Involvement of 5-HT2A receptor and a2-adrenoceptor blockade in the asenapine-induced elevation of prefrontal cortical monoamine outflow

The psychotropic drug asenapine is approved for the treatment of schizophrenia and manic or mixed episodes associated with bipolar I disorder. Asenapine exhibits higher affinity for several 5-HT receptors and a2-adrenoceptors than for D2 receptors. Noteworthy, blockage of both the 5-HT2A and a2-adrenergic receptors has been shown to enhance prefrontal dopamine release induced by D2 receptor antagonists. Previous results show that asenapine, both systemically and locally, increases dopamine, noradrenaline, and serotonin release in the medial prefrontal cortex (mPFC), and that the increased dopamine release largely depends on an intracortical action. Using reverse microdialysis in freely moving rats, we here assessed the potency of low concentrations of asenapine to cause a pharmacologically significant blockage in vivo of 5-HT2A receptors and a2-adrenoceptors within the mPFC, and thus its ability to affect cortical monoamine release by these receptors. Intracortical administration of 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride (DOI), a 5-HT2A/2C receptor agonist, increased cortical monoamine release, effects that were antagonized both by asenapine and the selective 5-HT2A antagonist M100907. Application of clonidine, an a2-adrenoceptor agonist, significantly reduced monoamine release in the mPFC. The selective a2-adrenoceptor antagonist idazoxan blocked, whereas asenapine partially blocked clonidine-induced cortical dopamine and noradrenaline decrease. The effects of asenapine and idazoxan on clonidine-induced serotonin decrease were less pronounced. Our results propose that low concentrations of asenapine in the mPFC exhibit a pharmacologically significant 5-HT2A and a2 receptor antagonistic activity, which may contribute to enhance prefrontal monoamine release in vivo and, secondarily, its clinical effects in schizophrenia and bipolar disorder. Synapse, 2012. (c) 2012 Wiley Periodicals, Inc.