This study reports the pharmacologic induction of behavioral pharmacologic hypersensitivity in an animal model of tardive dyskinesia. Four groups of rats received IP injections twice daily of 2.5 mg/kg haloperidol (H), 10 mg/kg benztropine (B), 2.5 mg/kg H plus 10 mg/kg benztropine (H + B), or saline for 4 weeks. Drug-induced catalepsy and spontaneous oral activity were measured daily during treatment. At 1 and 2 weeks after withdrawal of treatment, all groups were tested with apomorphine (AP) for the induction of stereotyped behavior. At 6 weeks after withdrawal of treatment, all animals were tested for catalepsy after receiving 2.5 mg/kg H. During the chronic treatment phase, H inhibited and B enhanced spontaneous oral activity. Also, H induced profound catalepsy during week 1, with partial tolerance to this effect observed during weeks 2-4. At 2 weeks after withdrawal, equivalent enhancement of AP stereotypy was seen in the H and B groups, but H + B (and saline) did not cause enhancement. At 6 weeks after withdrawal, enhancement of catalepsy was observed in the H and B groups, while H + B and control groups did not differ. Both H and B administered chronically can produce hypersensitivity when given alone, but this effect is attenuated when H and B are given in combination. While preservation of the dopamine-(DA)-acetylcholine balance during treatment appears to protect against hypersensitivity, the blockade of DA reuptake by benztropine, rather than its anticholinergic properties, may explain both the failure of combined treatment to induce hypersensitivity and the ability of B alone to induce hypersensitivity.