title: Dopamine D3 receptor antagonism contributes to blonanserin-induced cortical dopamine and acetylcholine efflux and cognitive improvement.
abstract: Blonanserin is a novel atypical antipsychotic drug (APD), which, unlike most atypical APDs, has a slightly higher affinity for dopamine (DA) D2 than serotonin (5-HT)2A receptors, and is an antagonist at both, as well as at D3 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 D3 antagonist NGB 2904, and the typical APD, haloperidol, a D2 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, 10mg/kg, i.p., increased DA, norepinephrine (NE), and ACh efflux in mPFC and dSTR. NGB 2904, 3mg/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 D3 agonist PD 128907 partially blocked the blonanserin-induced cortical ACh, DA, NE and striatal DA efflux. NGB 2904, 3mg/kg, like blonanserin, 1mg/kg, and the combination of sub-effective doses of NGB 2904 and blonanserin (both 0.3mg/kg), ameliorated the scPCP-induced NOR deficit in rats. These results suggest that D3 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.
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Northwestern Feinberg School of Medicine, Chicago, IL 60611, USA.
authors.forename: Mei
authors.initials: M
authors.lastname: Huang
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Northwestern Feinberg School of Medicine, Chicago, IL 60611, USA.
authors.forename: Sunoh
authors.initials: S
authors.lastname: Kwon
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Northwestern Feinberg School of Medicine, Chicago, IL 60611, USA; Sumitomo Dainippon Pharma Co., Ltd., Osaka 564-0053, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Oyamada
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Northwestern Feinberg School of Medicine, Chicago, IL 60611, USA.
authors.forename: Lakshmi
authors.initials: L
authors.lastname: Rajagopal
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Northwestern Feinberg School of Medicine, Chicago, IL 60611, USA; Sumitomo Dainippon Pharma Co., Ltd., Osaka 564-0053, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Miyauchi
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Northwestern Feinberg School of Medicine, Chicago, IL 60611, USA. Electronic address: h-meltzer@northwestern.edu.
authors.forename: Herbert Y
authors.initials: HY
authors.lastname: Meltzer
mesh_terms: D000109:Acetylcholine / Q000378:metabolism*; D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology; D001923:Brain Chemistry / Q000187:drug effects; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism*; D018492:Dopamine Antagonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005449:Fluorenes / Q000494:pharmacology; D006220:Haloperidol / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018697:Nootropic Agents / Q000494:pharmacology*; D010078:Oxazines / Q000494:pharmacology; D010622:Phencyclidine / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology*; D020318:Rats, Long-Evans; D050637:Receptors, Dopamine D3 / Q000037:antagonists & inhibitors*
chemical_list: D001578:Benzopyrans; D018492:Dopamine Antagonists; D018691:Excitatory Amino Acid Antagonists; D005449:Fluorenes; C116818:NGB 2904; D018697:Nootropic Agents; D010078:Oxazines; D010879:Piperazines; D010880:Piperidines; D050637:Receptors, Dopamine D3; C062458:3,4,4a,10b-tetrahydro-4-propyl-2H,5H-(1)benzopyrano(4,3-b)-1,4-oxazin-9-ol; C079310:blonanserin; D010622:Phencyclidine; D006220:Haloperidol; D000109:Acetylcholine; D004298:Dopamine
keywords: Blonanserin; Cognition; Dopamine D(3) receptor; Microdialysis