Academic journal article The Psychological Record

Lipopolysaccharide-Induced Immunostimulation Produces a Dose- and Time-Dependent Decrease in General Activity and Weight Gain in Preweanling Rats

Academic journal article The Psychological Record

Lipopolysaccharide-Induced Immunostimulation Produces a Dose- and Time-Dependent Decrease in General Activity and Weight Gain in Preweanling Rats

Article excerpt

Organisms react to pathogenic threats and signals with diverse and highly interdependent sets of responses (Newberry, Jaikins-Madden, & Gerstenberger, 1991), among them activation of the innate and adaptive arms of the immune system and its widespread sequelae. The consequences of innate immune system activation have been known for some time to include potent effects on the central nervous system and behavior. Several types of molecules and particulates have been employed in studying the consequences of innate immune system activation without the complexities of infecting the organism with living pathogens (Gayle, lliyn, Flynn, & Plata-Salaman, 1998; Oluyomi, Nguyen, Towbin, Dawson, & Vosbeck, 1995; Stitt & Shimada, 1989).

Gram-negative bacterial lipopolysaccharide (LPS, a.k.a. endotoxin) is one of the most frequently used of these innate immune system stimulants (Raetz et al., 1991).

In adult rodents, peripheral administration of LPS commonly produces a variety of physiological responses including, but by no means limited to, hyperthermia and hypothermia (Kluger, 1991; Kozak, Conn, & Kluger, 1994; McCarthy, Kluger, & Vander, 1984; Romanovsky, Shido, Sakurada, Sugimoto, & Nagasaka, 1997), weight loss (Langhans, Balkowski, & Savoldelli, 1991), changes in central catecholamine and serotonin metabolism (Dunn, 1992), hyperalgesia (Watkins et al., 1994), and activation of the hypothalamic-pituitary-adrenal (H PA) axis (Chrousos, 1995; Tilders et al., 1994). These diverse effects are mediated largely through the production of proinflammatory cytokines by macrophages and other cells of the mononuclear phagocyte (Mn[PHI]) lineage, with interleukin-1 (IL-1[beta]), IL-6, and tumor necrosis factor (TNF-[alpha]) appearing to be the cytokines primarily involved (Cerami, 1992). Increased cytokine production and activity within the brain seem to be included among the physiological responses to peripheral LPS (Ban, Haour, & Lenstra, 1992; Laye, Parnet, Goujon, & Dantzer, 1994; Quan, Sundar, & Weiss, 1994).

Behaviorally, LPS produces changes often collectively referred to as sickness behavior (Dantzer, Bluth6, Kent, & Goodall, 1993; Dantzer, Bluthe, Kent, & Kelley, 1991). Sickness behavior includes reductions in food consumption (Aubert, Kelley, & Dantzer, 1997; Jepson, Pell, Bates, & Millward, 1986), sexual activity (Yirmiya, 1996), locomotor activity (Carman, Newberry, & Fountain, 1993; Kozak et al., 1994), and social behaviors (Klein & Nelson, 1999; Yirmiya, 1996) as well as increases in slow-wave sleep (Krueger, Kubillus, Shoham, & Davenne, 1986). Recently, a number of studies have been conducted to investigate more distinctively cognitive processes and have suggested impairments in learning and memory following LPS (Aubert, Vega, Dantzer, & Goodall, 1995; Flint & Newberry, 1996; Pugh et al., 1998). Peripheral administration of LPS has even been proposed as an animal model for some forms of human depression (Yirmiya, 1996).

Both the number of factors capable of moderating cytokine production by Mn[PHI]s and the nature of the likely pathways linking Mn[PHI] activation to behavior attest to the complexity of the processes underlying sickness behavior. Cytokine production and its downstream consequences are affected by a variety of factors, including diet (Kozak, Soszynski, Rudolph, Conn, & Kluger, 1997), glucocorticoids (Chrousos, 1995), cytokines produced by cells of the adaptive immune system (Trinchieri, 1997), and previous exposure to innate immune activators Ziegler-Heitbrock, 1995). There may be multiple routes by which cytokines, and hence innate immune stimulants such as LPS, affect behavior (Hart, 1988; Maier & Watkins, 1998). In a thorough series of studies, Watkins et al. (1994) traced a neuronal pathway from the periphery to the brain, establishing the neurocircuitry mediating the hyperalgesia induced by intraperitoneally administered LPS, and demonstrating one conduit, vagal afferents, through which immunoactivation c an impinge upon the central nervous system and ultimately alter behavior. …

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