Dopamine D 3 receptor antagonism contributes to blonanserin-induced cortical dopamine and acetylcholine efflux and cognitive improvement Mei Huang a , Sunoh Kwon a , Yoshihiro Oyamada a,b , Lakshmi Rajagopal a , Masanori Miyauchi a,b , Herbert Y. Meltzer a, ⁎ a Department of Psychiatry and Behavioral Sciences, Northwestern Feinberg School of Medicine, Chicago, IL 60611, USA b Sumitomo Dainippon Pharma Co., Ltd., Osaka 564-0053, Japan abstract article info Article history: Received 8 July 2015 Received in revised form 9 September 2015 Accepted 11 September 2015 Available online 14 September 2015 Keywords: Blonanserin Cognition Dopamine D 3 receptor Microdialysis Blonanserin is a novel atypical antipsychotic drug (APD), which, unlike most atypical APDs, has a slightly higher affinity for dopamine (DA) D 2 than serotonin (5-HT) 2A receptors, and is an antagonist at both, as well as at D 3 receptors. The effects of atypical APDs to enhance rodent cortical, hippocampal, limbic, and dorsal striatal (dSTR) DA and acetylcholine (ACh) release, contribute to their ability to improve novel object recognition (NOR) in rodents treated with sub-chronic (sc) phencyclidine (PCP) and cognitive impairment associated with schizophrenia (CIAS). Here we determined the ability of blonanserin, the D 3 antagonist NGB 2904, and the typical APD, haloperidol, a D 2 antagonist, to enhance neurotransmitter efflux in the medial prefrontal cortex (mPFC) and dSTR of mice, and to ameliorate the scPCP-induced deficit in NOR in rats. Blonanserin, 10 mg/kg, i.p., increased DA, norepinephrine (NE), and ACh efflux in mPFC and dSTR. NGB 2904, 3 mg/kg, increased DA and ACh, but not NE, efflux in mPFC, and DA, but not ACh, efflux in dSTR. Haloperidol increased DA and NE efflux in dSTR only. The selective D 3 agonist PD 128907 partially blocked the blonanserin-induced cortical ACh, DA, NE and striatal DA efflux. NGB 2904, 3 mg/kg, like blonanserin, 1 mg/kg, and the combination of sub-effective doses of NGB 2904 and blonanserin (both 0.3 mg/kg), ameliorated the scPCP-induced NOR deficit in rats. These results suggest that D 3 receptor blockade may contribute to the ability of blonanserin to increase cortical DA and ACh efflux, as well as to restore NOR and improve CIAS. © 2015 Elsevier Inc. All rights reserved. 1. Introduction Cognitive impairment is a characteristic feature of schizophrenia, affecting all domains of cognition, including cognitive flexibility and de- clarative memory (Saykin et al., 1991). Novel treatments to alleviate the cognitive impairment associated with schizophrenia (CIAS) are needed, as current treatments are only partially effective (Woodward et al., 2005). Impairment in memory and learning following sub-chronic (sc) administration of the N-methyl-D-aspartate non-competitive an- tagonist, phencyclidine (PCP), is a widely used model to test putative treatments for CIAS (Meltzer et al., 2013; Neill et al., 2014). The deficit in novel object recognition (NOR) is considered a model of the declara- tive memory deficit in schizophrenia (Ennaceur, 2010; Meltzer et al., 2013). We have previously shown that atypical antipsychotic drugs (APDs), e.g. risperidone and lurasidone, many of which are more potent serotonin (5-HT) 2A than dopamine (DA) D 2 receptor antagonists (Meltzer and Huang, 2008), amisulpride, a D 2 /D 3 , 5-HT 7 receptor antag- onist (Horiguchi et al., 2011), and blonanserin, a 5-HT 2A /D 2 /D 3 antago- nist and indirect 5-HT 1A agonist, a novel atypical APD approved in Japan (Hori et al., 2014), can acutely reverse the NOR deficit induced by scPCP (Horiguchi and Meltzer, 2013), while typical APDs, which are selective for D 2 receptor blockade, are ineffective in this model (Snigdha et al., 2010; Meltzer et al., 2013; Neill et al., 2014). Blonanserin, unlike other atypical APDs, is an equal potent at D 2 and 5-HT 2A antagonist in vitro (Une and Kurumiya, 2007; Ohoyama et al., 2011). The Ki values for blonanserin to inhibit the specific binding of [ 3 H]spiperone to the DA D 2 receptor and of [ 3 H]ketanserin to 5-HT 2A re- ceptors are 2.0 ± 0.2 and 2.9 ± 0.4 nM, respectively, indicating approx- imate equivalence, unlike the marked differences favoring 5-HT 2A receptors of other atypical APDs (Meltzer and Huang, 2008; Ohoyama et al., 2011). Moreover, blonanserin, unlike most atypical APDs, with the exception of amisulpride, a substituted benzamide (Perrault et al., 1997), is also a potent D 3 receptor antagonist (Tadori et al., 2011; Takaki and Ujike, 2013; Une and Kurumiya, 2007). Thus, the affinity of blonanserin for human D 3 receptor with [ 3 H]7-OH-DPAT as ligand was Pharmacology, Biochemistry and Behavior 138 (2015) 49–57 Abbreviations: ACh, acetylcholine; APD, antipsychotics; CIAS, cognitive impairment associated with schizophrenia; DA, dopamine; DOPAC, 3,4-dihydroxyphenylacetic acid; dSTR, dorsal striatum; 5-HIAA, 5-hydroxyindole acetic acid; HVA, homovanillic acid; mPFC, medial prefrontal cortex; NE, norepinephrine; NOR, novel object recognition; PCP, phencyclidine. ⁎ Corresponding author at: Department of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, 303 E. Chicago Ave., Ward Building 7-014, Chicago, IL 60611, USA. E-mail address: h-meltzer@northwestern.edu (H.Y. Meltzer). http://dx.doi.org/10.1016/j.pbb.2015.09.011 0091-3057/© 2015 Elsevier Inc. All rights reserved. Contents lists available at ScienceDirect Pharmacology, Biochemistry and Behavior journal homepage: www.elsevier.com/locate/pharmbiochembeh