The general characteristics observed in MPTP-treated primates and those induced by subsequent drug treatment are summarised in Table 3. All primate species treated with MPTP develop ­slowness of movement, impairment of normal motor tasks (motor disability) and postural abnormalities. The characteristic rest tremor of PD is not seen in all laboratories or in all primate species. While rest tremor is reported in vervet monkeys, in other species it is often postural in nature or appears on intention of movement (26). The onset of motor disability can affect balance and cause postural instability that is very apparent in species that move between perches. Freezing or impairment of gait can also be present. The alterations in motor function may impair feeding and drinking and these need to be carefully monitored through direct measurement and by monitoring body weight. Associated with MPTP treatments are reports of alterations in visual fields, cognitive change and sleep disturbance, all of which are also features of PD (27–30). Autonomic function may be impaired, but this has not been extensively investigated.

Reversal of motor abnormalities is produced by the administration of dopamine replacement therapy, and this may lead to hyperactivity and stereotyped behaviour at higher dosages. Repeated treatment with l-dopa has been consistently found to induce dyskinesia consisting of chorea, dystonia and athetosis that closely resembles involuntary movements observed in PD (11, 31–33). Chronic treatment has also been reported to cause other motor complications and fluctuations, including “wearing off” and “on-off” (34). However, with the exception of dyskinesia, these have not been extensively studied or characterised. There are reports of hallucinations/psychosis in response to dopaminergic treatment of MPTP-treated primates, but assessment of this requires further validation (35).

In general, motor dysfunction responds to dopaminergic therapy in a manner that is highly predictive of the drug effect in man. Most studies of drug effect have been undertaken in relatively few laboratories in a few species, so it is difficult to be certain that there is consistency of drug response or of drug dosage or duration of drug effect. Certainly, those drugs used clinically to treat PD are effective – these include l-dopa and the ergot and non-ergot dopamine agonists. Amantadine is used to suppress dyskinesia in man and it can block dyskinetic movements in MPTP-treated primates, but the dosages required are relatively high and these effects are not easy to see when high doses of l-dopa are employed. The value of the MPTP-treated primate in assessing non-dopaminergic approaches to the treatment of PD remains to be validated by iteration from subsequent clinical trials. A number of pharmacological classes have been reported to produce symptomatic improvement of motor function and to prevent or suppress dyskinesia, but there have been gaps in attempting to translate these in to the clinic either because of lack of efficacy, problems with bioavailability or the occurrence of side-effects. The ability of the MPTP-treated primate to successfully predict a neuroprotective or neurorestorative effect is so far unproven and there have been disappointing results on subsequent clinical investigation for disease modification. However, the model should be viable for assessing the effects of neurotrophic factors, viral vectors and other gene therapies and for cell-based approaches to treatment (see later). Indeed, some approaches that have been demonstrated to be effective in the MPTP-treated primate have now been advanced to the clinic with some degree of both success and failure.

The way in which motor dysfunction is assessed in MPTP-treated primates varies between the laboratories undertaking these studies (Table 4). Many laboratories use the automated rating of locomotor activity with technologies ranging from the use of photocells through actimeters and telemetry to computerised positional monitoring through video linkage. Visual rating is also used, but this can be subjective and only semi-quantitative in nature.

When considering components of motor disability, then invariably a rating scale is employed as the aspects of behaviour that are altered do not lend themselves to any type of automated recording. Ratings scales range from basic descriptions of the extent of motor disability through to those that break motor impairment down in to discrete categories and reflect worsening movement. In some laboratories, the rating of animals is undertaken in real time, whereas others utilise the subsequent rating of video recordings. Our own view is that the behaviour of the animals cannot be adequately assessed from a single angle and that a trained observer is more likely to correctly rate all behavioural components. Even so, ratings of motor disability are only made at intervals during the course of a study and as such are merely snapshots of events that occur.

Dyskinesia also does not lend itself to automated assessment, and rating scales are invariably employed. The involuntary movements can be focal, segmental or generalised and involve different body parts. Dyskinesia is a general term covering all involuntary movement, but there are clearly choreic, dystonic and athetotic components. Some scoring systems do not distinguish between these components, whereas others measure chorea and dystonia as being distinct. Rating scales are semi-quantitative and vary in the depth of assessment made as for motor disability. There have been attempts to produce a unified rating scale, but this has not been widely adopted (36). This probably reflects differences in opinion over what constitutes dyskinesia in different primate species. One clear distinction that must be made is between dyskinesia and stereotypy. We would describe stereotypy as the onset of repetitive purposeless movements that remain within the normal repertoire of voluntary movement, whereas dyskinesia is characterised by its involuntary, abnormal and fleeting expression.

There has been an attempt to rate psychosis and hallucinations induced by dopaminergic drugs in MPTP-treated primates (35). Our own view is that while strange behaviours are observed where animals are gazing in to the distance and appear startled by unseen events, it is difficult to relate this to the accepted features of a ­psychotic state.

The common marmoset (C. jacchus) is commonly utilised for MPTP treatment and for the evaluation of potential antiparkinsonian therapies. This small, laboratory bred species has many advantages as the animal of choice for this type of investigation. The advantages of the common marmoset are listed in Table 5. We have utilised the common marmoset for 25 years and have found it to be highly suited to studies involving MPTP treatment and very predictive of drug effect subsequently uncovered in PD in man.

In the following sections, we describe in detail the exact procedure that is utilised in our laboratories for MPTP treatment that is necessary to ensure both appropriate animal welfare and the production of motor deficits closely resembling those that occur in PD. We also describe the procedure, which we use to subsequently evoke consistent dyskinesia. The methods for the assessment of locomotor activity, motor disability and dyskinesia are also described.