Abstract
We have previously shown that risperidone, an antipsychotic drug with high affinity for 5-hydroxytryptamine (5-HT)2A and dopamine (DA)2 receptors, as well as for α1- and α2-adrenoceptors, enhances 5-HT metabolism selectively in the rat frontal cortex (FC). To further study the influence of risperidone on central 5-HT systems, we compared its effects on dialysate 5-HT in the FC, as assessed by microdialysis, with those obtained with other antipsychotic drugs, i.e., clozapine, haloperidol, and amperozide, as well as with the selective α2- or 5-HT2A receptor antagonists idazoxan or MDL 100,907, respectively. The underlying mechanism for risperidone’s effect on 5-HT output in the FC was also investigated using single-cell recording in the dorsal raphe nucleus (DRN). Administration of risperidone (0.2, 0.6, and 2.0 mg/kg, SC) dose-dependently increased 5-HT levels in the FC. This stimulatory action was mimicked by amperozide (10 mg/kg, SC) and, to some extent, by idazoxan (0.25 mg/kg, SC). In contrast, clozapine (10 mg/kg, SC), haloperidol (2.0 mg/kg, SC), and MDL 100,907 (1.0 mg/kg, SC) exerted only minor effects on 5-HT output in brain. Local administration of risperidone or idazoxan (1.0–1000 μmol/L) in the FC dose-dependently increased dialysate levels of 5-HT in this region. On the other hand, risperidone 25-800 μg/kg, IV) dose-dependently decreased the firing rate of 5-HT cells in the DRN, an effect that was largely antagonized by pretreatment with the selective 5-HT1A receptor antagonist WAY 100,635 (5.0 μg/kg, IV). These results indicate that the risperidone-increased 5-HT output in the FC may be related to its α2-adrenoceptor antagonistic action, a property shared with both amperozide and idazoxan, and that this action probably is executed at the nerve terminal level. The inhibition of 5-HT cell firing by risperidone is probably secondary to increased 5-HT availability, e.g., in the DRN, since it could be antagonized by a 5-HT1A receptor antagonist. The enhanced 5-HT output in the FC by risperidone may be of particular relevance for the treatment of schizophrenia when associated with depression and in schizoaffective disorder.
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Acknowledgements
This work was supported by grants from the Swedish Medical Research Council (projects 4747 and 11026), the Karolinska Institutet, Torsten och Ragnar Söderbergs Stiftelser, Fredrik och Ingrid Thurings Stiftelse, AB LEOs i Helsingborg Stiftelse för Forskning, Janssen Pharmaceutica N.V., Beerse, and Astra Arcus AB, Södertälje. The authors gratefully acknowledge Anna Malmerfelt and Martin Svensson for excellent technical assistance. We also thank Dr. Josée E. Leysen, Dr.Sci., Janssen Research Foundation, for valuable advice and discussion throughout this work.
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Hertel, P., Nomikos, G., Schilström, B. et al. Risperidone Dose-Dependently Increases Extracellular Concentrations of Serotonin in the Rat Frontal Cortex: Role of α2 –Adrenoceptor Antagonism. Neuropsychopharmacol 17, 44–55 (1997). https://doi.org/10.1016/S0893-133X(97)00002-X
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DOI: https://doi.org/10.1016/S0893-133X(97)00002-X
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