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 3H-N-[1-(2-thienyl)cyclohexyl]piperidine (3H-TCP) to cultured neuronal cells prepared from fetal rat telencephalon. The 3H-TCP binding was saturable, reversible, and inhibited by a selective NMDA receptor antagonist, D-amino-5-phosphonovaleric acid. MII-limolar Mg2+ inhibited 3H-TCP binding both in the absence and presence of L-glutamate. 5-Methyl-10,11-dihydro-5H-dibenzo [a,d]cyclohepten-5,10-imine maleate (MK801) inhibited 3H-TCP intact cell binding in a competitive manner, while haloperidol inhibited it in a noncompetitive manner. The effect of the test drugs to inhibit 3H-TCP intact cell binding was in the order of dextromethorphan, haloperidol > (+/-)MK 801 > (+)pentazocine > (-)pentazocine > DTG > PCP > (+)-N-allylnormetazocine [(+)SKF 10047] > (+)3-(3-hydroxyphenyl)-N- (1-propyl)piperidine [(+)3-PPP] > (-)SKF 10047 > (-)3-PPP. The IC50 values of the six sigma ligands for 3H-TCP binding were closely correlated with the Ki values of the corresponding drugs for DTG site 1 in the guinea pig brain reported by Rothman et al. (1991). These findings suggest that the sigma ligand indirectly modulates the NMDA receptor ion channel complex, presumably through sigma 1 sites in vivo as well as in vitro.
Yamamoto
H
H
Department of Psychopharmacology, Tokyo Institute of Psychiatry, Japan.
Yamamoto
T
T
Sagi
N
N
Klenerová
V
V
Goji
K
K
Kawai
N
N
Baba
A
A
Takamori
E
E
Moroji
T
T
D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D016291:Dizocilpine Maleate / Q000494:pharmacology; D018698:Glutamic Acid / Q000494:pharmacology; D007473:Ion Channels / Q000378:metabolism*; D008024:Ligands; D009474:Neurons / Q000378:metabolism*; D010622:Phencyclidine / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D017480:Receptors, sigma / Q000378:metabolism*
D007473:Ion Channels; D008024:Ligands; D016194:Receptors, N-Methyl-D-Aspartate; D017480:Receptors, sigma; D018698:Glutamic Acid; D016291:Dizocilpine Maleate; D015763:2-Amino-5-phosphonovalerate; C012058:tenocyclidine; D010622:Phencyclidine