title: Administration of pegylated interferon-alpha-2a or -2b does not induce sickness behavior in Lewis rats.
abstract: Repeated administration of interferon-alpha (IFN-alpha) or pegylated IFN-alpha to patients with chronic hepatitis C viral infection induces a flu-like syndrome as well as neuropsychiatric side effects, which are well recognized, but poorly understood. Although pegylation appears to have improved viral response rates in patients with hepatitis C, there are still neurotoxicities associated with pegylated IFN-alpha therapy, in particular, depression, which can compromise and sometime prevent successful completion of antiviral treatment. This study assessed the effects of two forms of pegylated IFN-alpha [peginterferon-alfa-2a (PEG-2a) and peginterferon-alfa-2b (PEG-2b)] in rats in order to develop an animal model of IFN-induced "depression" (often described as sickness behavior) that can be used to more comprehensively investigate the neurochemical mechanisms of IFN-induced depression. Sixty male and female Lewis rats were randomly assigned to one of six treatment groups: (1) saline (SAL)+SAL (2) SAL+PEG-2a; (3) SAL+PEG-2b; (4) selective serotonin reuptake inhibitor (SSRI)+SAL, (5) SSRI+PEG-2a; (6) SSRI+PEG-2b. Rats were pretreated with intraperitoneal (i.p.) saline (0.9%) or 7.5mg/kg/day fluoxetine for 1 week, followed by 3 weeks of concurrent i.p. administration of 650 microg/wk of PEG-2a or PEG-2b. Using locomotor activity, the forced swim test, and weight gain as behavioral measures of sickness behavior, our data showed that Lewis rats did not develop an IFN-induced "depressive syndrome." Western blot analyses of brain and liver tissue indicated that signal transducer and activator of transcripton (STAT1) was not phosphorylated following IFN-alpha administration, suggesting that the pegylated compounds may not have bound type I IFN receptors in the rat. Collectively, our data suggest that Lewis rats are likely not a useful model to study IFN-induced depression.
authors.affiliation: Behavioral Health and Clinical Neurosciences Division, Portland VA Medical Center, 3710 SW US Veteran's Hospital Road, Portland, OR 97239, USA. Jennifer.loftis2@med.va.gov
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Loftis
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Wall
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Pagel
authors.forename: Peter
authors.initials: P
authors.lastname: Hauser
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D001921:Brain / Q000378:metabolism; D003866:Depressive Disorder / Q000139:chemically induced*; D004195:Disease Models, Animal; D005260:Female; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000494:pharmacology*; D008099:Liver / Q000378:metabolism; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D011092:Polyethylene Glycols / Q000494:pharmacology*; D051381:Rats; D011917:Rats, Inbred Lew; D011994:Recombinant Proteins; D050794:STAT1 Transcription Factor / Q000378:metabolism; D013550:Swimming
chemical_list: D000928:Antidepressive Agents; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins; D050794:STAT1 Transcription Factor; C494081:Stat1 protein, rat; D011092:Polyethylene Glycols; C417083:peginterferon alfa-2b; C100416:peginterferon alfa-2a