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 clomipram ine (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 signific antly alter extracellular 5-HT in the frontal cortex. Infusion of 25 muM NM DA into the raphe decreased extracellular 5-HT in this region and increased terminal extracellular 5-HT in the frontal cortex. In contrast, infusion o f 100 muM NMDA into the raphe was followed by an increase in local dialysat e 5-HT and a decrease in 5-HT release in the cortex. When NMDA infusion, at either 25 or 100 muM was preceded by one acute injection of CIM the effect s of NMDA on 5-HT release in both brain structures were generally more mark ed 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 muM NMDA on 5-HT release in raphe and front al cortex were greatly attenuated or abolished. This suggests that adaptive functional changes occur in NMDA receptor function during treatment with a n antidepressant. The possible significance of this in the aetiology and tr eatment of depression is discussed. (C) 2001 Elsevier Science Ltd. All righ ts reserved.