CHRONICAL HALOPERIDOL AND CLOZAPINE TREATMENT IN RATS - DIFFERENTIAL RNA DISPLAY ANALYSIS, BEHAVIORAL-STUDIES AND SERUM LEVEL DETERMINATION

1. Adult, female rats were treated orally for 23 days with 1.6 mg/kg h aloperidol or 36 mg/kg clozapine per day, to study chronic effects of the two neuroleptics. 2. At five time points during the neuroleptic tr eatment, animal behavior was recorded in an open field and locomotive activity was analysed. At the end of the experiment, rats were decapit ated, blood samples were collected and serum concentrations of haloper idol and clozapine were determined by a radioreceptor or HPLC assay, r espectively. RNA was isolated from each brain, without cerebellum, and subjected to differential RNA display. 3. Mean serum concentrations w ere 8 ng/ml for haloperidol smd 21 ng/ml for clozapine. Analysis of op en field behavior showed that haloperidol and clozapine decreased the total distance moved and the velocity as measures of the overall activ ity, whereas the number of rearings and the number of entries into the center, reflecting risk assessment behavior, were differentially affe cted. Three neuroleptic-regulated gene fragment bands were identified in differential RNA display experiments. Two gene fragments of 281 bp and 266 bp. were sequenced. 4. We conclude that our study design that used behavioral, pharmacokinetic and molecular analysis increase the l ikelihood of finding relevant molecular events underlying the pharmaco therapeutic effects of neuroleptics in animal models.