Repeated but not acute clomipramine decreases the effect of N-methyl-D-aspartate receptor activation on serotonergic transmission between the raphe nuclei and frontal cortex.

The effect of acute or repeated treatment with the antidepressant clomipramine (CIM) on N-methyl-D-aspartate (NMDA) evoked changes in extracellular 5-hydroxytryptamine (5-HT) in the raphe nuclei and frontal cortex of the same rat has been studied using microdialysis. Acute injection of CIM (10 or 20 mg/kg) caused an increase in raphe extracellular 5-HT but did not significantly alter extracellular 5-HT in the frontal cortex. Infusion of 25 microM NMDA into the raphe decreased extracellular 5-HT in this region and increased terminal extracellular 5-HT in the frontal cortex. In contrast, infusion of 100 microM NMDA into the raphe was followed by an increase in local dialysate 5-HT and a decrease in 5-HT release in the cortex. When NMDA infusion, at either 25 or 100 microM was preceded by one acute injection of CIM the effects of NMDA on 5-HT release in both brain structures were generally more marked than in vehicle injected controls. Repeated (15 day) treatment with CIM (10 or 20 mg/kg) caused a dose-dependent increase in basal extracellular 5-HT in both raphe and frontal cortex. In these animals, however, the effects of infusion of both 25 and 100 microM NMDA on 5-HT release in raphe and frontal cortex were greatly attenuated or abolished. This suggests that adaptive functional changes occur in NMDA receptor function during treatment with an antidepressant. The possible significance of this in the aetiology and treatment of depression is discussed.