Disposition and pharmacological effects of m-Chlorophenylpiperazine in rats

1-( m-Chlorophenyl)piperazine (CPP) was a potent inhibitor of [ 3H]-serotonin binding to membrane receptors from rat brain in vitro, its K i being 138 nM. It had less effect on [ 3H]-lysergic acid diethylamide binding ( K i = 300 nM), the relative K i , values indicating CPP to be a serotonin receptor agonist. A dose-related decrease in 5-hydroxyindoleacetic acid (5-HIAA) concentration in rat brain in vivo, was caused by CPP, with no effect on serotonin concentration, and CPP reduced the rate of 5-HIAA accumulation after probenecid. Also, CPP caused a dose-related increase in corticosterone concentration in rat serum, as did'fluoxetine (an inhibitor of serotonin uptake). Milk-drinking was suppressed by CPP in non-fasted rats, whereas fluoxetine had no effect; the effect of CPP was doserelated and was antagonized by metergoline. These results are consistent with the idea that CPP acts principally as a direct serotonin agonist rather than as a serotonin uptake inhibitor in vivo. The half-life of CPP in brain was just over 1 hr in control rats and about 3hr in rats pretreated with iprindole, an inhibitor of aromatic ring hydroxylation. In iprindole-treated rats, the dose-response curve for lowering the concentration of 5-HIAA CPP at 4hr was shifted to the left, and the duration of 5-HIAA concentration lowering by a 10 mg/kg dose of CPP was prolonged. 1-( p-Chlorophenyl)piperazine had a longer half-life in rat brain than did CPP and caused almost as much serotonin receptor stimulation in vivo as did CPP due to the higher drug levels, despite its lower affinity for serotonin receptors in vitro. In iprindole-treated rats, CPP was more potent than in control rats in elevating serum corticosterone and prolactin. 1-( m-Chlorophenyl)piperazine is a known metabolite of the antidepressant drug trazodone and may contribute to or account for some of the in vivo effects of trazodone.