Behavioral Responses To Mptp

Systemic rather than intracarotid or intrastriatal administration of MPTP produces bilateral clinical manifestations. These effects may be severe at first and then gradually diminish over time. Clinical manifestations include bradyki-nesia, akinesia (or lack of spontaneous activity), flexed posturing, and tremor. A few reports have also documented paradoxical kinesia, which is the abrupt onset of rather fast movement when a severely affected animal is confronted with a sudden threat such as the approach of an investigator (Degryse and Colpaert 1986). This response is well known in human PD and adds to the clinical validity of the animal model. However, in animals exposed to MPTP that have severe bilateral clinical manifestations, these motor deficits may gradually reduce over the course of one to two years (Oiwa et al. 2003). For some longitudinal research studies, this reduction can be a major limiting factor or potential confound.

Unilateral internal carotid administration of MPTP produces reduction of dopaminergic neurons and reduction of striatal dopamine content on only one side of the brain. MPTP was administered this way in a wide variety of nonhuman primates including baboons (Todd et al. 1996), rhesus macaques (Chen et al. 1991), marmosets (Jenner et al. 1984), nemestrina (Barrio et al. 1990), and cynomolo-gous macaques (Joyce et al. 1986). The original intent was to provide a model of Parkinsonism with its attendant clinical features produced by striatal dopamine deficiency. However, many investigators described an acute phase beginning within one day of MPTP administration before more typical parkinsonian manifestations developed. Upon further evaluation, this early, transient phase appears to have features similar to human dystonia with abnormal extensor-type posturing of the upper and lower limbs contralateral to the side of MPTP administration (Perlmutter et al. 1997a). This may be associated with ipsiversive (with respect to the side of MPTP injection) spontaneous rotation of the animal. This transient dystonic phase may last several weeks and then is followed by stable parkinsonism lasting at least one to two years (Perlmutter et al. 1997a). Interestingly, dystonia may be an early manifestation of PD, especially in young onset PD (Lucking et al. 2000; Bonifati et al. 2001; Khan et al. 2003; Fishman and Oyler 2002; Lohmann et al. 2003). Thus intracarotid administration of MPTP may provide a model of transient dystonia as well as chronic, stable parkinsonism.

The behavioral responses to MPTP appear to be age-dependent, whether given systemically or via the intra-carotid route (Degryse et al. 1986; Ovadia et al. 1995; Irwin et al. 1997; Narabayashi et al. 1987). Younger immature or adolescent animals may have no or little behavioral response to MPTP. At least in adolescent animals, repeated exposures may produce a behavioral deficit suggesting that sensitivity to MPTP reflects an age-dependence of the nigrostriatal damage induced by MPTP (Guttman 1988; Ovadia 1995; Burns 1991; Doudet 1998). The pathophysiology of this age-related sensitivity remains to be determined.

Some researchers have also used this model of nigrostri-atal injury to assess its effects on cognitive function. For example, cognitive and oculomotor impairments may develop before onset of motor deficits in MPTP monkeys (Slovin et al. 1999). More specifically, spatial working memory may be impaired by MPTP and then improved by selective nicotinic receptor agonists (Schneider et al. 2003). Another study has investigated the effects of MPTP-induced dopamine depletion on the function of mesial frontal areas with prioprioceptive-guided limb movements (Escola et al. 2002).

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