PMID- 28844812
OWN - NLM
STAT- MEDLINE
DCOM- 20180711
LR  - 20180711
IS  - 1090-2139 (Electronic)
IS  - 0889-1591 (Linking)
VI  - 67
DP  - 2018 Jan
TI  - Antidepressant-like effects of 3-carboxamido seco-nalmefene (3CS-nalmefene), a 
      novel opioid receptor modulator, in a rat IFN-alpha-induced depression model.
PG  - 152-162
LID - S0889-1591(17)30404-X [pii]
LID - 10.1016/j.bbi.2017.08.016 [doi]
AB  - Patients receiving the cytokine immunotherapy, interferon-alpha (IFN-alpha) 
      frequently present with neuropsychiatric consequences and cognitive impairments. 
      Patients (25-80%) report symptoms of depression, including, anhedonia, 
      irritability, fatigue and impaired motivation. Our lab has previously 
      demonstrated treatment (170,000IU/kg sc, 3 times per week for 4weeks) of the 
      pro-inflammatory cytokine, IFN-alpha, induced a depressive phenotype in rats in the 
      forced swim test (FST). Here, we examine the biological mechanisms underlying 
      behavioral changes induced by IFN-alpha, which may be reflective of mechanisms 
      underlying inflammation associated depression. We also investigate the potential 
      of 3-carboxamido seco-nalmefene (3CS-nalmefene), a novel opioid modulator 
      (antagonist at mu and partial agonist at kappa and delta opioid receptors in 
      vitro), to reverse IFN-alpha induced changes. In vitro radioligand receptor binding 
      assays and the [(35)S] GTPgammaS were performed to determine the affinity of 
      3CS-nalmefene for the mu, kappa and delta opioid receptors. IFN-alpha treatment 
      increased circulating and central markers of inflammation and 
      hypothalamic-pituitaryadrenal (HPA) axis activity (IL-6, IL-1beta and 
      corticosterone) while increasing immobility in the FST, impairing of object 
      displacement learning in the object exploration task (OET), and decreasing 
      neuronal proliferation and brain-derived neurotrophic factor (BDNF) in the 
      hippocampus. Treatment with 3CS-nalmefene (0.3mg/kg/sc twice per day, 3 times per 
      week for 4weeks) prevented IFN-alpha-induced immobility in the FST and impaired 
      object displacement learning. In addition, 3CS-nalmefene prevented IFN-alpha-induced 
      increases in inflammation and hyperactivity of the HPA-axis, the IFN-alpha-induced 
      reduction in both neuronal proliferation and BDNF expression in the hippocampus. 
      Overall, these preclinical data would support the hypothesis that opioid receptor 
      modulation is a relevant target for treatment of depression.
CI  - Copyright (c) 2017 Elsevier Inc. All rights reserved.
FAU - Callaghan, Charlotte K
AU  - Callaghan CK
AD  - Trinity College Institute of Neuroscience, Trinity College, Dublin 2, Ireland. 
      Electronic address: callaghc@tcd.ie.
FAU - Rouine, Jennifer
AU  - Rouine J
AD  - Trinity College Institute of Neuroscience, Trinity College, Dublin 2, Ireland.
FAU - Dean, Reginald L
AU  - Dean RL
AD  - Alkermes, Inc., Life Sciences-Toxicology, 852 Winter Street, Waltham, MA 02451, 
      USA.
FAU - Knapp, Brian I
AU  - Knapp BI
AD  - University of Rochester, Department of Pharmacology and Physiology, School of 
      Medicine and DentistryUniversity of Rochester, Rochester, NY 14642, USA.
FAU - Bidlack, Jean M
AU  - Bidlack JM
AD  - University of Rochester, Department of Pharmacology and Physiology, School of 
      Medicine and DentistryUniversity of Rochester, Rochester, NY 14642, USA.
FAU - Deaver, Daniel R
AU  - Deaver DR
AD  - Alkermes, Inc., Life Sciences-Toxicology, 852 Winter Street, Waltham, MA 02451, 
      USA.
FAU - O'Mara, Shane M
AU  - O'Mara SM
AD  - Trinity College Institute of Neuroscience, Trinity College, Dublin 2, Ireland.
LA  - eng
PT  - Journal Article
DEP - 20170824
PL  - Netherlands
TA  - Brain Behav Immun
JT  - Brain, behavior, and immunity
JID - 8800478
RN  - 0 (Antidepressive Agents)
RN  - 0 (Brain-Derived Neurotrophic Factor)
RN  - 0 (Interferon-alpha)
RN  - 0 (Narcotic Antagonists)
RN  - 0 (Receptors, Opioid)
RN  - 5S6W795CQM (Naltrexone)
RN  - TOV02TDP9I (nalmefene)
SB  - IM
MH  - Animals
MH  - Antidepressive Agents/*administration & dosage
MH  - Anxiety/chemically induced/drug therapy
MH  - Behavior, Animal/drug effects
MH  - Brain-Derived Neurotrophic Factor/metabolism
MH  - Cell Proliferation/drug effects
MH  - Depression/chemically induced/drug therapy
MH  - Depressive Disorder/chemically induced/*drug therapy
MH  - Disease Models, Animal
MH  - Hippocampus/drug effects/metabolism
MH  - Interferon-alpha/administration & dosage
MH  - Male
MH  - Naltrexone/administration & dosage/*analogs & derivatives
MH  - Narcotic Antagonists/*administration & dosage
MH  - Neurons/drug effects/metabolism
MH  - Rats, Wistar
MH  - Receptors, Opioid/*agonists
OTO - NOTNLM
OT  - 3CS-nalmefene
OT  - Cognition
OT  - Depression
OT  - IFN-alpha
OT  - Inflammation
OT  - Opioids
EDAT- 2017/08/29 06:00
MHDA- 2018/07/12 06:00
CRDT- 2017/08/29 06:00
PHST- 2017/05/09 00:00 [received]
PHST- 2017/07/27 00:00 [revised]
PHST- 2017/08/22 00:00 [accepted]
PHST- 2017/08/29 06:00 [pubmed]
PHST- 2018/07/12 06:00 [medline]
PHST- 2017/08/29 06:00 [entrez]
AID - S0889-1591(17)30404-X [pii]
AID - 10.1016/j.bbi.2017.08.016 [doi]
PST - ppublish
SO  - Brain Behav Immun. 2018 Jan;67:152-162. doi: 10.1016/j.bbi.2017.08.016. Epub 2017 
      Aug 24.