title: Antidepressant-like Effects of Buprenorphine are Mediated by Kappa Opioid Receptors.
abstract: Previous studies have identified potential antidepressant effects of buprenorphine (BPN), a drug with high affinity for mu opioid receptor (MORs) and kappa opioid receptors (KORs) and some affinity at delta opioid receptor (DOR) and opioid receptor-like 1 (ORL-1) receptors. Therefore, these studies examined which opioid receptors were involved in BPN's effects on animal behavior tests sensitive to antidepressant drugs. The acute effects of BPN were tested in the forced swim test (FST) using mice with genetic deletion of individual opioid receptors or after pharmacological blockade of receptors. For evaluating the effects of BPN on chronic stress, separate groups of mice were exposed to unpredictable chronic mild stress (UCMS) for 3 weeks and treated with BPN for at least 7 days before behavioral assessment and subsequent measurement of Oprk1, Oprm1, and Pdyn mRNA expression in multiple brain regions. BPN did not reduce immobility in mice with KOR deletion or after pretreatment with norbinaltorphimine, even though desipramine remained effective. In contrast, BPN reduced immobility in MOR and DOR knockout mice and in mice pretreated with the ORL-1 antagonist JTC-801. UCMS reduced sucrose preference, decreased time in the light side of the light/dark box, increased immobility in the FST and induced region-specific alterations in Oprk1, Oprm1, and PDYN mRNA expression in the frontal cortex and striatum. All of these changes were normalized following BPN treatment. The KOR was identified as a key player mediating the effects of BPN in tests sensitive to antidepressant drugs in mice. These studies support further development of BPN as a novel antidepressant.
authors.affiliation: Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Edgardo
authors.initials: E
authors.lastname: Falcon
authors.affiliation: Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Caroline A
authors.initials: CA
authors.lastname: Browne
authors.affiliation: Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Rosa M
authors.initials: RM
authors.lastname: Leon
authors.affiliation: Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Vanessa C
authors.initials: VC
authors.lastname: Fleites
authors.affiliation: Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Rachel
authors.initials: R
authors.lastname: Sweeney
authors.affiliation: Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA, USA.
authors.forename: Lynn G
authors.initials: LG
authors.lastname: Kirby
authors.affiliation: Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA.|Department of Pharmacology, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Irwin
authors.initials: I
authors.lastname: Lucki
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000008:administration & dosage*; D001522:Behavior, Animal / Q000187:drug effects*; D001921:Brain / Q000378:metabolism*; D002047:Buprenorphine / Q000008:administration & dosage*; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017465:Receptors, Opioid, delta / Q000235:genetics / Q000378:metabolism; D017473:Receptors, Opioid, kappa / Q000235:genetics / Q000378:metabolism*; D017450:Receptors, Opioid, mu / Q000235:genetics / Q000378:metabolism; D013315:Stress, Psychological / Q000378:metabolism
chemical_list: D000928:Antidepressive Agents; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D002047:Buprenorphine