The cytochromes P-450 are not involved in the modulation of the N-methyl-D-aspartate response by sigma ligands in the rat CA3 dorsal hippocampus.
Recent in vitro radioligand binding studies have shown that several cytochrome P-450 inhibitors can displace [3H] sigma ligands, suggesting that these ligands might bind to the cytochrome P-450 superfamily of enzymes. Using an in vivo electrophysiological model of extracellular recordings performed in the CA3 region of the rat dorsal hippocampus, we have previously shown that intravenous administration of low doses of several sigma ligands, such as 1,3-di(2-tolyl) guanidine (DTG), JO-1784, and (+)pentazocine potentiate the neuronal response induced by microiontophoretic applications of N-methyl-D-aspartate (NMDA) without affecting those induced by quisqualate and kainate, suggesting that they act as sigma agonists. Conversely, the sigma ligands haloperidol, (+)3-PPP, and BMY-14802, which have no effect by themselves on the NMDA response, prevent and suppress the potentiating effect of sigma agonists on the NMDA response, suggesting that they act as sigma antagonists. The present studies were undertaken to determine if cytochromes P-450 could be involved in the modulation of the NMDA response by sigma ligands. For this purpose, two cytochrome P-450 inhibitors, proadifen (SKF-525A) and piperonyl butoxide (PB), have been tested in our model. Unlike sigma agonists, at low doses, neither SKF-525A nor PB affected the NMDA response of CA3 dorsal hippocampus pyramidal neurons. Unlike sigma antagonists, neither of these drugs reversed or prevented the DTG-induced potentiation of the NMDA response. In addition, following high doses of SKF-525A or PB, sufficient to induce a complete inactivation of cytochromes P-450, DTG still potentiated the NMDA response.(ABSTRACT TRUNCATED AT 250 WORDS)
Monnet
F P
FP
Department of Psychiatry, McGill University, Montréal, Québec, Canada.
Debonnel
G
G
de Montigny
C
C
D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D006146:Guanidines / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D007478:Iontophoresis; D008024:Ligands; D008297:Male; D016202:N-Methylaspartate / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects; D010243:Paralysis / Q000139:chemically induced / Q000517:prevention & control; D010634:Phenobarbital / Q000494:pharmacology; D011335:Proadifen / Q000494:pharmacology; D016318:Quisqualic Acid / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017480:Receptors, sigma / Q000187:drug effects*; D015049:Zoxazolamine
D006146:Guanidines; D008024:Ligands; D017480:Receptors, sigma; D016202:N-Methylaspartate; D016318:Quisqualic Acid; D003577:Cytochrome P-450 Enzyme System; D015049:Zoxazolamine; D011335:Proadifen; C050232:1,3-ditolylguanidine; D010634:Phenobarbital