Effect of short‐term and long‐term treatments with σ ligands on the N ‐methyl‐ d ‐aspartate response in the CA 3 region of the rat dorsal hippocampus

Long‐term treatments with the σ ligand haloperidol decrease the density of σ receptors in mammalian CNS. We have shown that σ 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 CA 3 region of the rat dorsal hippocampus. σ Ligands producing such a potentiation were denoted ‘agonists’. This potentiation was suppressed by low doses of other σ 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 σ ‘agonists’. 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 σ ‘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. 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 σ ‘agonists’ was unchanged. 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. The present data suggest that long‐term treatments with σ ‘antagonists’ induce a desensitization of the σ receptors, whereas long‐term treatments with σ ‘agonists’ induce a supersensitivity of the σ receptors.British Journal of Pharmacology (1997) 120 , 1351–1359; doi: 10.1038/sj.bjp.0701042