Effect of novel atypical antipsychotic, blonanserin, on extracellular neurotransmitter level in rat prefrontal cortex

Abstract

To clarify the mechanisms of action of blonanserin, an atypical antipsychotic drug, we studied the effects of systemic administration of blonanserin and risperidone on extracellular levels of norepinephrine, dopamine, serotonin, GABA and glutamate in the medial prefrontal cortex using microdialysis, and neuronal firing in the ventral tegmental area, locus coeruleus, dorsal raphe nucleus and mediodorsal thalamic nucleus using radiotelemetry. The binding affinities of blonanserin to D₂ and 5-HT_2A receptors in the rat brain were confirmed and found to be similar. Blonanserin transiently increased neuronal firing in locus coeruleus and ventral tegmental area but not in dorsal raphe nucleus or mediodorsal thalamic nucleus, whereas risperidone increased the firing in locus coeruleus, ventral tegmental area and dorsal raphe nucleus but not in mediodorsal thalamic nucleus. Blonanserin persistently increased frontal extracellular levels of norepinephrine and dopamine but not serotonin, GABA or glutamate, whereas risperidone persistently increased those of norepinephrine, dopamine and serotonin but not GABA or glutamate. These results suggest a pharmacological correlation between the stimulatory effects of these antipsychotics on frontal monoamine release and neuronal activity in monoaminergic nuclei. Inhibition of the α₂ adrenoceptor increased extracellular monoamine levels and enhanced blonanserin-induced increase in extracellular serotonin level. These results indicated that the combination of antagonism of D₂ and 5-HT_2A receptors contribute to the rise in extracellular levels of norepinephrine and dopamine, and that α₂ adrenoceptors play important roles in frontal serotonin release. They also suggest that blonanserin-induced activation of monoaminergic transmission could be, at least partially, involved in atypical antipsychotic properties of blonanserin.

Introduction

2-(4-ethyl-1-piperazinyl)-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocycloocta [b] pyridine, blonanserin, was developed by Dainippon Pharmaceutical Co. (Osaka, Japan: currently Dainippon-Sumitomo Pharma Co.) as a novel antipsychotic drug for schizophrenia in Japan and Korea (Deeks and Keating, 2010, Garcia et al., 2009, Miura, 2008). Double-blind clinical trials demonstrated that blonanserin is equal to haloperidol and risperidone with regard to primary endpoints, and better than haloperidol in improving negative symptoms (Deeks and Keating, 2010, Garcia et al., 2009, Miura, 2008, Miyake et al., 2008, Murasaki, 2007). Clinically, blonanserin exhibits atypical antipsychotic properties with efficacy against negative and positive symptoms of schizophrenia (Deeks and Keating, 2010, Garcia et al., 2009, Miura, 2008).

The receptor binding profiles of atypical antipsychotics such as clozapine, olanzapine, quetiapine, risperidone and zotepine, have potent serotonin 5-HT_2A with dopamine D₂ receptors antagonistic properties (Meltzer et al., 2003). Furthermore, atypical antipsychotics increase frontal extracellular dopamine level (Gessa et al., 2000, Ichikawa et al., 2001, Ichikawa et al., 2002, Liegeois et al., 2002, Rowley et al., 2000, Zhang et al., 2000). Contrary to atypical antipsychotics, the typical antipsychotics, haloperidol and sulpiride, with mainly D₂ antagonistic properties (Bymaster et al., 1997), and M100907, with selective 5-HT_2A receptors antagonist, do not alter frontal extracellular dopamine level (Adams and Moghaddam, 2001, Lopez-Gil et al., 2007, Rowley et al., 2000, Zhang et al., 2000); however, co-administration of these two types of agents could increase frontal extracellular dopamine level (Ichikawa et al., 2002, Meltzer et al., 2003). Therefore, it seems that the potent 5-HT_2A with D₂ receptors antagonism plays important roles in the clinical outcome as atypical antipsychotic drugs (Meltzer et al., 2003). In spite of these efforts, there are no atypical antipsychotics that are selective antagonists to 5-HT_2A with D₂ receptors, since the conventional atypical antipsychotics (clozapine, olanzapine, quetiapine, risperidone and zotepine) have high affinity to 5-HT_2A and D₂ receptors as well as other receptors including α₁,α₂ adrenoceptors and histamine H₁ receptor.

Blonanserin shows a unique binding profile different from other atypical antipsychotics with affinities to D₂ receptor and 5-HT_2A receptor but weak affinities to D₁, 5-HT_1A, 5-HT_2B, 5-HT_2C, H₁, muscarinic M₁ receptors and α₁, α₂, β adrenoceptors in human (Oka et al., 1993, Une and Kurumiya, 2008); however, the neurobiological features of blonanserin remain obscure. Therefore, to clarify the mechanism of action of blonanserin, the present study determined is effects on frontal extracellular levels of dopamine, norepinephrine, serotonin, GABA and glutamate in freely moving rats, using ion-exchange high-performance liquid chromatography, high-speed and highly-sensitive extreme liquid chromatography. In addition, we determined the neuronal firing frequencies in the locus coeruleus, ventral tegmental area, dorsal raphe nucleus and mediodorsal thalamic nucleus in freely moving rats after administration of blonanserin. The binding affinities of blonanserin to dopamine D₂ and serotonin 5-HT_2A receptors of rat brain were also investigated.