title: Brexpiprazole Alters Monoaminergic Systems following Repeated Administration: an in Vivo Electrophysiological Study.
abstract: BACKGROUND
  Brexpiprazole was recently approved as adjunctive therapy for depression and treatment of schizophrenia in adults. To complement results from a previous study in which its acute effects were characterized, the present study assessed the effect of repeated brexpiprazole administration on monoaminergic systems.
  
  
  METHODS
  Brexpiprazole (1mg/kg, subcutaneous) or vehicle was administered once daily for 2 and 14 days. Single-unit electrophysiological recordings from noradrenaline neurons in the locus coeruleus, serotonin neurons in the dorsal raphe nucleus, dopaminergic neurons in the ventral tegmental area, and pyramidal neurons in the hippocampus CA3 region were obtained in adult male Sprague-Dawley rats under chloral hydrate anesthesia within 4 hours after final dosing.
  
  
  RESULTS
  Brexpiprazole blunted D2 autoreceptor responsiveness, while firing activity of ventral tegmental area dopaminergic neurons remained unaltered. Brexpiprazole increased the firing rate of locus coeruleus noradrenaline neurons and increased noradrenaline tone on α2-adrenergic receptors in the hippocampus. Administration of brexpiprazole for 2 but not 14 days increased the firing rate of serotonin neurons in the dorsal raphe nucleus. In the hippocampus, serotonin1A receptor blockade significantly disinhibited pyramidal neurons after 2- and 14-day brexpiprazole administration. In contrast, no significant disinhibition occurred after 24-hour washout or acute brexpiprazole.
  
  
  CONCLUSIONS
  Repeated brexpiprazole administration resulted in a marked occupancy of D2 autoreceptors, while discharge activity of ventral tegmental area dopaminergic neurons remained unaltered. Brexpiprazole enhanced serotonergic and noradrenergic tone in the hippocampus, effects common to antidepressant agents. Together, these results provide further insight in the neural mechanisms by which brexpiprazole exerts antidepressant and antipsychotic effects.
authors.affiliation: Institute of Mental Health Research (Dr Oosterhof, Dr El Mansari, and Dr Blier), and Department of Cellular and Molecular Medicine (Dr Oosterhof and Dr Blier), University of Ottawa, Ottawa, Ontario, Canada; Neuroscience Drug Discovery, H. Lundbeck A/S, Valby, Denmark (Dr Bundgaard). Pierre.Blier@rohcg.on.ca.
authors.forename: Chris A
authors.initials: CA
authors.lastname: Oosterhof
authors.affiliation: Institute of Mental Health Research (Dr Oosterhof, Dr El Mansari, and Dr Blier), and Department of Cellular and Molecular Medicine (Dr Oosterhof and Dr Blier), University of Ottawa, Ottawa, Ontario, Canada; Neuroscience Drug Discovery, H. Lundbeck A/S, Valby, Denmark (Dr Bundgaard).
authors.forename: Mostafa
authors.initials: M
authors.lastname: El Mansari
authors.affiliation: Institute of Mental Health Research (Dr Oosterhof, Dr El Mansari, and Dr Blier), and Department of Cellular and Molecular Medicine (Dr Oosterhof and Dr Blier), University of Ottawa, Ottawa, Ontario, Canada; Neuroscience Drug Discovery, H. Lundbeck A/S, Valby, Denmark (Dr Bundgaard).
authors.forename: Christoffer
authors.initials: C
authors.lastname: Bundgaard
authors.affiliation: Institute of Mental Health Research (Dr Oosterhof, Dr El Mansari, and Dr Blier), and Department of Cellular and Molecular Medicine (Dr Oosterhof and Dr Blier), University of Ottawa, Ottawa, Ontario, Canada; Neuroscience Drug Discovery, H. Lundbeck A/S, Valby, Denmark (Dr Bundgaard).
authors.forename: Pierre
authors.initials: P
authors.lastname: Blier
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000502:physiology*; D004298:Dopamine / Q000378:metabolism; D008297:Male; D009474:Neurons / Q000187:drug effects* / Q000502:physiology*; D018377:Neurotransmitter Agents / Q000097:blood / Q000494:pharmacology; D009638:Norepinephrine / Q000378:metabolism; D011619:Psychotropic Drugs / Q000097:blood / Q000494:pharmacology*; D015363:Quinolones / Q000097:blood / Q000494:pharmacology*; D017207:Rats, Sprague-Dawley; D017981:Receptors, Neurotransmitter / Q000037:antagonists & inhibitors / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism; D013876:Thiophenes / Q000097:blood / Q000494:pharmacology*; D013997:Time Factors; D046509:Tissue Culture Techniques
chemical_list: D018377:Neurotransmitter Agents; D011619:Psychotropic Drugs; D015363:Quinolones; D017981:Receptors, Neurotransmitter; D013876:Thiophenes; C000591922:brexpiprazole; D012701:Serotonin; D004298:Dopamine; D009638:Norepinephrine
keywords: brexpiprazole; dopamine; norepinephrine; serotonin; single unit electrophysiological recordings