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Lipopolysaccharide-induced immunostimulation produces a dose- and time-dependent decrease in general activity and weight gain in preweanling rats.

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. Other neural afferents and transduction of humoral messages at circumventricular organs have also been suggested as routes for innate immune system influences on the CNS (Bluthe, Michaud, Kelley, & Dantzer, 1996; Shibata & Blatteis, 1991).

Most research on LPS and other innate immune system stimulants has concerned their effects on adult organisms. The study of LPS effects on immature organisms has focused primarily on disruptions in physiology or behavior seen after the organism has reached maturity. Studies of this nature have indicated a relationship between early endotoxin exposure and adult social behaviors (Granger, Hood, Ikeda, Reed, & Block, 1996) as well as alterations in the HPA axis (Reul et al., 1994; Shanks, LaRocque, & Meaney, 1995; Witek-Janusek, 1988) that may contribute to alterations in an organism's behavior and reaction to stress. Despite the research demonstrating an effect of early endotoxin exposure on adult physiology and behavior, studies have not examined the immediate effects of LPS on the behavior of immature rodents.

Because behavior change induced by immunostimulants depends upon the status of the immune system, the central nervous system, and the endocrine system, the developmental changes that occur in each of these systems during and beyond the preweaning period in rodents (and the comparable periods in humans) (Adkins, Ghanei, & Hamilton, 1993; Ba & Seri, 1995; Koning, Baert, Oranje, Savelkoul, & Neijens, 1996; Tice, Hashemi, Taylor, & McQuade, 1996; Witek-Janusek, 1988) could affect the appearance of sickness behavior. Any residual manifestation of a stress-hyporesponsive period (Guillet, Saffran, & Michaelson, 1980; Witek-Janusek, 1988) could, for instance, intensify sickness behavior caused by a reduction in the glucocorticoid negative feedback effect on cytokine production (Chrousos, 1995). Low ability of juveniles' lymphocytes to secrete the Mn[PHI] costimulant interferon-gamma (Adkins et al., 1993) could attenuate sickness behavior. Thus, although it would be reasonable to expect the behavioral effects of innat e immune system activators on juvenile animals to be similar to those found in adults, that outcome is not a foregone conclusion; a direct test is needed.

Accordingly, we conducted two studies of LPS effects on locomotor activity and weight gain, as an indirect measure of food consumption, in preweanling Sprague-Dawley rats. In the first experiment we examined locomotor activity shortly after LPS administration in 20-day-old preweanling rats and monitored weight gain for 3 days as an indirect measure of consummatory behavior. The results demonstrated a decline in locomotor activity 1 hr postinjection and a decline in weight gain at 24 hr postinjection. In the second study we replicated Experiment 1 and extended our examination of activity to 24 hr post-LPS administration. Although weight gain as assessed at 24 hr following exposure to the endotoxin was again well below that of control animals, locomotor activity level had recovered.

Experiment 1

LPS, when administered peripherally to adult rodents, produces significant disruptions in physiology and behavior. Two of the most prominent aspects of sickness behavior in adult rodents are large declines in both locomotor activity and food consumption. In this experiment, the effects of intraperitoneal (IP) injections of LPS on locomotor activity and body weight (the latter taken as an indirect measure of food consumption) were examined in preweanling rat pups.

Method

Subjects. Thirty-nine male 20-day-old preweanling Sprague-Dawley rats served as subjects. Subjects were received and maintained in litters of 10, with a dam for each litter. Animals were ordered from Hilltop Lab Animals (Scottdale, PA) with specific instructions that no two pups in a single litter come from the same dam. These instructions, paired with the random assignment of no more than 4 subjects per litter to a group, helped to reduce the likelihood of intralitter correlations. For the duration of the study, the rats were housed in large clear polycarbonate cages on a 12:12 light:dark cycle. Food and water were available ad libitum throughout the experiment and the ambient room temperature was maintained at approximately 21 [degrees]C. All animals had previously been subjected to a mild passive-avoidance conditioning paradigm at 17 days of age as part of another experiment.

