Clozapine modulates midbrain dopamine neuron firing via interaction with the NMDA receptor complex

The mode of action by which the atypical antipsychotic drug clozapine exerts its superior efficacy to ameliorate both positive and negative symptoms is still relatively unknown. A recent study shows that a pharmacologically increased concentration of brain kynurenic acid, an endogenous antagonist at the glycine-site of the NMDA receptor as well as at the alpha7* nicotinic receptor, reverses the excitatory effects of clozapine on ventral tegmental area (VTA) dopamine (DA) neurons into an inhibitory action. In the present in vivo electrophysiological study, we further investigated the mechanisms of action of clozapine on VTA DA neurons. In control rats intravenously administered clozapine (1.25-10 mg/kg) was associated with increased firing rate and burst firing activity of VTA DA neurons. However, administration of the N-methyl-D-aspartate (NMDA)-receptor antagonist MK 801 blocked the excitatory action of clozapine. Moreover, in rats pretreated with the antagonist of the glycine-site of the NMDA receptor, L-701,324, the effects of clozapine on VTA DA neurons were converted to purely inhibitory responses, including a decrease in firing rate and burst firing activity. Pretreatment with the alpha7* nicotinic receptor antagonist MLA did not affect the excitatory action of clozapine on VTA DA neurons. The results of the present study suggest that clozapine interacts with the NMDA receptor complex. In this regard, clozapine could affect the glycine site of the NMDA receptor or tentatively inhibit the glycine transporter. The inhibitory action of clozapine on VTA DA neurons may account for its beneficial effects in ameliorating symptoms of schizophrenia and may suggest further studies to investigate a role of the glycine site of the NMDA receptor as a target for novel antipsychotics.