Social stress induces glucocorticoid resistance in macrophages.

Stress-induced levels of plasma glucocorticoid hormones are known to modulate leukocyte function. These experiments examined the effects of a social stressor on the responsiveness of peripheral immune cells. Male mice experienced six evening cycles of social disruption (SDR), in which an aggressive male intruder was placed into their home cage for 2 h. Although circulating corticosterone was elevated in SDR mice, they had enlarged spleens and increased numbers of splenic leukocytes. Splenocytes from SDR and control mice were cultured with lipopolysaccharide and corticosterone. Cells from SDR mice exhibited decreased sensitivity to the antiproliferative effects of corticosterone, suggesting that the peripheral immune cells were resistant to glucocorticoids. In addition, SDR cells produced more interleukin (IL)-6. To determine which cell population was affected, we used antibody-labeled magnetic beads to deplete splenocyte suspensions of B cells or macrophages. Depletion of macrophages from SDR cultures, but not depletion of B cells, abolished both the corticosterone resistance and enhanced IL-6 secretion. These findings demonstrate that a psychosocial stressor induced glucocorticoid resistance in mouse splenic macrophages.

Social stress induces glucocorticoid resistance in subordinate animals.

Introducing an aggressive intruder into a cage of mice (social disruption, SDR) resulted in intense fighting and defeat of the cage residents. Defeat was accompanied by elevated levels of serum corticosterone and nerve growth factor (NGF). Repeated exposure to an intruder induced a state of glucocorticoid resistance in peripheral immune cells. The present study sought to examine the behavioral factors that mediated the development of glucocorticoid resistance following SDR. Glucocorticoid resistance developed in animals that exhibited a subordinate behavioral profile, which consisted of a low tendency for social investigation and a high level of submissive behavior in response to the intruder's attacks. Glucocorticoid resistance was also linked to the presence of injuries due to fighting, but not to changes in systemic levels of either corticosterone or NGF. Since a submissive behavioral profile is associated with increased risk for injuries due to fighting, it may be that the development of glucocorticoid resistance is an adaptive mechanism that allows the inflammatory component of wound healing to occur in the presence of high levels of corticosterone. Together, these findings demonstrate that the outcomes of social stress may be modified by physiological changes associated with wounding, as well as by behavioral variables such as social status.

Social stress increases the susceptibility to endotoxic shock.

The influence of social disruption stress (SDR) on the susceptibility to endotoxic shock was investigated. SDR was found to increase the mortality of mice when they were challenged with the bacterial endotoxin lipopolysaccharide (LPS). Histological examination of SDR animals after LPS injection revealed widespread disseminated intravascular coagulation in the brain and lung, extensive meningitis in the brain, severe hemorrhage in the lung, necrosis in the liver, and lymphoid hyperplasia in the spleen, indicating inflammatory organ damage. In situ hybridization histochemical analysis showed that the expression of the glucocorticoid receptor mRNA was down-regulated in the brain and spleen of SDR animals while the ratio of expression of AVP/CRH-the two adrenocorticotropic hormone secretagogue, increased. After LPS injection, the expression of pro-inflammatory cytokines, IL-1beta and TNF-alpha, was found significantly higher in the lung, liver, spleen, and brain of the SDR mice as compared with the LPS-injected home cage control animals. Taken together, these results show that SDR stress increases the susceptibility to endotoxic shock and suggest that the development of glucocorticoid resistance and increased production of pro-inflammatory cytokines are the mechanisms for this behavior-induced susceptibility to endotoxic shock.

Effects of antidepressant drugs on the behavioral and physiological responses to lipopolysaccharide (LPS) in rodents.

Antidepressants produce various immunomodulatory effects, as well as an attenuation of the behavioral responses to immune challenges, such as lipopolysaccharide (LPS). To explore further the effects of antidepressants on neuroimmune interactions, rats were treated daily with either fluoxetine (Prozac) or saline for 5 weeks, and various behavioral, neuroendocrine, and immune functions were measured following administration of either LPS or saline. Chronic fluoxetine treatment significantly attenuated the anorexia and body weight loss, as well as the depletion of CRH-41 from the median eminence and the elevation in serum corticosterone levels induced by LPS. Chronic treatment with imipramine also attenuated LPS-induced adrenocortical activation. In rats and in mice, which normally display a biphasic body temperature response to LPS (initial hypothermia followed by hyperthermia), chronic treatment with fluoxetine completely abolished the hypothermic response and facilitated and strengthened the hyperthermic response. The effects of antidepressants on the responsiveness to LPS are probably not mediated by their effects on peripheral proinflammatory cytokine production, because LPS-induced expression of TNFalpha and IL-1beta mRNA in the spleen (assessed by semiquantitative in situ hybridization) was not altered following chronic treatment with either fluoxetine or imipramine. The effects of antidepressants on the acute phase response may have important clinical implications for the psychiatric and neuroendocrine disturbances that are commonly associated with various medical conditions.

