Trifluoperazine (2.5–3.5 mg/kg/day) or thioridazine (30–40 mg/kg/day) were given in the drinking water to male Wistar rats for 12 months. Initial catalepsy and inhibition of spontaneous locomotion disappeared by 3 months and thereafter. Initial inhibition of stereotypy induced by s.c. apomorphine also disappeared by 3 months to be replaced by an enhanced stereotypy response after 6 and 12 mohths' drug intake. Drug-treated animals exhibited a greatly increased incidence of spontaneous mouth movements after 12 months' intake compared with control animals. Lower doses of both drugs (trifluoperazine 0.7–0.9 mg/kg/day; thioridazine 6–8 mg/kg/day) also initially suppressed behavioural responses but by 1 month and thereafter these animals were indistinguishable from controls. At 12 months, however, these animals also exhibited an incidence of spontaneous mouth movements.
The data demonstrate a reversal of the initial dopamine receptor-blocking properties of trifluoperazine or thioridazine to be raplaced by an enhanced response of cerebral dopamine systems while animals were still continuously receiving the drug.