The effects of meta-chlorophenylpiperazine (mCPP) were studied on exploratory behaviour in the open field test, using a procedure designed to evaluate the emergence of rats into a novel environment. mCPP reduced the exploratory activity in a dose-related manner after subcutaneous (s.c.), intraperitoneal (i.p.) and intravenous (i.v.) administration. The inhibition was manifest in all the parameters used to quantify the exploration of the open field area. Additional neuroendocrine experiments in a parallel group of rats revealed a dose-related increase in plasma prolactin and ACTH levels after i.v. mCPP, pointing to a general state of arousal in these mCPP-treated animals. A number of 5-HT antagonists were tested for their ability to prevent or reverse the behavioural inhibition induced by an i.v. injection of 1.0 g/kg mCPP given 15 min before testing in the open field. The antagonists were injected s.c. or given orally at various time intervals before mCPP, or they were injected i.v. 10 min after mCPP. The lowest active doses for the attentuation of the mCPP-induced behavioural inhibition after s.c., oral and i.v. administration, respectively, were 0.04, 40 and 10 mg/kg for pizotifen; 0.16, 0.16 and 0.16 mg/kg for mianserin; 0.63, 0.16 and 0.16 mg/kg for methysergide, and 0.16, 2.5 and 2.5 mg/kg for ritanserin. The lowest active doses of mirtazapine after s.c. and i.v. treatment were 0.01 and 0.16 mg/kg. These data indicate that mixed 5-HT1/5-HT2 receptor antagonists such as pizotifen and methysergide, and mixed 5-HT and catecholamine antagonists such as mianserin and mirtazapine are more potent antagonists of mCPP-induced behavioural inhibition in rats than the more selective 5-HT2A/5-HT2C antagonist ritanserin.
