of the immune system via administration of cytokines is used for the treatment of chronic viral infections such as hepatitis C and for cancers resistant to radiotherapy. saline for six days. Sickness behavior was evaluated using body weight assessments and forced swim screening (FST). Blood and brain samples were collected to measure cytokine p38 mitogen activated protein kinase (MAPK) and phospho-p38 MAPK levels using multiplex techniques. There were significant reductions in body weights and FST immobility occasions associated with IL-1β administration. Rats administered IL-1β experienced significantly higher serum levels of IL-10 but not interferon-γ. Within the hippocampus IL-1β Tenovin-3 reduced levels of p38 MAPK but experienced no impact on levels of phospho-p38 MAPK except in the presence of DMP904. When administered alone DMP904 experienced no significant effect on p38 MAPK or phospho-p38 MAPK in the hippocampus but when given with IL-1β led to increased phosphorylation of p38 MAPK. IL-1β and DMP904 reduced levels of p38 MAPK within the hypothalamus while co-administration of IL-1β and DMP904 abolished the effects of either drug alone. IL-1β decreased immobility time in the FST and led to reductions in body weight changes in serum cytokine levels and p38 MAPK regulation within the hippocampus and hypothalamus. DMP904 blocked some Tenovin-3 of the neurochemical effects of IL-1β but did not impact the behavioral steps or serum cytokines. Thus additional studies will be needed Tenovin-3 to determine whether CRF1 antagonism is an effective treatment for cytokine-induced sickness. 1 Introduction Activation of the immune system via administration of cytokines is used for the treatment of chronic viral infections such as hepatitis C and for cancers that are resistant to radiotherapy (Loftis and Hauser 2004 Solid wood et al. 2006 Regrettably a host of Tenovin-3 common side effects collectively termed “sickness” behavior Rabbit Polyclonal to STK36. frequently accompany treatment with pro-inflammatory cytokines. These side effects which have overlapping features with major depressive disorder generally fall into one of two sizes neurovegetative Tenovin-3 or psychological (Capuron et al. 2002 The neurovegetative dimensions affects the majority of patients and is characterized by fatigue loss of appetite and sleep disruption. The psychological dimensions affects a subset of patients and is characterized by stressed out mood stress and cognitive dysfunction. The neurochemical mechanisms that underlie these two dimensions appear to differ and therefore respond differentially to treatment by drugs such as antidepressant medications (Capuron et al. 2002 Capuron et al. 2004 In particular the neurovegetative symptoms are largely resistant to treatment with traditional selective serotonin re-uptake inhibitor (SSRI) antidepressants (e.g. paroxetine) (Capuron et al. 2002 Papakostas et al. 2003 The side effects of cytokine-based treatments present significant barriers to patient adherence therefore therapeutics that reduce Tenovin-3 these unwanted symptoms are needed. Systemic administration of the pro-inflammatory cytokine interleukin-1β (IL-1β) induces sickness behaviors such as taste aversions (Tazi et al. 1988 impairments in operant responding for food (Crestani et al. 1991 and reductions in interpersonal behavior (Kent et al. 1992 in rodents. In humans IL-1β levels significantly correlate with fatigue in cancer patients (Greenberg et al 1993 Bower et al. 2002 and with depressive symptoms in patients with hepatitis C (Loftis et al. 2008). IL-1β is usually critically involved in the innate immune response and is primarily produced by activated macrophages and blood monocytes but is also found in dendritic cells natural killer cells and B lymphocytes (Dinarello 2009 Within the central nervous system IL-1β is usually produced by astrocytes oligodendrocytes microglia and perivascular macrophages/monocytes (Sairanen et al. 1997 The physiological effects of activation of the IL-1 receptor 1 (IL-1R1) are hypotension fever neutrophilia thrombocytosis and production of acute-phase proteins (Gabay et..