title: The α2C-adrenoceptor antagonist, ORM-10921, has antipsychotic-like effects in social isolation reared rats and bolsters the response to haloperidol.
abstract: Early studies suggest that selective α2C-adrenoceptor (AR)-antagonism has anti-psychotic-like and pro-cognitive properties. However, this has not been demonstrated in an animal model of schizophrenia with a neurodevelopmental construct. The beneficial effects of clozapine in refractory schizophrenia and associated cognitive deficits have, among others, been associated with its α2C-AR modulating activity. Altered brain-derived neurotrophic factor (BDNF) has been linked to schizophrenia and cognitive deficits. We investigated whether the α2C-AR antagonist, ORM-10921, could modulate sensorimotor gating and cognitive deficits, as well as alter striatal BDNF levels in the social isolation reared (SIR) model of schizophrenia, comparing its effects to clozapine and the typical antipsychotic, haloperidol, the latter being devoid of α2C-AR-activity. Moreover, the ability of ORM-10921 to augment the effects of haloperidol on the above parameters was also investigated. Animals received subcutaneous injection of either ORM-10921 (0.01mg/kg), clozapine (5mg/kg), haloperidol (0.2mg/kg), haloperidol (0.2mg/kg)+ORM-10921 (0.01mg/kg) or vehicle once daily for 14days, followed by assessment of novel object recognition (NOR), prepulse inhibition (PPI) of startle response and striatal BDNF levels. SIR significantly attenuated NOR memory as well as PPI, and reduced striatal BDNF levels vs. social controls. Clozapine, ORM-10921 and haloperidol+ORM-10921, but not haloperidol alone, significantly improved SIR-associated deficits in PPI and NOR, with ORM-10921 also significantly improving PPI deficits vs. haloperidol-treated SIR animals. Haloperidol+ORM-10921 significantly reversed reduced striatal BDNF levels in SIR rats. α2C-AR-antagonism improves deficits in cognition and sensorimotor gating in a neurodevelopmental animal model of schizophrenia and bolsters the effects of a typical antipsychotic, supporting a therapeutic role for α2C-AR-antagonism in schizophrenia.
authors.affiliation: Division of Pharmacology, North-West University (Potchefstroom Campus), Potchefstroom 2520, South Africa. Electronic address: madeleine.erasmus@gmail.com.
authors.forename: Madeleine
authors.initials: M
authors.lastname: Uys
authors.affiliation: Orion Pharma, Orion Corporation, Nottingham, UK. Electronic address: mo.shahid@orionpharma.com.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Shahid
authors.affiliation: Orion Pharma, Orion Corporation, Turku, Finland. Electronic address: jukka.sallinen@orionpharma.com.
authors.forename: Jukka
authors.initials: J
authors.lastname: Sallinen
authors.affiliation: Center of Excellence for Pharmaceutical Sciences, North-West University (Potchefstroom Campus), Hoffman Street, Potchefstroom 2520, South Africa. Electronic address: walter.dreyer@nwu.ac.za.
authors.forename: Walter
authors.initials: W
authors.lastname: Dreyer
authors.affiliation: Medicines Usage in South Africa, North-West University (Potchefstroom Campus), Hoffman Street, Potchefstroom 2520, South Africa. Electronic address: marike.cockeran@nwu.ac.za.
authors.forename: Marike
authors.initials: M
authors.lastname: Cockeran
authors.affiliation: Center of Excellence for Pharmaceutical Sciences, North-West University (Potchefstroom Campus), Hoffman Street, Potchefstroom 2520, South Africa. Electronic address: brian.harvey@nwu.ac.za.
authors.forename: Brian H
authors.initials: BH
authors.lastname: Harvey
mesh_terms: D000161:Acoustic Stimulation; D000818:Animals; D014150:Antipsychotic Agents / Q000627:therapeutic use*; D001572:Benzofurans / Q000627:therapeutic use*; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D004357:Drug Synergism; D006220:Haloperidol / Q000627:therapeutic use*; D008297:Male; D065808:Prepulse Inhibition / Q000187:drug effects; D054837:Quinolizidines / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D021641:Recognition, Psychology / Q000187:drug effects; D012559:Schizophrenia / Q000188:drug therapy* / Q000473:pathology; D012565:Schizophrenic Psychology; D012934:Social Isolation / Q000523:psychology*; D018709:Statistics, Nonparametric
chemical_list: D014150:Antipsychotic Agents; D001572:Benzofurans; D019208:Brain-Derived Neurotrophic Factor; C587546:ORM-10921; D054837:Quinolizidines; D006220:Haloperidol
keywords: Isolation rearing animal model; Neurodevelopment; Object recognition memory; Sensorimotor gating; Typical vs. atypical antipsychotic; α(2C)-Adrenoceptor