Behavioral aspects of experimental autoimmune encephalomyelitis.

Acute inflammation is known to induce a depressive-like sickness behavior syndrome in humans and in experimental animals. In the present study, we sought to determine whether a chronic neuroautoimmune inflammation is also associated with a similar behavioral syndrome. Experimental autoimmune encephalomyelitis (EAE) was induced in SJL/J female mice by adoptive transfer of lymph node cells, and sickness behavior symptoms, including anorexia, loss of body weight, reduced social exploration, and decreased preference for sucrose solution were measured. We report that these components of sickness behavior were induced during the acute phase of the disease, and recovered in later phases. Moreover, the onset and recovery of the behavioral symptoms preceded the onset and recovery of the neurological signs, respectively. Since EAE is considered a model for multiple sclerosis (MS), it is suggested that EAF-induced behavioral changes may serve as a model for the depressive symptomatology that characterizes most MS patients.

Illness, cytokines, and depression.

Various medical conditions that involve activation of the immune system are associated with psychological and neuroendocrine changes that resemble the characteristics of depression. In this review we present our recent studies, designed to investigate the relationship between the behavioral effects of immune activation and depressive symptomatology. In the first set of experiments, we used a double-blind prospective design to investigate the psychological consequences of illness in two models: (1) vaccination of teenage girls with live attenuated rubella virus, and (2) lipopolysaccharide (LPS) administration in healthy male volunteers. In the rubella study, we demonstrated that, compared to control group subjects and to their own baseline, a subgroup of vulnerable individuals (girls from low socioeconomic status) showed a significant virus-induced increase in depressed mood up to 10 weeks after vaccination. In an ongoing study on the effects of LPS, we demonstrated significant LPS-induced elevation in the levels of depression and anxiety as well as memory deficits. These psychological effects were highly correlated with the levels of LPS-induced cytokine secretion. In parallel experiments, we demonstrated in rodents that immune activation with various acute and chronic immune challenges induces a depressive-like syndrome, characterized by anhedonia, anorexia, body weight loss, and reduced locomotor, exploratory, and social behavior. Chronic treatment with antidepressants (imipramine or fluoxetine) attenuated many of the behavioral effects of LPS, as well as LPS-induced changes in body temperature, adrenocortical activation, hypothalamic serotonin release, and the expression of splenic TNF-alpha mRNA. Taken together, these findings suggest that cytokines are involved in the etiology and symptomatology of illness-associated depression.

Social disruption, immunity, and susceptibility to viral infection. Role of glucocorticoid insensitivity and NGF.

Glucocorticoid (cort) responses have been shown to suppress inflammatory reactions by inhibiting the trafficking of immune cells. Recently, it was demonstrated that restraint stress (RST) and psychosocial stress (social reorganization; SRO) differentially affected the pathophysiology and survival in the mouse influenza viral infection model. While both stressors activated the HPA axis, only SRO affected survival. In RST, elevated cort diminished recruitment of inflammatory cells following intranasal challenge of C57BL/6 mice with A/PR8 virus. However, infected SRO mice developed hypercellularity in the lungs and were more likely to die from lung consolidation than controls. Since elevated cort failed to be anti-inflammatory in SRO mice, the hypothesis that psychosocial stress induced steroid insensitivity was tested. An in vitro cort suppression test was performed by stimulating splenocytes from SRO and control mice with mitogen in the presence or absence of cort. Proliferation of ConA-stimulated cells was inhibited by cort in a dose-dependent fashion in controls, but splenocytes from SRO mice stimulated with ConA were resistant to cort-induced suppression. Thus, psychosocial stress induced a state of steroid insensitivity. SRO also induced the release of nerve growth factor (NGF) from the salivary glands into circulation; plasma NGF correlated with development of steroid insensitivity. NGF has been reported to negatively regulate the expression of type II glucocorticoid receptors, and thus may be a key factor in the induction of steroid insensitivity.

