p-Hydroxyamphetamine (p-OHA) is an active metabolite of amphetamine (AMPH) and methamphetamine (METH), and can be detected in the brain for a relatively long period after high-dose administration of AMPH in rodents. p-OHA may be involved in the abnormal behavior observed during the withdrawal period after a chronic administration of AMPH or METH. Therefore, we investigated the effect of an intracerebroventricular (i.c.v.) administration of p-OHA on the changes of locomotor activity and prepulse inhibition (PPI) in the acoustic startle response in rodents. The i.c.v. administration of p-OHA significantly increased locomotor activity in mice. This effect was prevented by a pretreatment with a dopamine (DA) uptake inhibitor. Furthermore, local infusion of p-OHA into the nucleus accumbens (NAc) significantly increased locomotor activity in rats. Together these results suggest that dopaminergic systems in the rodent NAc may play important roles in p-OHA-induced locomotor activity. Next, we tested the effects of the i.c.v. administration of p-OHA on PPI in mice. p-OHA induced PPI disruptions that were significantly improved by the pretreatment with a typical or an atypical antipsychotic, D2 or D4 receptor antagonists, respectively. p-OHA-induced PPI disruptions were also improved by a serotonin (5-HT) 2A receptor antagonist, a 5-HT synthesis inhibitor or a 5-HT neurotoxin. These results suggest that p-OHA-induced PPI disruptions were mediated by DA and 5-HT release and subsequent stimulation of D2, D4 and 5-HT2A receptors. Our recent series of reports indicate that the study of p-OHA may provide new insights into drug abuse as well as psychiatric disorders such as schizophrenia.
