Receptor-mediated regulation of serotonin output in the rat dorsal raphe nucleus: effects of risperidone

Abstract.

Objectives: The present study was undertaken to characterize the regulation of serotonin (5-HT) efflux and neuronal activity in the dorsal raphe nucleus (DRN) as well as to examine the potential ability of the antipsychotic drug risperidone to interfere with these mechanisms. Methods and results: By using microdialysis in freely moving rats, it was found that administration of the α₂ adrenoceptor antagonist idazoxan (0.25 mg/kg, SC), the 5-HT_1B/D receptor antagonist GR 127,935 (1.0 mg/kg, SC) and risperidone (0.6 or 2.0 mg/kg, SC) increased 5-HT output in the DRN. Local DRN perfusion with GR 127,935 or risperidone via reversed dialysis (100 or 10–100 µM, respectively) enhanced 5-HT efflux in this area, whereas idazoxan (10–100 µM) failed to affect this parameter. Both systemic administration and reversed DRN dialysis of the D_2/3 and 5-HT_2A receptor antagonists raclopride (2.0 mg/kg, SC or 10–100 µM) and MDL 100,907 (1.0 mg/kg, SC or 10–100 µM), respectively, were without effect. Intraraphe dialysis of the 5-HT_1B/D receptor agonist CP 135,807 (0.2 µM) decreased the efflux of 5-HT in the DRN, an effect which was antagonized by co-administration of either GR 127,935 or risperidone (10 and 3.3 µM, respectively). By using single-cell recording, it was found that administration of GR 127,935 (50–400 µg/kg, IV) decreased, whereas CP 135,807 (2.5–20 µg/kg, IV) increased firing of 5-HT cells in the DRN. Conclusions: Our findings suggest a regulatory role of local 5-HT_1B/D receptors on 5-HT efflux as well as cell firing in the DRN and indicate that risperidone may interfere with the regulation of 5-HT availability in this area primarily via blockade of 5-HT_1D receptors.