The immunobiology of sexual behavior: gender differences in the suppression of sexual activity during illness.

Following infection or injury, sick individuals experience profound psychological and behavioral changes, such as anorexia, depressed activity, and reduced self-care behavior. In the present review, we present evidence for a gender-difference in the behavioral response to sickness. Specifically, following immune activation, sexual activity is suppressed in female, but not in male rats. This gender difference is specific to sexually related responses, because other behaviors, such as locomotion, are equally affected by immune challenges in males and estrous females. The suppression of female sexual behavior, induced by either endotoxin (lipopolysaccharide), or the cytokine interleukin-1 (IL-1), are mediated by central mechanisms that are independent of alterations in ovarian hormone secretion. Furthermore, synergistic effects of the cytokines IL-1 and tumor necrosis factor alpha (TNF alpha) are involved in modulating sexual behavior in sick females, and prostaglandins synthesis is required for the effects of IL-1 on female sexual behavior. The gender difference in the behavioral response to immune activation may be related to the findings that at the same doses and timing in which IL-1 suppressed sexual activity in female but not in male rats, females produced more prostaglandin E2 (PGE2) in the brain, and less corticosterone than males. Finally, we are suggesting that the suppressive effect of cytokines on female reproductive behavior may serve as a mechanism to reduce conception during infection, which exposes the mother and the fetus to dangers such as spontaneous abortions, preterm labor and maternal mortality.

Cytokines inhibit sexual behavior in female rats: I. Synergistic effects of tumor necrosis factor alpha and interleukin-1.

The secretion of cytokines such as tumor necrosis factor alpha (TNFalpha) and interleukin-1 (IL-1) during immune activation induces sickness behavior. We have previously demonstrated that administration of either lipopolysaccharide (LPS) or IL-1 suppresses sexual behavior in female, but not in male rats. In the present study we sought to determine some of the mechanisms that are involved in mediating the alterations of female sexual behavior during immune activation. We report that sexual motivation of estrous females was reduced by intracerebroventricular administration of either recombinant rat (rr)TNFalpha (7.5 microg/rat) or rrIL-1beta (100 ng/rat), whereas sexual receptivity was altered only by IL-1beta. A significant reduction of both sexual motivation and receptivity was also induced by the combined administration of subthreshold doses of TNFalpha (3 microg/rat) and IL-1beta (20 ng/rat). These findings indicate that TNFalpha and IL-1beta act synergistically to suppress sexual motivation and receptivity. Moreover, LPS (100 microg/kg, ip)-induced reduction of sexual motivation was antagonized by the combined administration of the TNFalpha synthesis blocker pentoxifylline (50 mg/kg, ip) and IL-1 receptor antagonist (10 mg/kg, ip), but not by the administration of each of these substances by itself. In contrast, LPS-induced reduction of sexual receptivity was completely prevented by pentoxifylline. These findings indicate that the effects of LPS on sexual motivation are mediated by the synergistic effects of TNFalpha and IL-1, but only TNFalpha is required for the effect of LPS on receptivity.

Cytokines inhibit sexual behavior in female rats: II. Prostaglandins mediate the suppressive effects of interleukin-1beta.

The proinflammatory cytokine interleukin-1 (IL-1) induces several behavioral alterations that are characteristic of illness, such as anorexia and reduced locomotor and social activity. We have recently demonstrated that IL-1 inhibits sexual activity, motivation and attractivity in female, but not in male rats following either central or peripheral administration. In the present study we examined the involvement of prostaglandin (PG) synthesis in mediating IL-1-induced suppression of female sexual behavior. Administration of the cyclooxygenase blockers indomethacin or ibuprofen completely prevented IL-1-induced suppression of female sexual behavior, including the reduction in proceptive behavior, the lordosis response to a male's mounts, and the preference for a sexually active partner. In a subsequent study, ex-vivo release of hypothalamic PGE2 and the secretion of corticosterone (CS) were measured in males and estrous females following IL-1 administration. At the same time and dose of IL-1 administration that significantly reduced sexual behavior in female but not male rats, IL-1 produced a significant increase in PGE2 release in female, but not in male rats. In contrast, IL-1 induced a significant elevation of serum CS levels in males but not in females. These findings suggest that PG synthesis is involved in mediating the effects of IL-1 on female sexual behavior. Furthermore, differential secretion of PGs and CS may underlie the gender difference in the effects of IL-1 on sexual behavior.

