SIGMA-LIGANDS INDIRECTLY MODULATE THE NMDA RECEPTOR-ION CHANNEL COMPLEX ON INTACT NEURONAL CELLS VIA SIGMA-1-SITE

To investigate the modulatory effects of sigma ligands on the N-methyl -D-aspartate (NMDA) receptor-ion channel complex in vivo, we examined the intact cell binding of H-3-N-[1-(2-thienyl)cyclohexyl]piperidine ( H-3-TCP) to cultured neuronal cells prepared from fetal rat telencepha lon, The H-3-TCP binding was saturable, reversible, and inhibited by a selective NMDA receptor antagonist, D-amino-5-phosphonovaleric acid. Millimolar Mg2+ inhibited H-3-TCP binding both in the absence and pres ence of L-glutamate, 5-Methyl-10,11-dihydro-5H-dibenzo [a,d]cyclohepte n-5,10-imine maleate (MK801) inhibited H-3-TCP intact cell binding in a competitive manner, while haloperidol inhibited it in a noncompetiti ve manner, The effect of the test drugs to inhibit H-3-TCP intact cell binding was in the order of dextromethorphan, haloperidol > (+/-)MK 8 01 > (+)pentazocine > (-)pentazocine > DTG > PCP >(+)-N-allylnormetazo cine [(+)SKF 10047] > (+)3-(3-hydroxyphenyl)-N(1-propyl)piperidine [()3-PPP]> (-)SKF 10047 > (-)3-PPP. The IC50 values of the six sigma lig ands for H-3-TCP binding were closely correlated with the K-i values o f the corresponding drugs for DTG site 1 in the guinea pig brain repor ted by Rothman et al, (1991), These findings suggest that the sigma li gand indirectly modulates the NMDA receptor ion channel complex, presu mably through sigma 1 sites in vivo as well as in vitro.