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Enhancement of the antipsychotic effect of risperidone by sodium nitroprusside in rats
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Karolinska Inst, Sect Neuropsychopharmacol, Dept Physiol & Pharmacol, SE-17177 Stockholm, Sweden.ORCID iD: 0000-0002-2882-5202
Karolinska Inst, Sect Neuropsychopharmacol, Dept Physiol & Pharmacol, SE-17177 Stockholm, Sweden.
Karolinska Inst, Sect Neuropsychopharmacol, Dept Physiol & Pharmacol, SE-17177 Stockholm, Sweden.
Karolinska Inst, Sect Neuropsychopharmacol, Dept Physiol & Pharmacol, SE-17177 Stockholm, Sweden.
2019 (English)In: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 29, no 11, p. 1282-1287Article in journal (Refereed) Published
Abstract [en]

Recently, a single injection of the nitric oxide donor sodium nitroprusside (SNP) was found to induce a rapid and sustained antipsychotic effect in treatment-resistant schizophrenia (TRS). Moreover, a single i.p. injection of SNP in rats was found to generate both rapid and persisting changes in brain synaptic plasticity, including enhanced excitatory postsynaptic current responses and spine morphology in layer V pyramidal cells in the medial prefrontal cortex (mPFC) brain slices. Here we used the conditioned avoidance response (CAR) test in rats to investigate the antipsychotic-like efficacy of SNP in combination with low-dose risperidone. In addition, we performed microdialysis experiments in freely moving rats to measure neurotransmitter efflux in the mPFC and the nucleus accumbens (NAc). Risperidone caused only 20% suppression of CAR, which is far below the degree of CAR suppression required to predict a significant clinical antipsychotic effect. Addition of a low dose of SNP to risperidone dramatically enhanced the antipsychotic-like effect to a clinically relevant level. SNP significantly enhanced the risperidone-induced dopamine output in the mPFC but not in the NAc. The increased prefrontal dopamine release induced by the drug combination may also improve cognition as indicated by previous preclinical and clinical studies and, furthermore, via enhanced synaptic spine function and morphology in mPFC generate a both rapid and prolonged antipsychotic and pro-cognitive effect. Our results delineate SNP as a promising new treatment option for schizophrenia, including TRS, when added to currently available antipsychotic medication in order to improve efficacy at maintained or even reduced dosage. 

Place, publisher, year, edition, pages
ELSEVIER , 2019. Vol. 29, no 11, p. 1282-1287
Keywords [en]
Nitric oxide, Risperidone, Schizophrenia, Antipsychotic drugs, Sodium nitroprusside
National Category
Pharmacology and Toxicology
Identifiers
URN: urn:nbn:se:uu:diva-397780DOI: 10.1016/j.euroneuro.2019.08.302ISI: 000493896100010PubMedID: 31537475OAI: oai:DiVA.org:uu-397780DiVA, id: diva2:1373236
Available from: 2019-11-26 Created: 2019-11-26 Last updated: 2019-11-26Bibliographically approved

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