The role of brain cytokines in mediating the behavioral and neuroendocrine effects of intracerebral mycoplasma fermentans.

Intracerebral administration of Mycoplasma fermentans (MF), a small microorganism that has been found in the brain of some AIDS patients, induces behavioral and neuroendocrine alterations in rats. To examine the role of tumor necrosis factor-alpha (TNFalpha) and interleukin-1 (IL-1) in mediating these effects we measured MF-induced expression of TNFalpha and IL-1beta mRNA in various brain regions, and the effects of TNFalpha synthesis blockers and IL-1 receptor antagonist (IL-1ra) on MF-induced sickness behavior and adrenocortical activation. Intracerebroventricular (i.c.v.) administration of heat-inactivated MF induced the expression of both TNFalpha and IL-1beta mRNA in the cortex, dorsal hippocampus, amygdala, and hypothalamus. Pre-treatment of rats with either TNFalpha synthesis blockers, pentoxifylline or rolipram, or with IL-1ra did not attenuate MF-induced anorexia, body weight loss, and suppression of social behavior. However, simultaneous administration of both pentoxifylline and IL-1ra markedly attenuated MF-induced anorexia and body weight loss, but had no effect on the suppression of social behavior. Pre-treatment with pentoxifylline, but not with IL-1ra, significantly attenuated MF-induced corticosterone (CS) secretion. Together, these findings indicate that both TNFalpha and IL-1 participate, in a complementary manner, in mediating some of the behavioral effects of MF, whereas only TNFalpha, but not IL-1, is involved in mediating MF-induced adrenocortical activation. We suggest that cytokines within the brain are involved in mediating at least some of the neurobehavioral and neuroendocrine abnormalities that may be produced by MF in AIDS patients.

The partner preference paradigm: a method to study sexual motivation and performance of female rats.

Sexual behavior of the female rat consists of initiative, as well as receptive components. Previous studies on female sexual behavior have focused on the reflexive response to a male's mount, i.e., the lordosis reflex, whereas the initiative and soliciting gestures that are exhibited by the female during copulation were ignored by most researchers. This bias led to a misconception of the female's role in the sexual act, according to which the female is passive and submissive, whereas the male rat is sexually dominant or even aggressive. In this paper, we describe a procedure, the partner preference paradigm, designed to investigate and quantify sexual motivation, initiation and solicitation in female rats. In this paradigm, the female can control the sexual act because the mobility of her sexual partner is limited. This setting enables to measure a variety of soliciting behaviors that reflect the active seeking of sexual contact by an estrous female. In addition, this paradigm enables the evaluation of the females' motivation to engage in a sexual act, by measuring the preference for a sexually appropriate over an indifferent partner. Moreover, the partner preference paradigm may be easily adopted for studies in male subjects, allowing the comparison of males' and females' responses to various experimental conditions.

Effects of prenatal morphine exposure on NK cytotoxicity and responsiveness to LPS in rats.

Prenatal exposure to opiates can adversely affect fetal development, resulting in long-term growth retardation and impairments in physiological and behavioral functions. In the present study we studied long-term effects of prenatal morphine exposure on immune functions, including the activity of natural killer (NK) cells and the febrile and behavioral responses to lipopolysaccharide (LPS). Pregnant Fischer 344 rats were given increasing doses of morphine in slow release emulsion during gestational days 12-18. Control rats were injected with vehicle and were either pair fed to morphine rats or fed ad lib. Postnatal experiments were conducted when offspring were 10-12 weeks old. Compared to both control groups, rats prenatally exposed to morphine exhibited: 1) suppressed cytotoxic activity of NK cells; 2) reduced LPS-induced fever measured by a biotelemetric system; 3) reduced hyperalgesia measured by the hot-plate test at 30 min, and augmented hypoalgesia at 2-6 h post-LPS; 4) higher open-field activity in saline-treated animals, and more pronounced suppression of activity in LPS-injected animals; 5) LPS-induced reduction of food consumption, body weight, and social exploration, which did not differ from the reduction observed in control animals. These findings indicate that prenatal exposure to morphine induces long-term impairment of host-defense mechanisms, which may render the offspring more susceptible to infectious diseases.

