Differential liabilities of haloperidol and thioridazine for inducing apomorphine hypersensitivity

In an animal model of tardive dyskinesia, sensitivity to apomorphine-induced stereotyped behavior reflects increased dopamine receptor activity induced by chronic neuroleptic treatment. Four groups of Sprague-Dawley rats received haloperidol (H) 0.5 mg/kg, haloperidol 0.5 mg/kg + benztropine 2.0 mg/kg (H + B), thioridazine (T) 25 mg/kg, or saline (S) ip daily for 18 days, were withdrawn for 21 days, and then received another 10 days of drug. Drug-induced catalepsy was measured daily during the second phase of drug treatment. Sensitivity to apomorphine 0.125 mg/kg and 0.250 mg/kg was assessed during the first and second weeks of withdrawal from each phase of drug treatment. Catalepsy scores for H, H + B, and T groups showed an unexpected progressive increase over treatment days. Following withdrawal from the first drug phase, only H and H + B rats showed enhanced apomorphine stereotypy. H rats were hypersensitive for both weeks of testing while H + B rats were only hypersensitive for the first week. All rats showed changes in apomorphine sensitivity after withdrawal from the second drug phase. H and H + B rats showed significant enhancement of stereotypy at both apomorphine dose levels and at both weeks of testing. T rats showed a significant enhancement but only at the higher apomorphine dose level and only during the first withdrawal week. S rats had a significant enhancement of apomorphine-induced stereotypy during the second withdrawal week. We conclude that H, H + B, and T have differential liability for inducing dopamine receptor hypersensitivity, with haloperidol being most effective and thioridazine being least effective.