Apparatus and materials. Activity was assessed with an infrared beam activity monitor (OptoVarimex; Columbus Instruments; Columbus, OH). The monitor was equipped with 15 infrared photo-beams spaced approximately 3 cm apart. Activity was assessed by placing rat pups individually into an empty clear polycarbonate cage (44 cm x 21 cm x 23 cm) situated inside the photobeam area. The monitor recorded the number of adjacent beam interruptions (ambulatory behavior) and the total number of beam interruptions (ambulatory behavior plus repeat beam interruptions as in repetitive stereotypical behavior like head bobbing, grooming, etc.). Data were taken by a PC, using software provided by the activity monitor vendor. The experimental room was illuminated by overhead fluorescent light. Animal weights were taken to the nearest gram using a standard laboratory balance. Animals received LPS (026:B6; Sigma Chemical Company; St. Louis, MO) at doses of either 200 [micro]g/kg or 400 [micro]g/kg dissolved in normal saline at a vo lume of 1.60 ml/kg. Control animals received an equivalent injection of saline solution. All injections were given intraperitoneally (ip). The doses of LPS were selected based on pilot studies in our lab as well as the results of prior studies examining the behavioral effects of LPS. These prior studies had used doses of LPS ranging from 125 [micro]g/kg to 2000 [micro]g/kg in juvenile rats (Pugh et al., 1998) and from 50 [micro]g/kg to 2500[micro]g/kg in adult rodents (Aubert et al., 1997; Carman et al., 1993; Granger et al., 1997; Pugh et al., 1998).

Procedure. Animals were randomly assigned to one of three groups of 13 animals each. No more than 4 animals from a single litter were assigned to one condition. Group 1 received an ip injection of saline, Group 2 was given 200 pg/kg LPS, and Group 3 received 400 pg/kg LPS. The doses of LPS were based upon bodyweight-dependent doses previously used in research with adult animals. Activity was assessed 1 hr postinjection for a total of 15 min. Data were compiled into 1-mm time bins for both total and ambulatory activity. As an indirect measure of food consumption, all pups were weighed prior to the initial drug treatment and at the same time of day for 3 subsequent days. All procedures involving the use of nonhuman animals were first approved by the Animal Care and Use Committee at Kent State University.

Results and Discussion

A treatment by minute (3 between x 15 within) analysis of variance (ANOVA) for total activity revealed a significant effect of treatment, F(2, 36) = 4.18, p < .05; and minute, F(14, 504) = 29.42, p < .01; but no interaction, F(28, 504) = 1.12, p> .05. The same pattern was revealed for ambulatory behavior--with the treatment, F(2, 36) = 3.31, p < .05; and minute, F(14, 504) = 32.48, p < .01, effects again being significant, and not the interaction, F(28, 504) = 1.00, p > .05.

The data for each group were collapsed across the 15-mm session in order to provide a better picture of overall differences in activity with respect to the treatment. Figure 1 displays the mean total activity for each group and suggests that LPS administration suppressed total activity. The ambulatory activity data produced the same pattern of results; saline (M = 802.46), 200 [micro]g/kg (M = 627.92), and 400 [micro]g/kg LPS (M = 535.23). Tukey's tests for pairwise comparisons on the treatment groups indicated that animals receiving 400 [micro]g/kg of LPS had a significant decline in both total and ambulatory activity in comparison to animals that received saline, ps < .05. The 200 [micro]g/kg group did not differ significantly from either of the other groups.

The mean body weight gained across days for each group is given in Figure 2, which suggests that LPS leads to a reduced weight gain during the first 24-hr period following administration. Weight gain appears to return to normal during the second and third 24-hr periods. A treatment by day (3 between x 3 within) ANOVA revealed a significant effect of treatment, F(2, 36) = 11.40, p < .01; and day, F(2, 72) = 15.11, p < .01; but no interaction. These results indicate that there was less weight gain in animals that had received LPS and that weight gain generally increased across days.

