Clozapine Interacts with the Glycine Site of the NMDA Receptor: Electrophysiological Studies of Dopamine Neurons in the Rat Ventral Tegmental Area

Clozapine has a remarkable efficacy in treatment-resistant schizophrenia and is one of the most effective antipsychotic drugs used today. The clinical effects of clozapine are suggested to be related to a unique interaction with a variety of receptor systems, including the glutamatergic receptors. Kynurenic acid (KYNA) is an endogenous blocker of alpha7 nicotinic receptors and a glutamate-receptor antagonist, preferentially blocking N-methyl-D-aspartate (NMDA) receptors. In the present in vivo electrophysiological study, changes in endogenous concentration of brain KYNA were utilized to analyze an interaction between clozapine and the glycine site of NMDA receptors. In control rats intravenously administered clozapine (0.078-10 mg/kg) increased the firing rate and the burst firing activity of dopamine (DA) neurons in the ventral tegmental area (VTA). Pretreatment with indomethacin (50 mg/kg, i.p., 1-3.5 h), a cyclooxygenase (COX)-inhibitor with a preferential selectivity for COX-1, which produced a significant elevation in brain KYNA levels, reversed the excitatory action of clozapine into an inhibitory response. In contrast, pretreatment with the COX-2 selective inhibitor parecoxib (25 mg/kg, i.v., 1-1.5 h) decreased brain KYNA formation and furthermore, clearly potentiated the excitatory effect of clozapine. Our results show that endogenous levels of brain KYNA are of importance for the response of clozapine on VTA DA neurons. On the basis of the present data we propose that clozapine is able to interact with glutamatergic mechanisms, via actions at the NMDA/glycine receptor.