Quetiapine reverses altered locomotor activity and tyrosine hydroxylase immunoreactivity in rat caudate putamen following long-term haloperidol treatment

Haloperidol (HAL) is a typical antipsychotic drug and known to cause extrapyramidal symptoms (EPS) that may be associated with the blockade of dopamine D2-receptors in nigrostriatal pathway by the drug. In contrast, quetiapine (QTP) is an atypical antipsychotic drug that has the lowest incidence of producing EPS in patients with schizophrenia, while improving psychosis symptoms. In the present study, we investigated the possibility of reversing the HAL-induced changes in locomotor activity and in striatal tyrosine hydroxylase (TH) of rats. Rats were administered HAL (2 mg/kg/day, p.o.) for 3 months, followed by vehicle (VEH), QTP (10 mg/kg/day), HAL, or HAL + QTP for another 5 weeks. The locomotor activity and TH immunoreactivity of the rats were measured. Chronic administration of HAL caused significant increase in locomotor activity and lower levels of TH immunoreactivity in the caudate putamen of the striatum. When the long-term haloperidol treatment was removed, the change in TH immunoreactivity was normalized, while the HAL induced high level of locomotor activity was returned to normal level only in the rats that stopped HAL consumption and received QTP treatment. In the substantia nigra and ventral tegmental areas, all rats showed comparable numbers of TH-positive cell bodies, which had no shrinkage. These results support a previously proposed relationship between EPS and TH levels in the striatum and provide valuable preclinical information towards understanding why QTP produces a lowest incidence of EPS among antipsychotics and has been used to treat EPS caused by other antipsychotics, and eventually establish a principle of treating EPS.