The results of this experiment demonstrate that the immunostimulant LPS has a considerable short-term impact on locomotor activity and weight gain in 20-day-old preweanling rats, with 400 [micro]g/kg of LPS seeming to produce larger effects than 200 [micro]g/kg. The weight gain was rather severely depressed over the first 24 hr post-LPS but returned to control levels after 24 hr.

Experiment 2

The apparent strength of the effect on weight gain in Experiment 1, with weight gain reduced by nearly two thirds in the 400 [micro]g/kg group, raises the possibility that activity would still be depressed at 24 hr.

Experiment 2 therefore attempted to replicate Experiment 1 and also examined activity levels 24 hr following injection. Animals were given either saline or 400 [micro]g/kg of LPS and tested for activity either 1 or 24 hr later. As in Experiment 1, weight gain was recorded for 3 days following treatment. Because prior activity testing can alter subsequent activity levels (Van Tilburg, Carman, & Newberry, 1994), time of activity assessment was made a between-subjects variable.

Methods

Subjects. Forty male 20-day-old Sprague-Dawley rats served as subjects. Animals were specially ordered and were maintained in litters of 10 pups and 1 dam under the same conditions as in Experiment 1. All subjects had been previously used in a passive-avoidance conditioning paradigm at 17 days of age as part of another experiment. All procedures involving the use of nonhuman animals were first approved by the Animal Care and Use Committee at Kent State University.

Apparatus and materials. The materials, drug administration, activity apparatus, and experimental room used in Experiment 2 were the same as those used in Experiment 1.

Procedure. Animals were randomly assigned to one of four groups based on type of injection (saline or 400 [micro]g/kg of LPS) and time of activity test (1 hr or 24 hr postinjection)., No more than three animals from a single litter were assigned to a particular group. Other aspects of the procedure were identical to those of Experiment 1.

Results and Discussion

In general, all groups demonstrated a gradual decline in locomotor activity across the 15-min test session. LPS appears to have induced a large decline in locomotor activity only when activity was assessed 1 hr following endotoxin exposure.

Post hoc Tukey's tests for pairwise comparisons between groups for each minute yielded some significant differences, but the overall mean group differences for the entire activity session provide a clearer picture. Figures 3A and 3B present mean scores, collapsed for the entire 15-min session, for total and ambulatory activity, respectively. Tukey's tests on the overall group differences revealed that for both dependent measures the LPS 1-hr group differed significantly from all other groups, ps < .01. No other pairwise comparisons reached significance. These results replicate those from Experiment 1, clearly demonstrating an LPS-induced decrease in locomotor activity 1 hr following exposure. This effect dissipated completely by 24 hr following exposure to the endotoxin, suggesting that the LPS influence on activity level is transient.

A drug by test time by minute (2 between x 2 between x 15 within) ANOVA for total activity indicated significant effects for minute, F(14, 476) = 6.55, p < .01; drug, F(1, 34) = 8.34, p < .01; and test time, F(1, 34) = 7.12, p < .05. The drug x test time, F(1, 34) = 19.56, p < .01; and mm x drug x test time, F(14, 476) = 2.06, p < .05, interactions were also significant. The analysis of ambulatory activity produced a similar pattern of results. The effects of minute, F(14, 476) 6.16, p < .01; drug, F(1, 34) = 6.08, p < .05; test time, F(1, 34) = 5.57, p < .05; the drug x test time interaction, F(1, 34) = 14.83, p < .01; and minute x drug x test time interaction, F(14, 476) = 2.05, p < .05; all reached significance. These results indicate that LPS produces a significant reduction in locomotor activity in animals given LPS and tested at 1 hr postadministration.

