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Rapid augmentation of antipsychotic drugs by sodium nitroprusside: behavioural assessment and effect on brain dopaminergic transmission in rats
Behavioural and systems P.2.026 Rapid augmentation of antipsychotic drugs by sodium nitroprusside: behavioural assessment and effect on brain dopaminergic transmission in rats J. Titulaer1*, T.H. Svensson1, A. Malmerfelt1, M.M. Marcus1. 1Karolinska Institute, Dept. of Physiology and Pharmacology, Stockholm, Sweden Background: A few years ago a single injection of the nitric oxide donor sodium nitroprusside (SNP) was found to induce a rapid (within 4 hours) and sustained (several weeks) antipsychotic effect in treatment-resistant schizophrenic patients [1]. Moreover, a single injection of SNP was found produce a prolonged block of the psychotomimetic effects of phencyclidine or ketamine in rats that lasts for at least a week [2], as well as to generate both rapid and persisting changes in brain synaptic plasticity, including enhanced excitatory postsynaptic current (EPSC) responses and spine morphology in layer V pyramidal cells in rat medial prefrontal cortex (mPFC) brain slices [3]. Here we have studied the antipsychoticlike effect of SNP in rats using behavioral techniques, both when given alone and in combination with a sub-effective dose of risperidone (RISP). Correlative biochemical studies of regional dopamine release in brain were also performed. Methods: We used the conditioned avoidance response (CAR) test to investigate the antipsychotic-like efficacy, since this behavioral assay has shown a very high predictive validity to identify drugs with clinical antipsychotic activity, and in vivo microdialysis in freely moving animals to measure neurotransmitter efflux in the mPFC and the nucleus accumbens (NAc), respectively. Results: RISP 0.25 mg/kg i.p. caused when given alone only 20% suppression of CAR, which is far below the degree of CAR suppression required to indicate a significant clinical antipsychotic effect, which is 70– 80%. Addition of SNP 1, 1.5 and 2 mg/kg i.p. to RISP dramatically enhanced the antipsychotic-like effect to 67, 86 and 100% CAR suppression, respectively, albeit addition of the highest dose of SNP, i.e. 2 mg/kg, resulted in escape failures indicating risk of non-specific side effects. SNP 2 mg/kg given alone generated only a small
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(11%) and clinically irrelevant CAR suppression. In the NAc, addition of SNP 1 mg/kg did not enhance the risperidone-induced dopamine output. The effect on dopamine output in the mPFC is still under investigation and the definite results will be presented at the meeting. Conclusions: The present preclinical results support the clinical observation that a single injection of SNP can rapidly and dramatically augment the clinical efficacy of antipsychotic drugs in schizophrenia, albeit within a relatively narrow dose-range. That a single injection of SNP alone was not found to exert any clinically relevant suppression of CAR makes it similar to other drugs that both clinically and preclinically have been shown to augment the antipsychotic effect of various neuroleptics, thus a major advantage of SNP over these compounds is the long-lasting augmentation generated by single exposure to the NO-donor. However, our present data do not support any antipsychotic activity of SNP alone as proposed recently (c.f. above), Although the antipsychotic-like effect of drugs as assessed by the CAR-test in rats is primarily localized in the ventral striatum, the fact that add-on SNP did not change DA efflux in this region may indicate that the site of the augmentation rather resides in the prefrontal cortex, as has previously been shown with other compounds that augment antipsychotic drugs. Reference(s) [1] Hallak, J.E.C. et al. 2013. Rapid improvement of acute Schizophrenia symptoms after intravenous sodium nitroprusside. A randomized, double-blind, placebocontrolled trial. JAMA Psychiatry 70, 668–676. [2] Maia-de-Oliveira, J.P. et al. 2015. Nitroprusside single-dose prevents the psychosis-like behavior induced by ketamine for up to one week. Schizophr. Res. 162, 2011–2015. [3] Aghajanian, G.K. 2015. Effects of the rapidly-acting antipsychotic agent sodium nitroprusside (SNP) on synaptic spine function and morphology in medial prefrontal cortex. Abstract ACNP Annual Meeting. Disclosure statement: This abstract is financially supported by an educational grant from BDD GmbH, Germany.
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(11%) and clinically irrelevant CAR suppression. In the NAc, addition of SNP 1 mg/kg did not enhance the risperidone-induced dopamine output. The effect on dopamine output in the mPFC is still under investigation and the definite results will be presented at the meeting. Conclusions: The present preclinical results support the clinical observation that a single injection of SNP can rapidly and dramatically augment the clinical efficacy of antipsychotic drugs in schizophrenia, albeit within a relatively narrow dose-range. That a single injection of SNP alone was not found to exert any clinically relevant suppression of CAR makes it similar to other drugs that both clinically and preclinically have been shown to augment the antipsychotic effect of various neuroleptics, thus a major advantage of SNP over these compounds is the long-lasting augmentation generated by single exposure to the NO-donor. However, our present data do not support any antipsychotic activity of SNP alone as proposed recently (c.f. above), Although the antipsychotic-like effect of drugs as assessed by the CAR-test in rats is primarily localized in the ventral striatum, the fact that add-on SNP did not change DA efflux in this region may indicate that the site of the augmentation rather resides in the prefrontal cortex, as has previously been shown with other compounds that augment antipsychotic drugs. Reference(s) [1] Hallak, J.E.C. et al. 2013. Rapid improvement of acute Schizophrenia symptoms after intravenous sodium nitroprusside. A randomized, double-blind, placebocontrolled trial. JAMA Psychiatry 70, 668–676. [2] Maia-de-Oliveira, J.P. et al. 2015. Nitroprusside single-dose prevents the psychosis-like behavior induced by ketamine for up to one week. Schizophr. Res. 162, 2011–2015. [3] Aghajanian, G.K. 2015. Effects of the rapidly-acting antipsychotic agent sodium nitroprusside (SNP) on synaptic spine function and morphology in medial prefrontal cortex. Abstract ACNP Annual Meeting. Disclosure statement: This abstract is financially supported by an educational grant from BDD GmbH, Germany.