Abstract
Rationale
Although the behavioral effects of systemic injection of lipopolysaccharide (LPS) have been extensively investigated, the modulation of these effects by natural environmental factors has received little attention.
Objectives
The present study investigated whether or not locomotor activity reductions and the development of behavioral tolerance in response to LPS treatment would occur to the same degree if male and female rats were treated with LPS at four distinct time points across the light-dark (LD) cycle.
Methods
On day 1, male and female rats were injected with either LPS (200 μg/kg IP) or saline at light onset (0400 hours), 2 h into light period (0600 hours), at dark onset (1600 hours) or 2 h into the dark period (1800 hours). Two hours after injection, rats were placed in non-novel, automated open-fields and locomotor activity was assessed. The development of behavioral tolerance to LPS was evaluated three days later (day 4) using the same procedure.
Results
On day 1, LPS-treated animals displayed robust activity decrements during the light period with males displaying greater reductions than females. During the dark period, LPS-treated animals showed a similar hypoactivity response. After LPS treatment on day 4, all rats exhibited some behavioral tolerance to LPS. Rats given LPS treatment at light onset and during the dark period showed complete tolerance development while LPS-treated rats during the light phase at dark onset showed incomplete tolerance, still displaying significant reductions in some activity variables.
Conclusions
It appears that the magnitude of hypoactivity and the development of behavioral tolerance in response to LPS depend on the phase of the LD cycle during which it is administered.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Atkinson HC, Waddell BJ (1997) Circadian variation in basal plasma corticosterone and adrenocorticotropin in the rat: sexual dimorphism and changes across the estrous cycle. Endocrinology 138:3842–3848
Aubert A, Goodall G, Dantzer R (1995) Compared effects of cold ambient temperature and cytokines on macronutrient intake in rats. Physiol Behav 57:869–873
Aubert A, Goodall G, Dantzer R, Gheusi G (1997) Differential effects of lipopolysaccharide on pup retrieving and nest building in lactating mice. Brain Behav Immun 11:107–118
Beishuizen A, Thijs LG (2003) Endotoxin and the hypothalamo-pituitary-adrenal (HPA) axis. J Endotoxin Res 9:3–24
Bluthe RM, Dantzer R, Kelley KW (1991) Interleukin-1 mediates behavioural but not metabolic effects of tumor necrosis factor alpha in mice. Eur J Pharmacol 209:281–283
Bluthe RM, Dantzer R, Kelley KW (1992) Effects of interleukin-1 receptor antagonist on the behavioral effects of lipopolysaccharide in rat. Brain Res 573:318–320
Bluthe RM, Michaud B, Poli V, Dantzer R (2000) Role of IL-6 in cytokine-induced sickness behavior: a study with IL-6 deficient mice. Physiol Behav 70:367–373
Bluthe RM, Lestage J, Rees G, Bristow A, Dantzer R (2002) Dual effect of central injection of recombinant rat interleukin-4 on lipopolysaccharide-induced sickness behavior in rats. Neuropsychopharmacology 26:86–93
Chautard T, Spinedi E, Voirol M, Pralong FP, Gaillard RC (1999) Role of glucocorticoids in the response of the hypothalamo-corticotrope, immune and adipose systems to repeated endotoxin administration. Neuroendocrinology 69:360–369
Cross-Mellor SK, Kent WD, Kavaliers M, Ossenkopp KP (2000) Examining the effects of lipopolysaccharide and cholecystokinin on water ingestion: comparing intake and palatability. Brain Res 861:220–232
Dunn AJ, Swiergiel AH (1998) The role of cytokines in infection-related behavior. Ann NY Acad Sci 840:577–585
Engeland CG, Nielsen DV, Kavaliers M, Ossenkopp KP (2001) Locomotor activity changes following lipopolysaccharide treatment in mice: a multivariate assessment of behavioral tolerance. Physiol Behav 72:481–491
