Animal models based on N-methyl-d-aspartate (NMDA) receptor blockade have been widely reported. Ketamine and MK- 801, the two noncompetitive antagonists of NMDA receptors, produce behaviors related to schizophrenia and exacerbated symptoms in patients with schizophrenia. The study presented here investigated the effect of subchronic dosing (once-daily, 7 day) of histamine H3 receptor (H3R) antagonists, ciproxifan (CPX) (3 mg/kg, i.p.) and clobenpropit (CBP) (15 mg/kg, i.p) including clozapine (CLZ) (3.0 mg/kg, i.p.) and chlorpromazine (CPZ) (3.0 mg/kg, i.p.), the atypical and typical antipsychotic, respectively, on MK-801(0.2 mg/kg, i.p.)-induced locomotor activity, and dopamine and histamine levels in rats. Atypical and typical antipsychotic was used to serve as clinically relevant reference agents to compare the effects of the H3R antagonists. MK-801 significantly increased horizontal activity which was reduced with CPX and CBP. The attenuation of MK-801-induced locomotor hyperactivity produced CPX and CBP were comparable to CLZ and CPZ. Dopamine and histamine levels were measured in striatum and hypothalamus, respectively, of rat brain. The MK-801 induced increase of the striatal dopamine level was reduced in rats pretreated with CPX and CBP including CLZ. CPZ also significantly lowered striatal dopamine levels, though the decrease was less robust compared to CLZ, CPX and CBP. MK-801 increased histamine content although to a lesser degree. Subchronic treatment with CPX and CBP exhibited further increased histamine levels in the hypothalamus compared to MK-801 treatment alone. Histamine H3 receptor agonist, R-α methylhistamine (10 mg/kg, i.p.) counteracted the effect of CPX and CBP. The findings of the present study support our previous work showing positive effects of CPX and CBP on MK-801-induced schizophrenia like behaviors in rodents. However, clinical studies have reported no antipsychotic effects with histamine H3 receptor antagonists.