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0.5 mg/kg + benztropine 2.0 mg/kg (H + B), thioridazine (T) 25 mg/kg, or saline (S) ip daily for 18 days, were withdrawn for 21 days, and then received another 10 days of drug.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.
D000818:Animals; D001058:Apomorphine / Q000494:pharmacology*; D001590:Benztropine / Q000008:administration & dosage; D003342:Corpus Striatum / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006220:Haloperidol / Q000494:pharmacology*; D006801:Humans; D008032:Limbic System / Q000187:drug effects; D008297:Male; D009043:Motor Activity / Q000187:drug effects*; D051381:Rats; D011919:Rats, Inbred Strains; D011954:Receptors, Dopamine / Q000187:drug effects; D013239:Stereotyped Behavior / Q000187:drug effects*; D013375:Substance Withdrawal Syndrome / Q000209:etiology; D013881:Thioridazine / Q000494:pharmacology*
D011954:Receptors, Dopamine; D001590:Benztropine; D006220:Haloperidol; D001058:Apomorphine; D013881:Thioridazine