Engeland CG, Kavaliers M, Ossenkopp KP (2003) Sex differences in the effects of muramyl dipeptide and lipopolysaccharide on locomotor activity and the development of behavioral tolerance in rats. Pharmacol Biochem Behav 74:433–447
Flohe S, Dominguez FE, Ackermann M, Hirsch T, Borgermann J, Schade FU (1999) Endotoxin tolerance in rats: expression of TNF-alpha, IL-6, IL-10, VCAM-1 AND HSP 70 in lung and liver during endotoxin shock. Cytokine 11:796–804
Gaillard RC, Spinedi E (1998) Sex- and stress-steroids interactions and the immune system: evidence for a neuroendocrine-immunological sexual dimorphism. Domest Anim Endocrinol 15:345–352
Hart BL (1988) Biological basis of the behavior of sick animals. Neurosci Biobehav Rev 12:123–137
Huang QH, Hruby VJ, Tatro JB (1999) Role of central melanocortins in endotoxin-induced anorexia. Am J Physiol 276:R864–R871
Kozak W, Conn CA, Kluger MJ (1994) Lipopolysaccharide induces fever and depresses locomotor activity in unrestrained mice. Am J Physiol 266:R125–R135
Kozak W, Zheng H, Conn CA, Soszynski D, van der Ploeg LH, Kluger MJ (1995) Thermal and behavioral effects of lipopolysaccharide and influenza in interleukin-1 beta-deficient mice. Am J Physiol 269:R969–R977
Linthorst AC, Flachskamm C, Hopkins SJ, Hoadley ME, Labeur MS, Holsboer F, Reul JM (1997) Long-term intracerebroventricular infusion of corticotropin-releasing hormone alters neuroendocrine, neurochemical, autonomic, behavioral, and cytokine responses to a systemic inflammatory challenge. J Neurosci 17:4448–4460
Luker FI, Mitchell D, Laburn HP (2000) Fever and motor activity in rats following day and night injections of Staphylococcus aureus cell walls. Am J Physiol Regul Integr Comp Physiol 279:R610–R616
Martin JT (2000) Sexual dimorphism in immune function: the role of prenatal exposure to androgens and estrogens. Eur J Pharmacol 405:251–261
Mathias S, Schiffelholz T, Linthorst AC, Pollmacher T, Lancel M (2000) Diurnal variations in lipopolysaccharide-induced sleep, sickness behavior and changes in corticosterone levels in the rat. Neuroendocrinology 71:375–385
Mead LA, Hargeaves EL, Galea LAM (1996) Sex differences in rodent spontaneous activity levels. In: Sanberg PR, Ossenkopp KP, Kavaliers M (eds) Motor activity and movement disorders. Humana Press, Totowa, New Jersey, pp 111–139
Mekaouche M, Siaud P, Givalois L, Barbanel G, Malaval F, Maurel D, Assenmacher I, Ixart G (1996) Different responses of plasma ACTH and corticosterone and of plasma interleukin-1 beta to single and recurrent endotoxin challenges. J Leukoc Biol 59:341–346
Mistlberger RE (1996) Circadian organization of locomotor activity in mammals. In: Sanberg PR, Ossenkopp KP, Kavaliers M (eds) Motor activity and movement disorders. Humana Press, Totowa, New Jersey, pp 81–104
Munck A, Naray-Fejes-Toth A (1994) Glucocorticoids and stress: permissive and suppressive actions. Ann NY Acad Sci 746:115–130
Murakami N, Ono T (1987) Sex-related differences in fever development of rats. Am J Physiol 252:R284–R289
Opp MR, Toth LA (1998) Somnogenic and pyrogenic effects of interleukin-1beta and lipopolysaccharide in intact and vagotomized rats. Life Sci 62:923–936
Ossenkopp KP, Kavaliers M (1996) Measuring spontaneous locomotor activity in small mammals. In: Ossenkopp KP, Kavaliers M, Sanberg PR (eds) Measuring movement and locomotion: from invertebrates to humans. R.G. Landes, Austin, Texas, pp 33–59
Ossenkopp KP, Mazmanian DS (1985) The measurement and integration of behavioral variables: aggregation and complexity as important issues. Neurobehav Toxicol Teratol 7:95–100
Ossenkopp KP, Macrae LK, Teskey GC (1987) Automated multivariate measurement of spontaneous motor activity in mice: time course and reliabilities of the behavioral measures. Pharmacol Biochem Behav 27:565–568