Effects of interleukin-1 on sexual attractivity in a model of sickness behavior.

Interleukin-1 (IL-1), a cytokine secreted by activated macrophages, inhibits sexual behavior in female but not male rats. The present study examined the effects of IL-1 on sexual attractiveness of the injected animal and on the sexual responses exhibited by its mating partner. In Experiment 1, a male rat was placed with an estrous female, injected with either IL-1 beta (2 or 10 micrograms/kg) or saline. Males exhibited more mounts and intromissions per ejaculation and longer ejaculation latencies with IL-1- than with saline-injected females. In a second experiment, a male was placed with two estrous females, one injected with IL-1 beta (5 micrograms/kg) and the other with saline. Males performed less sexual behavior and spent less time with the IL-1-injected female. In a third experiment, an estrous female was placed with two males, one injected with IL-1 beta (5 or 20 micrograms/kg) and the other with saline. IL-1 had no effect on the time spent by the female with each male, and only the high dose reduced proceptive (courtship) behavior. In conclusion, IL-1 administration to females reduces the quality of the sexual act, thus reducing the chances for conception during infection, which is associated with spontaneous abortion and abnormal development of the fetus. In males, the chances for reproduction are less affected by IL-1, possibly because reproduction during infection is not as risky in males as in females.

Different receptor mechanisms mediate the effects of endotoxin and interleukin-1 on female sexual behavior.

Activation of the immune system by lipopolysaccharide (LPS) produces physiological, neuroendocrine and behavioral effects, some of which are mediated by cytokine production. We have previously shown that the cytokine interleukin-1 (IL-1) inhibits sexual behavior in female, but not male rats, while producing a comparable suppression of locomotion in both sexes. The present study examined the effects of LPS on sexual behavior and locomotion of male and female rats, and the involvement of IL-1 receptors in mediating the effects of IL-1 and LPS on females' behavior. Peripheral (i.p.) administration of LPS (50 or 250 microg/kg) significantly decreased sexual behavior in females, up to 6 h after administration, while it had no effect on male sexual behavior. However, locomotor activity, measured in the open-field test, was similarly reduced by LPS in both males and females. Pretreatment with the IL-1 receptor antagonist (IL-1ra) either i.p. (10 mg/kg) or intracerebroventricularly (i.c.v.) (50 microg/rat) did not prevent the inhibition of female sexual behavior and locomotion induced by either i.p. (50 microg/kg) or i.c.v. (200 or 400 ng/rat) administration of LPS, respectively. However, identical doses of IL-1ra significantly reversed the effects of IL-1beta, administered either i.p. (5 microg/kg) or i.c.v. (50 ng/rat), respectively. These results demonstrate that both LPS and IL-1beta produce marked inhibition of sexual behavior in female, but not in male rats. However, IL-1 receptors are not required for the effects of LPS on sexual behavior in female rats.

Intracerebral administration of Mycoplasma fermentans produces sickness behavior: role of prostaglandins.

Mycoplasmas are small microorganisms, which cause various diseases in animals and in humans, activate the immune system, and induce the release of various cytokines. Some of the effects of mycoplasmas are mediated by the CNS. Moreover, Mycoplasma fermentans (MF) has recently been found in the brain, as well as other tissues of some AIDS patients, who usually display severe neurobehavioral disturbances. The present study was designed to examine the behavioral effects of central administration of MF, and the role of prostaglandins in mediating these effects. In one set of experiments, rats were injected intracerebroventricularly (i.c.v.) with either saline or a dose of MF (5.1-36 microg per rat), and several behavioral parameters were measured. In addition, body temperature and locomotor activity were continuously monitored by a biotelemetric system. MF induced a significant elevation in body temperature and suppression of motor activity levels. MF also significantly reduced the time spent in social exploration, decreased locomotor and exploratory activity in the open field test, suppressed the consumption of food and saccharine solution, and reduced body weight. In a second set of experiments, i.c.v. administration of MF (7.2 microg) was found to produce a significant increase in the production of prostaglandin E2 (PGE2) in hypothalamic, hippocampal, and cortical tissues. This effect was blocked by indomethacin, a prostaglandin synthesis inhibitor. Indomethacin also attenuated the effects of MF on body temperature, motor activity and body weight, suggesting the involvement of prostaglandins in mediating some of the effects of MF. Together, these findings suggest that the presence of MF in the brain may be responsible for some of the neurobehavioral abnormalities in HIV-infected patients.