The mean weight gained across the 3 days for saline and LPS animals is presented in Figure 4. The pattern of results is consistent with that from Experiment 1. The LPS group not only gained less weight than controls, they actually lost weight over the first 24-hr postinjection period. By 48 hr following LPS administration weight gain appeared to have returned to normal levels, In a group by day (2 between by 3 within) mixed ANOVA, the day, F(2, 68) = 74.30, p < .01; group, F(1, 34) = 45.20, p < .01; and group x day interaction, F(2, 68) = 33.74, p < .01, effects were all significant. Subsequent pairwise Tukey's tests on group differences revealed that animals receiving LPS gained significantly less weight during the first 24 hr following injection, ps < .05. No other pairwise comparisons on any day yielded significant effects.

The results of this experiment replicate and extend those of Experiment 1, demonstrating a significant effect of LPS on locomotor activity i hr following administration and a depression of weight gain during the first 24-hr period. In addition, this experiment shows that despite the decline in weight gain during the first day following LPS administration, the inhibition of locomotor activity had resolved by the end of that period.

General Discussion

In the studies reported here, we demonstrate that moderate doses of the immunostimulant LPS induce significant declines in activity and weight gain in 20-day-old preweanling rats. These findings generally parallel those obtained with adult animals. They suggest that the systems underlying sickness behavior are reasonably well developed at this age, although it remains possible that immaturity in pro- and anti-sickness systems compensate for each other in producing a final outcome that is similar to that seen in mature animals.

The transient nature of the LPS effect was apparent with both dependent variables: Weight gain was strongly suppressed over the first 24 hr post-LPS but was virtually identical to control values for Days 2 and 3. Activity levels had recovered by 24 hr postadministration (perhaps indicating that weight gain had begun to recover at some time during the first 24 hr). The seeming transitoriness of the effects raises the possibility that the long-term effects of prenatal and juvenile exposure to innate immune system activators on the HPA axis (Reul et al., 1994; Shanks et al., 1995) occur in the absence of lasting behavioral alterations, at least of an obvious sort. However, we note that weight gain in the present experiments, although normal for Days 2 and 3, showed no sign of a rebound above control values. In other words, the LPS animals were not beginning to make up for the weight gain deficit--something that suggests lingering, and conceivably truly long-term, effects of a single exposure to LPS at this age.

It is not completely clear what the weight gain decline implies on a behavioral level. Reduced food intake is a hallmark of sickness behavior (Aubert et al., 1997; Carman et al., 1993; Jepson et al., 1986; Yirmaya, 1996), but there is also thought to be a significant metabolic cost to the mobilization of defensive resources under immune activation (Hart, 1988; Maier & Watkins, 1998). Thus increased energy expenditure that is not completely offset by reduced activity could contribute to relative weight decline. It may be relevant to the question of energy balance in sickness, and to the question of whether weight gain rebound should be expected, that food hoarding is not influenced by LPS administration, even in animals whose food intake is reduced (Aubert et al., 1997). In any case it might be helpful for future studies to follow the effects of LPS for longer periods than were used in the present research and to take more direct measures of food intake and the time course of suppression.

A potential weakness in the studies reported here is the prior history of the animals at the time of LPS administration and behavior testing. All animals had previously been shipped from the animal vendor, and all animals had been subjected to a mild passive-avoidance conditioning paradigm at 17 days of age. It is feasible that these prior experiences could have added undue stress to the organism's immune system that in turn compounded with the endotoxin-induced immunostimulation, weakening the generalizability of these results.

