Effect of short-term and long-term treatments with sigma ligands on the N-methyl-D-aspartate response in the CA3 region of the rat dorsal hippocampus.
1. Long-term treatments with the sigma ligand haloperidol decrease the density of sigma receptors in mammalian CNS. We have shown that sigma ligands, such as di(2-tolyl)guanidin (DTG), potentiate dose-dependently, with bell-shaped dose-response curves, the neuronal response of pyramidal neurones to N-methyl-D-aspartate (NMDA) in the CA3 region of the rat dorsal hippocampus. sigma Ligands producing such a potentiation were denoted 'agonists'. This potentiation was suppressed by low doses of other sigma ligands denoted 'antagonists'. High doses of DTG and JO-1784 did not modify the NMDA response but acted as 'antagonists' by suppressing the potentiation induced by sigma 'agonists'. 2. Following a 21-day treatment with haloperidol as well as with high doses of DTG or JO-1784, after a 48 h washout, the acute administration of sigma 'agonists' failed to induce any potentiation of the NMDA response. Following a 21 day treatment with a low dose of DTG or JO-1784, after a 48 h washout, the neuronal response to microiontophoretic applications of NMDA was markedly increased. A 21 day treatment with low or high doses of (+)-pentazocine, after a 48 h washout, did not produce any change. 3. Following a two day treatment with a high dose of haloperidol, DTG, JO-1784 and (+)-pentazocine, after a 24 h washout, the potentiation of the NMDA response induced by the acute administration of the sigma 'agonists' was unchanged. 4. With the minipumps on board, with DTG and JO-1784, a dose-dependent enhancement of the NMDA response was seen but no effect was observed in the groups of rats treated at the same doses with haloperidol or (+)-pentazocine. 5. The present data suggest that long-term treatments with sigma 'antagonists' induce a desensitization of the th receptors, whereas long-term treatments with th 'agonists' induce a supersensitivity of the th receptors.
Bergeron
R
R
Department of Psychiatry, McGill University, Montréal, Québec, Canada.
de Montigny
C
C
Debonnel
G
G
D000818:Animals; D002934:Cinnamates / Q000494:pharmacology; D003521:Cyclopropanes / Q000494:pharmacology; D006146:Guanidines / Q000494:pharmacology; D006220:Haloperidol / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D016202:N-Methylaspartate / Q000494:pharmacology*; D010423:Pentazocine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017480:Receptors, sigma / Q000187:drug effects*
D002934:Cinnamates; D003521:Cyclopropanes; D006146:Guanidines; D017480:Receptors, sigma; D016202:N-Methylaspartate; D006220:Haloperidol; C050232:1,3-ditolylguanidine; D010423:Pentazocine; C065310:igmesine