The novel anticonvulsant MK-801 interacts with central phencyclidine recognition sites in rat brain.

The novel anticonvulsant MK-801 ([(+)-5methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten5,10-imine maleate]; Clineschmidt et al., 1982) has been described as a non-competitive antagonist of the excitatory amino acid neurotransmitter, Nmethyl-D-aspartate (NMDA) on the basis of binding and electrophysiological experiments (Wong et al., 1986). Consistent with this finding was the observation (Murphy et al., in press) that at concentrations up to 10 /xM, MK-801 was without significant effect on the binding of the radiolabeled selective NMDA antagonist, CPP [(3-(2carboxypiperazin-4-yl)-propyl-1 -phosphonic acid]. Binding of the phencylidine (PCP) analog, [3H]TCP (1-(2-thienyl)-cyclohexylpiperidine) to EDTA-washed rat brain membranes can be markedly stimulated (+265%) by 10 /xM glutamate (Loo et al. 1986). Furthermore, Anis et al. (1983) have shown that dissociative anesthetics such as phencyclidine and ketamine can inhibit NMDA-induced neuronal responses. Together, these findings provide evidence for the possible existence of an N M D A / P C P receptor complex in rat brain. In the present study, the possibility that MK801 might be producing its NMDA antagonist effects via a direct interaction with PCP sites was investigated. [3H]TCP binding was measured as described previously (Loo et al., 1986) using