at evaluating novel treatments for L-dopa-induced dyskinesia, they must combine ratings of dyskinesia with assessments of adaptive motor behavior in the same study. Indeed, clinically useful treatments against dyskinesia should eliminate abnormal movements and postures without compromising the therapeutic effect of L-dopa. Dyskinesias can indeed be reduced by treatments that have a general motor depressant effect and thus interfere with the anti-akinetic effect of L-dopa, but these treatments would obviously not bear any promise for a better management of PD. Thanks to the advances made in the behavioral analysis of 6-OHDA lesioned rats, investigators can now evaluate both anti-dyskinetic and anti-akinetic treatments for PD in the rat in a clinically relevant way.

Video Legends

SEGMENT 1 Axial dystonia/dyskinesia. After treatment with l-DOPA, rats with a unilateral 6-OHDA lesion show torsional movements and twisted postures of the trunk and the neck toward the side contralateral to the lesion. When the dystonic posture of the upper trunk is very severe it may cause the animal to lose balance and fall down to the floor, making one or more rotational movements before regaining a bipedal sitting position (note that the asymmetric body posture precedes and accompanies the rotational movement).

SEGMENT 2 Limb dyskinesia. After administration of l-DOPA, the forelimb contralateral to the lesion is engaged in hyperkinetic, fluttering movements involving both the proximal and distal forelimb and the digits. Note the random (chorea-like) variation in the direction, amplitude and frequency of the movements. The movements are purposeless and not part of the normal motor repertoire of the rat.

SEGMENT 3 Orolingual dyskinesia. These video recordings show empty, asymmetric jaw movements, associated with rapid twitching of orofacial muscles, and protrusion of the tongue towards the side contralateral to the lesion. These movements are induced by l-dopa and are not part of the grooming and gnawing behavior that is normal for a rat.

SEGMENT 4 Locomotive dyskinesia. In this sequence, the animal shows persistent hyperactive locomotion with a contralateral side bias. In our rating scale, locomotive AIM scores are given only when all four limbs contact the floor to perform an active turn (passive turns caused by side falling are not scored).

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