The dopamine D 3 receptor mediates locomotor hyperactivity induced by NMDA receptor blockade

Abstract

N-methyl-D-aspartate (NMDA)/glutamate receptor antagonists, like phencyclidine, generate schizophrenic-like symptoms in humans and behavioural abnormalities in animals, such as hyperactivity. We investigated the role of the dopamine D 3 receptor in locomotor hyperactivity produced in mice by dizocilpine (MK-801), another NMDA receptor antagonist, at a low dose (0.12 mg/kg). BP 897, a highly D 3 receptor-selective partial agonist, or nafadotride, a preferential D 3 receptor antagonist, both at low doses (1 mg/kg and lower), had no effects on spontaneous activity and completely inhibited MK-801-induced hyperactivity. Clozapine, an atypical antipsychotic, produced the same effect as BP 897 and nafadotride. Haloperidol, a typical antipsychotic, reduced both spontaneous activity and MK-801-induced hyperactivity. In D 3 receptor knockout mice, MK-801-induced hyperactivity was weaker than that observed in wild-type mice while BP 897 and nafadotride were inactive. On the contrary, the effects of clozapine and haloperidol, which target multiple receptors in addition to the D 3 receptor, were almost completely preserved in D 3 receptor knockout mice. Our results show that hyperactivity produced by a low dose of MK-801 is dependent upon D 3 receptor stimulation and constitutes the first simple response to assess the in vivo activity of D 3 receptor-selective drugs. In addition, since D 3 receptor antagonists and antipsychotics produced very similar effects, our results add to the growing evidence suggesting that D 3 receptor blockade might produce antipsychotic effects.