1 Department of Clinical Medicine - Translational Neuropsychiatry Unit, Department of Clinical Medicine, Health, Aarhus University2 Centre for Psychiatric Research, Faculty of Health Sciences, Aarhus University, Aarhus University3 Department of Clinical Medicine - The Department of Endocrinology and Diabetes, Department of Clinical Medicine, Health, Aarhus University4 Department of Clinical Medicine - Translational Neuropsychiatry Unit, Department of Clinical Medicine, Health, Aarhus University5 Department of Clinical Medicine - The Department of Endocrinology and Diabetes, Department of Clinical Medicine, Health, Aarhus University
Background: A subpopulation of individuals with major depressive disorder (MDD) show increased levels of peripheral inflammatory biomarkers, indicating an association of MDD with a chronically activated immune system. Administration of the immune stimulating cytokine, interferon-alpha (IFN-(alpha)), also used in the treatment of cancer and hepatitis, commonly leads to neuropsychiatric side effects with approximately 16- 45% of patients developing depressive-like symptoms during the course of therapy. Given that treatmentresistant depression has been associated with increased levels of inflammatory markers, the development of an inflammation-induced model of depression is highly relevant. Aim: The objective of this study was to investigate whether IFN-(alpha) can induce a chronic low-grade inflammatory state in rats, and whether this may lead to a depressive phenotype. Methods: Male Sprague-Dawley rats (n=40, mean weight 328.3 (plus or minus) 1.55 g) received daily subcutaneous injections with human recombinant IFN-(alpha) (1null106 U/kg/day) or vehicle (saline) for one week. After six days, animals were tested either 1h or 24 hours after injection for depressive-like behavior using the saccharin preference test (SPT) and Forced Swim test (FST), which respectively measure anhedonia and behavioral despair in rodents. Results: IFN-a did not induce sickness behavior, indicated by similar body weight, food and water intake, temperature measurement and locomotor activity between the groups. However, daily injections with IFN- (alpha) for one week induced a depressive-like phenotype as measured both after 1h and 24h in the FST and SPT. Discussion and perspective: Peripherally injected IFN- (alpha) crosses the blood-brain-barrier and reaches the central nervous system where psychological side-effects including depression can be induced. The finding in this study that IFN-(alpha)-treated rats show depressive-like behavior supports this notion, and indicates that IFN-(alpha) treatment in rats could represent a viable inflammationinduced animal model of depression. Several theories have been suggested to link inflammation and depression, such as increased levels of the neurotoxic tryptophan metabolite, quinolinic acid (QUIN), and decreased brain-derived neurotrophic factor (BDNF), a protein that plays an important role in survival, differentiation and growth of neurons. The successful development of an inflammation-induced model of depression will be pivotal for our understanding of the underlying pathophysiological immune mechanisms in MDD and may lead to the design of better and more effective treatment options in the near future.
Acta Neuropsychiatrica, 2013, Vol 25, Issue 1, p. 20-21
alpha interferon interferon marker cytokine saccharin quinolinic acid brain derived neurotrophic factor protein sodium chloride factor A rat college psychopharmacology human inflammation phenotype side effect injection model Sprague Dawley rat locomotion hepatitis therapy patient neoplasm hopelessness illness behavior body weight food fluid intake blood brain barrier anhedonia male forced swim test rodent major depression subcutaneous drug administration temperature measurement weight central nervous system animal model tryptophan metabolism immune system survival nerve cell