Administration of interleukin-1 into the hypothalamic paraventricular nucleus induces febrile and behavioral effects.

Administration of interleukin-1 (IL-1) into the cerebral ventricles produces marked physiological and behavioral effects. However, the precise locations within the central nervous system that mediate these effects have not been determined. Previous studies indicated that IL-1 induces neurophysiological, neurochemical and neuroendocrine changes within the hypothalamic paraventricular nucleus (PVN). These findings suggest that the PVN is also involved in mediating the behavioral effects of IL-1. This hypothesis was tested by examining the effects of administration of IL-1beta (10 or 50 ng/rat) or saline, either intracerebroventricularly or into the PVN, on fever and several behavioral parameters. IL-1beta, administered into both locations, induced a comparable suppression of motor activity, reduction in food and saccharine consumption, and loss of body weight. The febrile response to IL-1beta, assessed by a biotelemetric system, was significantly greater following administration into the PVN than into the lateral ventricle. Additionally, IL-1 administration into adjacent thalamic locations had no febrile or behavioral effects. These findings suggest that the PVN may be one of the brain structures involved in mediating the response to IL-1.

Interleukin-1 inhibits sexual behavior in female but not in male rats.

The cytokine interleukin-1 (IL-1) is released by a variety of cells in response to infection or injury. IL-1 produces several neuroendocrine and behavioral effects, including a suppression of reproductive functions and goal-directed behaviors. The present study examined the effect of IL-1 on sexual behavior in male and female rats. The following behavioral tests were employed: preference for a sexually appropriate partner, proceptive (soliciting) behavior, the lordosis quotient (sexual receptivity), and mating performance. Peripheral (ip) IL-1 beta, 2 or 10 micrograms/kg, injected 2 h before testing, significantly suppressed proceptive behavior and sexual receptivity in intact, normally cycling females. In ovariectomized rats treated with ovarian hormones, IL-1 beta (2 or 10 micrograms/kg) significantly decreased the preference for a sexually active male partner and suppressed proceptive behavior and sexual receptivity. These effects were evident 2, but not 4 or 6, h after IL-1 beta administration. Intracerebroventricular administration of IL-1 beta (10 ng/rat) also suppressed the preference for a male partner and proceptive behavior in normally cycling females. Similar doses of IL-1 beta had no suppressive effect on any aspect of male sexual behavior, and the highest dose even increased the preference for a receptive female partner. In contrast to the gender-specific effects on sexual behavior, the suppressive effects of IL-1 beta on activity in the open-field test were comparable in male and female rats. The inhibition of female sexual behavior by IL-1 may be adaptive, in that it prevents conception while the animal is sick, thus reducing the risk of spontaneous abortion or abnormal development.

Behavioral effects of interleukin-1 beta: modulation by gender, estrus cycle, and progesterone.

Endogenous release or exogenous administration of the cytokine Interleukin-1 (IL-1) produces several behavioral alterations, including suppression of locomotion and exploration. Because there are bidirectional interactions between IL-1 and the hypothalamic-pituitary-gonadal axis, we investigated possible differences between males and females in various phases of the estrus cycle in the behavioral effects of IL-1. In addition, we assessed the role of progesterone in mediating estrus cycle-dependent differences in these effects. Female rats in either the estrus or the non-estrus phase of their cycle and male rats were injected with either IL-1 beta (2 or 5 micrograms/kg) or saline. Activity in the open field test was measured 2 h later by counting the number of line crossings and rearings. In saline-injected rats, nonestrus females performed less line crossings than estrus females. IL-1 produced a significant dose-dependent reduction of line crossing in males and estrus females. In contrast, in nonestrus females the lower dose of IL-1 had no effect, and the effect of the higher dose was significantly smaller in nonestrus than in estrus females. The higher dose of IL-1 suppressed rearing in all three groups, but the effect of the lower dose on the number of rearings was significant only in estrus females. In a second experiment, ovariectomized females were injected with either progesterone (2 mg/rat) or oil, followed 2 h later by an injection of either IL-1 beta (2 micrograms/kg) or saline. Activity was measured continuously by a biotelemetric system. IL-1 reduced activity in progesterone-treated ovariectomized females but not in oil-injected controls. These findings suggest that changes in progesterone secretion along the estrus cycle modulate the behavioral responsiveness to IL-1 in female rats.