Our latest paper: Antidepressant-like effects of 3-carboxamido seco-nalmefene (3CS-nalmefene), a novel opioid receptor modulator, in a rat IFN-α-induced depression model

Antidepressant-like effects of 3-carboxamido seco-nalmefene (3CS-nalmefene), a novel opioid receptor modulator, in a rat IFN-α-induced depression model is published in Brain, Behaviour and Immunity

Charlotte K. CallaghanJennifer Rouine, Reginald L. Dean, Brian I Knapp, Jean M. Bidlack, Daniel R. DeaverShane M. O’Mara

Highlights

  • IFN-α treatment induced depressive-like and cognitive deficits in the rat.
  • IFN-α increased IL-6, IL-1β and corticosterone, and decreased neurogenesis and BDNF.
  • Opioid modulation prevented IFN-α-induced depressive and cognitive impairments.

Abstract

Patients receiving the cytokine immunotherapy, interferon-alpha (IFN-α) 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 (170,000 IU/kg sc, 3 times per week for 4 weeks) of the pro-inflammatory cytokine, IFN-α, induced a depressive phenotype in rats in the forced swim test (FST). Here, we examine the biological mechanisms underlying behavioral changes induced by IFN-α, 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-α induced changes. In vitro radioligand receptor binding assays and the [35S] GTPγS were performed to determine the affinity of 3CS-nalmefene for the mu, kappa and delta opioid receptors. IFN-α treatment increased circulating and central markers of inflammation and hypothalamic-pituitary-adrenal (HPA) axis activity (IL-6, IL-1β 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 4 weeks) prevented IFN-α-induced immobility in the FST and impaired object displacement learning. In addition, 3CS-nalmefene prevented IFN-α-induced increases in inflammation and hyperactivity of the HPA-axis, the IFN-α-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.

Keywords

  • Opioids;
  • Inflammation;
  • IFN-α;
  • Depression;
  • 3CS-nalmefene;
  • Cognition

Author: Shane O'Mara

Neuroscientist

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