Inhibition of conditional avoidance response by neuroleptics upon repeated administration

Development of tolerance to neuroleptic compounds tested in the conditional avoidance model was investigated. Since tolerance may manifest itself by a diminished potency and/or a shortened duration of effect, the complete time course of effect was registered in these experiments. Rats were pretreated approximately 2 weeks with daily oral doses of chlorprothixene (20 mg/kg), flupenthixol (10 mg/kg), fluphenazine (2.5 mg/kg), or haloperidol (10 mg/kg) or twice a week with piflutixol (0.31 mg/kg). Three days after withdrawal chlorprothixene and flupenthixon caused a slightly but significantly weaker inhibition of avoidance performance in rats pretreated with the respective compounds and compared with non-pretreated rats, the duration of effect was shortened. Six dasy after withdrawal of piflutixol the duration of effect of a dose of piflutixol causing maximum inhibition was significantly shortened, while no homologous tolerance could be demonstrated in fluphenazine-pretreated rats. Cross tolerance was found after haloperidol-pretreatment when the rats were tested with fluphenazine 6 days after withdrawal. Homologous piflutixol tolerance could be shown 4 weeks after withdrawal. These results indicate that it is possible to demonstrate a slight tolerance to the effect of neuroleptic compounds when these are tested in conditional avoidance experiments. The cause of this tolerance is discussed.