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

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 (170,000 IU/kg sc, 3 times per week for 4 weeks) 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 [S-35] GTP gamma S 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-1 beta 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 (0.3 mg/kg/sc twice per day, 3 times per week for 4 weeks) 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. (C) 2017 Elsevier Inc. All rights reserved.