Involvement of 5-HT2A receptor and α2-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 α(2)-adrenoceptors than for D(2) receptors. Noteworthy, blockage of both the 5-HT(2A) and α(2)-adrenergic receptors has been shown to enhance prefrontal dopamine release induced by D(2) 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-HT(2A) receptors and α(2)-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-HT(2A/2C) receptor agonist, increased cortical monoamine release, effects that were antagonized both by asenapine and the selective 5-HT(2A) antagonist M100907. Application of clonidine, an α(2)-adrenoceptor agonist, significantly reduced monoamine release in the mPFC. The selective α(2)-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-HT(2A) and α(2) receptor antagonistic activity, which may contribute to enhance prefrontal monoamine release in vivo and, secondarily, its clinical effects in schizophrenia and bipolar disorder.