It is difficult to make direct comparisons between our results and many of the results from prior studies examining the behavioral impact of LPS administration, especially given the variability in serotype (e.g., LPS 026:B6, LPS 0111:B4, LPS 0127:B8. LPS 08:B28), subject type (e.g., Sprague-Dawley rats, Wistar rats, Long-Evans rats, CF-1 mice, ICR mice bred for aggression), route of LPS administration (intraperitoneally or intravenously), subject age (35-day-old juvenile rats, or adult rats) and the sex of the subjects used in prior research. Despite these potentially important differences, we do find some general similarities between the results we obtained with 200 [micro]g/kg and 400 [micro]g/kg of LPS and the results of other studies examining locomotor activity and feeding behavior with similar doses. Carman et al. (1993) demonstrated that 1000 [micro]g/kg produced significant decreases in locomotor activity in rats and Granger et al. (1997) found that 250 [micro]g/kg LPS produced significant decreases i n locomotor activity, but this dose did not have an impact on social exploration, attack frequency or attack latency in adult ICR mice that had been selectively bred for high or low aggression. Feeding behavior studies have indicated that 250 [micro]g/kg greatly suppresses food intake, but has only a small effect on appetitive aspects of feeding (Aubert et al., 1997) and a dose as small as 83 [micro]g/kg of LPS differentially effects carbohydrate, protein, and fat intake (Aubert, Goodall, & Dantzer, 1995).

Recently, Engeland, Nielsen, Kavaliers, and Ossenkop (2001) conducted two experiments of behavioral tolerance and examined LPS-induced changes in variables including body weight and numerous forms of locomotor activity in novel and nonnovel environments. A single 50 [micro]g/kg, 100 [micro]g/kg, or 200 [micro]g/kg i.p. injection of LPS caused significant loss of weight and significant decreases in horizontal and vertical activity in a nonnovel open-field apparatus in mice. A second experiment demonstrated that this effect occurred only when a nonnovel apparatus was used, as 150 [micro]g/kg LPS did not have an effect on locomotor activity in a novel activity apparatus. Engeland et al. (2001) proposed that environmental novelty may attenuate or suppress sickness-induced behaviors because of the potentially threatening characteristics of an unfamiliar environment. Our results using 20-day-old preweanling rats generally parallel the previous literature in that a larger dose of LPS, 400 [micro]g/kg, produced signi ficant decreases in locomotor activity and weight gain, an indirect measure of feeding behavior. It is interesting that 200 [micro]g/kg of LPS did not have a significant impact on locomotor activity in Experiment 1, but did produce an apparent decrease in weight gain. These results are consistent with Engeland et al. (2001) and may reflect the temporary suppression of sickness behavior as a result of environmental novelty. The absence of a suppression in sickness behavior in the 400 [micro]g/kg group may simply be a result of the dose of LPS, as this dose is twice as large as the maximum dose used by Engeland et al. (2001). A dose of this magnitude may be sufficient to produce a level of immunostimulation leading to sickness behavior that is too robust to be overridden by the mechanisms activated by environmental novelty.

Beyond the rather narrow questions immediately relevant to the present findings are larger issues of the role of sickness behavior and the value of exploring it more fully. It has been clear for some time that the phenomena involved in brain-immune interactions are important to a basic understanding of both neurobiology and the immune system.

However, there are more practical concerns as well. The usefulness of sickness behavior in the practice of medicine, the role of immune activation in disease, and the interest in utilizing immune system stimulants, products, and antagonists as therapeutic agents (Ding, Nakoneczna, & Hsu, 1990; Kent, Bluthe, Kelley, & Dantzer, 1992; Langhans, 1996; Ridker, Hennekins, Buring, & Rifai, 2000; Saks & Rosenblum, 1g92), make a strong case for developing a thorough base of information on the behavioral changes that accompany illness and immune activation. Data on developmental changes in sickness behavior (or their absence) will be necessary to such an information base, and the present studies provide a small part of what will be needed.f

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The studies reported here were previously presented at the 69th annual Midwestern Psychological Association Meeting, Chicago, IL. Correspondence concerning this article should be addressed to R. W. Flint, Jr., The College of Saint Rose, Department of Psychology, 432 Western Avenue, Albany, NY 12203-1490. (E-mail: flintr@mail.strose.edu).
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Author:Flint, Robert W., Jr.; Haller, Nairmeen A.; Urban, Kimberly A.; Newberry, Benjamin H.
Publication:The Psychological Record
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Date:Mar 22, 2003
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