New Rodent Model of TD 1941 Development of the Model

To replicate the essential feature of TD, an animal model must display regularity of spontaneous orofacial dyskinesias, i.e., perioral movements occurring in the absence of any treatment. Occasional sporadic VCMs in rodents do not fulfill this criterion. Therefore, the behavioral outcome (VCMs) produced by long-term administration of haloperidol was the first true animal model of TD (Waddington et al. 1983; Waddington 1990). Long-term haloperidol administration did ultimately increase the number of VCMs in rats, but only after ~4 months; thus, the characteristic tardive feature was fulfilled. Additionally, the high level of perioral movements persisted for as long as haloperidol continued to be administered. However, as already noted, VCMs disappeared within 4-6 weeks after haloperidol treatment was discontinued.

Taking into account the finding of Gunne et al. (Gunne et al. 1982) regarding enhancement of neuroleptic-evoked perioral dyskinesias after brain injury, as well as the generally accepted notion of DA D1 receptor supersensitivity in TD and in animal models of TD, we undertook the combined approach of first DA-denervating neostriatum in neonates with 6-OHDA, then starting the daily haloperidol treatment regimen when rats attained adulthood (Huang and Kostrzewa 1994). Advantages of this animal model were as follows.

An increase in spontaneous oral dyskinesia occurred after 3 months of haloperi-dol administration (in drinking water) in 6-OHDA-lesioned rats versus 4 months in intact controls that received haloperidol.

Numbers of vacuous chewing movements were approximately fivefold greater in haloperidol-treated 6-OHDA-lesioned rats than in haloperidol-treated intact controls, beginning from its initiation and through the remainder of the 1-year halo-peridol treatment period.

After discontinuing haloperidol as a 1-year treatment, spontaneous oral dyskine-sias persisted at the same high level in 6-OHDA-lesioned rats as during the halo-peridol treatment phase - the first time that this effect was obtained in chronic haloperidol-treated rats.

In intact and in 6-OHDA-lesioned rats terminated 1 week after discontinuing haloperidol, the Bmax for raclopride binding in neostriatum was elevated, while the Kd was unaltered. This animal model thus replicated the effects of haloperidol in initiating TD. Moreover, the persistence of a high level of VCMs following withdrawal of haloperidol as a treatment in 6-OHDA-lesioned rats, more closely replicated the effects of human TD. Also, the biochemical parameters relating to haloperidol-induced proliferation of D2 receptor number in 6-OHDA-lesioned rats similarly mirrored findings of human Td (Huang et al. 1997).

One other finding revealed another aspect of TD. In 6-OHDA-lesioned rats terminated 8 months after discontinuing haloperidol, both the Bmax and Kd for raclo-pride binding to neostriatal homogenates were at the same level as in intact control rats. The finding that VCMs persist at a high level in 6-OHDA-lesioned rats following withdrawal from long-term haloperidol treatment, indicates that changes in D2 receptor number appear to be irrelevant in terms of sustenance of the high level of oral dyskinesia in the rats (Huang et al. 1997).

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