An antidepressant-induced decrease in the responsiveness of hippocampal neurons to group I metabotropic glutamate receptor activation

Imipramine, a serotonin and noradrenaline uptake inhibitor, is the prototyp ical tricyclic antidepressant. The effects of imipramine on neuronal respon siveness to the group I glutamate metabotropic (mGlu) receptor agonist (RS) -3,5-dihydroxyphenylglycine (DHPG) were studied ex vivo, in the CA1 area of rat hippocampus, using extracellular and intracellular recording. DHPG inc reased the population spike amplitude, depolarized CA1 cells and decreased the slow afterhyperpolarization. Imipramine (20 mu M) administered acutely in vitro did not change the effect of DHPG on population spikes. Repeated t reatment with imipramine (10 mg/kg, twice daily, for 14 days) significantly attenuated the enhancing effect of DHPG (2.5 and 5 mu M) on population spi kes, as well as the DHPG-induced depolarization and the decrease in the slo w afterhyperpolarization. Repeated treatment with imipramine had no effect on passive or active membrane properties of CA1 pyramidal cells. The result s of the time-course experiment demonstrated that the imipramine-induced de crease in the responsiveness of CA1 cells to DHPG was apparent after a 7-da y treatment; there was a further decrease after 14 days of treatment to a l evel which was not changed by longer (21-day) administration of imipramine. The attenuation of neuronal responsiveness to DHPG induced by a 14-day tre atment was still detectable 7 days after imipramine withdrawal. It is concl uded that repeated treatment with imipramine induces a decrease in the resp onsiveness of rat CA1 hippocampal neurons to group I mGlu receptor activati on with a time course which cell-elates with the delayed onset of the thera peutic effect of antidepressants in humans. This suggests that alterations in mGlu receptors may contribute to antidepressant efficacy. (C) 1999 Elsev ier Science B.V. All rights reserved.