Involvement of 5‐HT_2A receptor and α₂‐adrenoceptor blockade in the asenapine‐induced elevation of prefrontal cortical monoamine outflow

Abstract

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.

Asenapine alters the activity of monoaminergic systems following its subacute and long-term administration: An in vivo electrophysiological characterization

“…Interestingly, acute mirtazapine administration had this same effect (0.5 mg/kg; Haddjeri et al, 1996), while long-term mirtazapine administration did not occupy postsynaptic α 2 -adrenoceptors to a significant extent (Haddjeri et al, 1998a). In contrast to this latter result, sustained asenapine administration reduced the inhibitory response of iontophoretically applied NE, indicating that postsynaptic α 2 -adrenoceptors were blocked by asenapine -in line with a previous report (Frånberg et al, 2012). Importantly, this blockade was incomplete since acute idazoxan administration reduced the neural response to NE application even further ( Figure 4D).…”

“…Two-day and 21-day administration of asenapine almost completely blocked the effect of DOI, demonstrating potent in vivo antagonism at 5-HT 2A receptors by asenapine (see Figure 1D). In line with this finding, previous reports showed that acute asenapine administration reversed the inhibitory effect of DOI on LC NE neurons, and that local application of asenapine prevented prefrontal DOI-induced elevations in 5-HT, DA and NE (Frånberg et al, 2012;Ghanbari et al, 2009). Thus, the current observations support potent antagonistic properties of asenapine on 5-HT 2A receptors, a common pharmacological property of atypical antipsychotics that could be clinically relevant in adjunct to treatment of mood disorders (Blier and Szabo, 2005).…”

“…Asenapine also reversed the inhibitory effect of the preferential 5-HT 2A receptor agonist 2,5-dimethoxy-4-iodoamphetamine (DOI; ED 50 = 7572 mg/kg), indicating antagonistic action of asenapine at this receptor subtype (Ghanbari et al, 2009). In support of this, local perfusion of the prefrontal cortex with asenapine blocked both α 2 -adrenergic and 5-HT 2A receptors (Frånberg et al, 2012). Although acute systemic administration of asenapine did not alter the firing rate of 5-HT neurons in the dorsal raphe nucleus (DRN; Frånberg et al, 2009;Ghanbari et al, 2009), it acted as a partial 5-HT 1A agonist when applied microiontophoretically in both the DRN and hippocampus (Ghanbari et al, 2009).…”

Effect of Psilocin on Extracellular Dopamine and Serotonin Levels in the Mesoaccumbens and Mesocortical Pathway in Awake Rats

“…28,29) The hallucinogenic 5-HT 2A/2C agonist 4-iodo-2,5-dimethoxyamphetamine indirectly increases extracellular 5-HT release in the rat medial prefrontal cortex by stimulating glutamate release. 30) Most of the subjective effects of psilocybin are blocked by pretreatment with the 5-HT 2A/2C antagonist ketanserin, indicating that the hallucinogenic effects of psilocybin are mediated primarily by actions at the 5-HT 2A receptor. 14,15,31) We hypothesize that psilocin increases extracellular 5-HT levels through 5-HT 2A receptor activation in the mesocortical pathway.…”

The Comparative Effects of Risperidone Long-Acting Injection and Paliperidone Palmitate on Social Functioning in Schizophrenia: A 6-Month, Open-Label, Randomized Controlled Pilot Trial

“…However, their affinities for the α 2 -adrenergic receptor are different, since PAL has a higher affinity than RIS for this receptor [18]. Animal studies have shown that blockage of α 2 -adrenergic receptors greatly affects the release of dopamine and noradrenaline from the medial prefrontal cortex [32]. It has also been shown that noradrenaline is related to motivation and vigilance [33].…”