Oral dyskinesias and morphological changes in rat striatum during long-term haloperidol administration

Rationale: Neuroleptic-induced oral dyskinesias in rats, a putative analogu e to human tardive dyskinesia, may be due to increased glutamate release wi thin the striatum. This may lead to excitotoxic degeneration and, as a cons equence, persistent motor side effects. Objectives: To investigate whether alterations in glutamatergic synapses within the striatum are associated wi th the development of neuroleptic-induced oral dyskinesia. Methods: Haloper idol was administered for 20 weeks, and rats with high and low levels of va cuous chewing movements (VCM) were analyzed for morphological changes with electron microscopy at three time points. Results: At week 8, the high VCM rats had a larger nerve terminal area and lower density of nerve terminal g lutamate immunoreactivity than the other groups. After 18 weeks of treatmen t, the nerve terminal area was increased relative to controls in both the h igh and low VCM groups. After discontinuation of treatment, there were no s ignificant morphological differences between the groups, but the level of V CM was still significantly increased in the high VCM group. Conclusions: Th ese results show that striatal glutamatergic transmission is affected durin g haloperidol treatment and the nerve terminal area and the density of nerv e terminal glutamate immunoreactivity are important in determining the VCM response to haloperidol treatment. This indicates that increased glutamater gic synaptic activity in the striatum contributes to the development of hum an tardive dyskinesia.