Packard G, Boardman T (1999) The use of percentages and size-specific indices to normalize physiological data for variation in body size: wasted time, wasted effort? Comp Biochem Physiol A 122:37–44
Plata-Salaman CR, Borkoski JP (1993) Centrally administered bacterial lipopolysaccharide depresses feeding in rats. Pharmacol Biochem Behav 46:787–791
Porter MH, Arnold M, Langhans W (1998) TNF-alpha tolerance blocks LPS-induced hypophagia but LPS tolerance fails to prevent TNF-alpha-induced hypophagia. Am J Physiol 274:R741–R745
Reul JM, Labeur MS, Wiegers GJ, Linthorst AC (1998) Altered neuroimmunoendocrine communication during a condition of chronically increased brain corticotropin-releasing hormone drive. Ann NY Acad Sci 840:444–455
Roth J, McClellan JL, Kluger MJ, Zeisberger E (1994) Attenuation of fever and release of cytokines after repeated injections of lipopolysaccharide in guinea-pigs. J Physiol 477:177–185
Son YS, Park HJ, Kwon OB, Jung SC, Shin HC, Lim S (2002) Antipyretic effects of acupuncture on the lipopolysaccharide-induced fever and expression of interleukin-6 and interleukin-1β mRNAs in the hypothalamus of rats. Neurosci Lett 319:45–48
Soszynski D, Kozak W, Kluger MJ (1998) Endotoxin tolerance does not alter open field-induced fever in rats. Physiol Behav 63:689–692
Swiergiel AH, Smagin GN, Johnson LJ, Dunn AJ (1997) The role of cytokines in the behavioral responses to endotoxin and influenza virus infection in mice: effects of acute and chronic administration of the interleukin-1-receptor antagonist (IL-1ra). Brain Res 776:96–104
Taishi P, Bredow S, Guha-Thakurta N, Obal F Jr, Krueger JM (1997) Diurnal variations of interleukin-1 beta mRNA and beta-actin mRNA in rat brain. J Neuroimmunol 75:69–74
Takemura T, Makino S, Takao T, Asaba K, Suemaru S, Hashimoto K (1997) Hypothalamic-pituitary-adrenocortical responses to single vs. repeated endotoxin lipopolysaccharide administration in the rat. Brain Res 767:181–191
Tollner B, Roth J, Storr B, Martin D, Voigt K, Zeisberger E (2000) The role of tumor necrosis factor (TNF) in the febrile and metabolic responses of rats to intraperitoneal injection of a high dose of lipopolysaccharide. Pflugers Arch 440:925–932
Tropp J, Markus EJ (2001) Sex differences in the dynamics of cue utilization and exploratory behavior. Behav Brain Res 119:143–154
Turnbull AV, Rivier C (1995) Regulation of the HPA axis by cytokines. Brain Behav Immun 9:253–275
Turrin NP, Gayle D, Ilyin SE, Flynn MC, Langhans W, Schwartz GJ, Plata-Salaman CR (2001) Pro-inflammatory and anti-inflammatory cytokine mRNA induction in the periphery and brain following intraperitoneal administration of bacterial lipopolysaccharide. Brain Res Bull 54:443–453
Ucar DA, Tocco RJ, Kluger MJ (1983) Circadian variation in circulating pyrogen: possible role in resistance to infection. Proc Soc Exp Biol Med 173:319–323
Yirmiya R (1996) Endotoxin produces a depressive-like episode in rats. Brain Res 711:163–174
Yirmiya R, Rosen H, Donchin O, Ovadia H (1994) Behavioral effects of lipopolysaccharide in rats: involvement of endogenous opioids. Brain Res 648:80–86
Zeisberger E, Roth J (1998) Tolerance to pyrogens. Ann NY Acad Sci 856:116–131
Acknowledgements
This research was supported by Natural Sciences and Engineering Research Council (NSERC) operating and equipment grants to Martin Kavaliers and Klaus-Peter Ossenkopp. Andrew Franklin was supported by an Ontario Graduate Scholarship. We are grateful for continued technical support by Accuscan Instruments, Inc. Columbus, Ohio, USA.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Franklin, A.E., Engeland, C.G., Kavaliers, M. et al. Lipopolysaccharide-induced hypoactivity and behavioral tolerance development are modulated by the light-dark cycle in male and female rats. Psychopharmacology 170, 399–408 (2003). https://doi.org/10.1007/s00213-003-1554-3
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00213-003-1554-3