Single doses of haloperidol inhibit behavioral effects of the dopamine agonist apomorphine in rats for over a month. Whether these extended effects are due to the persistence of haloperidol in tissue or longstanding physiological changes following even brief exposure to the drug is unknown. Recently developed techniques, including HPLC with coulometric detection, as used here, have extended assay sensitivity for haloperidol into the picogram range, and longterm pharmacokinetic studies may now be possible to address this question. We propose studies in rats receiving single doses of haloperidol to determine the feasibility of concomitantly monitoring drug in tissue and the behavioral effects of drug for at least one month after dosing. Rats will receive representative doses of haloperidol and the reduction of apomorphine-induced stereotyped behavior will be determined from 1 to 42 days after dosing. Haloperidol will be determine din serum, brain, fat, and liver. Analysis of the data will provide preliminary answers to the following questions: (1) Does haloperidol persist in blood or tissue for weeks after dosing? (2) Does haloperidol remaining in tissue days to weeks after dosing vary proportionately with dose or is there a saturable pool of drug with slow release? (3) Does the relationship between haloperidol concentration in brain and sensitivity to apomorphine change with time after dosing, implying that longlasting physiological changes occur in brain even after a single dose of medication? In addition, sensitive HPLC techniques for assaying phenothiazines will be further explored so that studies similar to those described for haloperidol can be performed with phenothiazines. This will allow determination of whether persistence of drug in tissue is a general property of neuroleptics. If the results are promising, the data gathered will be used to design further experiments to define the size, nature, and physiological importance of slow-turnover pools of neuroleptics in tissue. Such studies would involve a broader range of drugs, doses, and treatment strategies and additional behavioral and biochemical measures of drug effects. The information gained may be crucial for delineating drug distribution and metabolism and, thus, is essential for understanding drug mechanisms of action, making decisions about drug dosing, timing, and withdrawal in clinical care, and designing research protocols, especially as regards patients previously treated with anti-psychotic drugs but now presumably drug free.
| Cohen, B M; Tsuneizumi, T; Baldessarini, R J et al. (1992) Differences between antipsychotic drugs in persistence of brain levels and behavioral effects. Psychopharmacology (Berl) 108:338-44 |
