title: Olfactory bulbectomy provokes a suppression of interleukin-1beta and tumour necrosis factor-alpha production in response to an in vivo challenge with lipopolysaccharide: effect of chronic desipramine treatment.
abstract: The olfactory bulbectomized (OB) rat has been developed as an animal model of depression and exhibits several behavioural and neurochemical characteristics that are qualitatively similar to those found in clinically depressed patients. In addition to the behavioural and neurochemical abnormalities seen in OB rats, it has been reported that these animals have alterations in a number ex vivo measures of immune function many of which are reversed following chronic antidepressant treatment. In the present study we sought to examine the effects of olfactory bulbectomy on responsiveness to an in vivo immune challenge with bacterial lipopolysaccharide (LPS; 100 microg/kg, i.p.). In addition, the effect of chronic treatment with the tricyclic antidepressant desipramine (7.5 mg/kg, i.p.) on bulbectomy related behavioural changes, hypothalamic-pituitary-adrenal axis activity and immune responsiveness was evaluated. To our knowledge this is the first time that in vivo immunological responsiveness has been examined in the OB rat model of depression. OB rats exhibited a characteristic hyperactive response in a novel 'open field' environment, which was attenuated following chronic desipramine treatment. LPS provoked a large increase in circulating interleukin (IL)-1beta and tumour necrosis factor (TNF)-alpha in vehicle treated sham operated animals. Vehicle treated OB rats displayed a significant impairment in LPS-induced IL-1beta (54%) and TNF-alpha (70%) secretion compared to their sham operated controls, an effect that was potentiated following chronic desipramine treatment. Furthermore, sham animals that were chronically treated with desipramine displayed decreases in LPS-provoked IL-1beta (51%) and TNF-alpha (49%) secretion compared to vehicle treated counterparts. In addition, LPS-induced alterations in corticosterone and adrenal ascorbic acid concentrations were also attenuated by bulbectomy, an effect that was further enhanced following chronic desipramine treatment. In conclusion, these data provide evidence that olfactory bulbectomy in the rat impairs the ability of macrophages to produce the proinflammatory cytokines IL-1beta and TNF-alpha following an in vivo challenge with bacterial LPS. Whilst chronic treatment with desipramine normalized the behavioural hyperactivity observed in OB rats, such treatment further impaired LPS-induced IL-1beta and TNF-alpha secretion in bulbectomized rats.
authors.affiliation: Department of Pharmacology, National University of Ireland, Galway, Ireland. thomas.connor@nuigalway.ie
authors.forename: T J
authors.initials: TJ
authors.lastname: Connor
authors.forename: A
authors.initials: A
authors.lastname: Harkin
authors.forename: J P
authors.initials: JP
authors.lastname: Kelly
authors.forename: B E
authors.initials: BE
authors.lastname: Leonard
mesh_terms: D000302:Adrenal Cortex / Q000737:chemistry; D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology*; D001205:Ascorbic Acid / Q000032:analysis; D001522:Behavior, Animal / Q000502:physiology; D003345:Corticosterone / Q000097:blood; D003863:Depression / Q000276:immunology; D003891:Desipramine / Q000494:pharmacology*; D004195:Disease Models, Animal; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects / Q000276:immunology; D007375:Interleukin-1 / Q000096:biosynthesis* / Q000097:blood / Q000276:immunology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D015213:Neuroimmunomodulation / Q000187:drug effects*; D009830:Olfactory Bulb / Q000276:immunology* / Q000601:surgery; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000276:immunology / Q000378:metabolism
chemical_list: D000929:Antidepressive Agents, Tricyclic; D007375:Interleukin-1; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D001205:Ascorbic Acid; D003891:Desipramine; D003345:Corticosterone