We have previously shown that low doses of selective sigma ([sigma ]) ligands produces a marked and selective dose-dependent potentiation of NMDA-induced firing activity of pyramidal neurons of the CA 3 region of the dorsal hippocampus. Olfactory bulbectomy (OBX) is recognized as a valuable animal model of major depression by inducing a variety of behavioral alterations, appearing two to three weeks after the surgery. Previous behavioral and radio-ligand binding studies from our laboratory have also shown that OBX alters NMDA receptors function. The present experiments were undertaken to assess the effects of short- and long-term treatments with the [sigma ] ligand JO-1784 in OBX rats.Twelve groups of male Sprague-Dawley rats were studied. Six groups underwent OBX, while the 6 others were sham operated. Following surgery, rats were given two weeks to recover and to permit the apparition of the [ldquo ]OBX syndrome[rdquo ] after which OBX and SHAM operated rats were randomly assigned to one of the treatment groups. JO-1784 at the dose of 50, 100, 200, 500 or 1000 [mu ]g/kg/day or saline was administered via an Alzet osmotic minipump. Behavioral experiments were carried out with the minipumps still on board.Behavioral experiments were carried out 7 or 14 days after the minipump implantation. Rats were administered a single injection of MK-801 (0.2 mg/kg, i.p.), placed in a circular open-field maze and were monitored for 40 min using a computer program which quantified the ambulatory distance, duration of ambulation, head-weavings, duration of inactivity, circlings. The experimenter recorded the number of rearings and of falls.Initially rats presented the usual exploratory behavior, which progressively disappeared within 5 to 10 min. As previously reported, OBX increased the basal locomotor activity during the first ten min. In sham-operated rats, MK-801-induced effects appeared within 10 to 15 min, with a progressive increase of the locomotion and the appearance of stereotypies (head wavings, circlings and falls). The maximal behavioural effects were observed after 30 min. OBX saline rats displayed a significantly higher locomotive activity than Sham saline rats.Sham rats treated with the different doses of JO-1784 for 7 or 14 days did not differ significantly from the Sham saline rats. JO-1784, administered for 7 days at the doses of 50 or 100 [mu ]g/kg/day did not modify the behavioral activity of OBX rats. At higher doses, JO-1784 induced a dose-dependent reduction of the increased activity provoked by MK-801 in OBX rats. Thus, the behavioral activity of OBX rats treated with 200 and 500 [mu ]g/kg/day was not significantly different from Sham saline rats, whereas OBX rats treated with 1000 [mu ]g/kg/day of JO-1784 for 7 days displayed significantly less locomotor activity than sham saline rats.Following a 14 day treatment with JO-1784, a similar dose-dependent decrease of MK-801-induced hyperactivity found in OBX rats, was shown by rats having received 50, 100, or 200 [mu ]g/kg/day, their degree of locomotor activity being not different from that of Sham saline rats. OBX rats treated with 500 and 1000 [mu ]g/kg/day for 14 days presented significantly less behavioral activity than Sham saline rats.The present data are consistent with the bell-shaped dose response curves obtained with the acute administration of [sigma ] ligands on NMDA response. A number of recent studies have already demonstrated interactions between several antidepressant medications and the NMDA receptor complex, the present data suggest that NMDA and [sigma ] receptors may be involved in the pathophysiology of depression and in the mechanism of action of antidepressant treatments.