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Asenapine elevates cortical dopamine, noradrenaline and serotonin release. Evidence for activation of cortical and subcortical dopamine systems by different mechanisms

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Abstract

Rationale

Asenapine, a psychopharmacologic agent developed for schizophrenia and bipolar disorder, has higher affinity for 5-HT2A/C,6,7 and α2 adrenergic receptors than for D2 receptors. Asenapine exhibits potent antipsychotic-like effects without inducing catalepsy, increases cortical and subcortical dopamine release, and facilitates cortical glutamatergic transmission in rats. In this study, we further analyzed the effects of asenapine on dopaminergic, noradrenergic, and serotonergic systems in the rat brain.

Materials and methods

We studied the effects of asenapine on (1) dopaminergic neurons in the ventral tegmental area (VTA) and noradrenergic neurons in the locus coeruleus using in vivo single cell recording, (2) release of dopamine and noradrenaline (medial prefrontal cortex), serotonin (frontal cortex), and dopamine (nucleus accumbens), using in vivo microdialysis.

Results

Systemic asenapine increased dopaminergic (0.001–0.2 mg/kg, i.v.) and noradrenergic (0.025–0.05 mg/kg i.v.) neuronal firing, and asenapine (0.1–0.2 mg/kg, s.c) increased cortical noradrenaline and serotonin output. Local asenapine administration increased all three monoamines in the cortex but did not affect accumbal dopamine output. Intra-VTA tetrodotoxin perfusion blocked asenapine-induced accumbal but not cortical dopamine outflow.

Conclusion

Asenapine at doses associated with antipsychotic activity enhanced cortical monoamine efflux. Whereas the asenapine-induced dopamine increase in nucleus accumbens is dependent on activation of dopaminergic neurons in the VTA, the increase of cortical dopamine outflow involves largely a local action at nerve terminals. Our data provide further insight on the pharmacologic characteristics of asenapine that may have bearing on its clinical efficacy in the treatment of schizophrenia and bipolar disorder.

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Acknowledgments

This research was supported by the Swedish Research Council (grant no. 4747), the Karolinska Institutet, and Schering-Plough. Dr Mohammed Shahid is an employee of Schering-Plough. We thank Mrs Anna Malmerfelt and Mrs Ann-Chatrine Samuelsson for skilful technical assistance. All experiments were approved by, and conducted in accordance with, the local Animal Ethics Committee, Stockholm North, and the Karolinska Institutet, Sweden.

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  1. Department of Physiology and Pharmacology, Section of Neuropsychopharmacology, Karolinska Institutet, Nanna Svartz väg 2, 171 77, Stockholm, Sweden

    Olivia Frånberg, Monica M. Marcus, Vladimir Ivanov, Björn Schilström & Torgny H. Svensson

  2. Schering-Plough, Newhouse, Lanarkshire, UK

    Mohammed Shahid

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  1. Olivia Frånberg
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  2. Monica M. Marcus
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  3. Vladimir Ivanov
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  6. Torgny H. Svensson
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Correspondence to Torgny H. Svensson.

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Frånberg, O., Marcus, M.M., Ivanov, V. et al. Asenapine elevates cortical dopamine, noradrenaline and serotonin release. Evidence for activation of cortical and subcortical dopamine systems by different mechanisms. Psychopharmacology 204, 251–264 (2009). https://doi.org/10.1007/s00213-008-1456-5

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