Sickness behavior as a new target for drug development.

Sickness behavior refers to the nonspecific symptoms (anorexia, depressed activity, loss of interest in usual activities, disappearance of body-care activities) that accompany the response to infection. Increasing evidence suggests that these symptoms are part of an organized defense response to antigenic challenge and that they are mediated by the neural effects of cytokines such as interleukin 1. An understanding of the mechanisms involved in these effects should permit development of new drugs aimed at decreasing sickness or promoting recovery processes.

Tumor necrosis factor(alpha) and insulin-like growth factor-I in the brain: is the whole greater than the sum of its parts?

The cytokine tumor necrosis factor(alpha) (TNFalpha) and the hormone insulin-like growth factor-I (IGF-I) have both been shown to regulate inflammatory events in the central nervous system (CNS). This review summarizes the seemingly independent roles of TNFalpha and IGF-I in promoting and inhibiting neurodegenerative diseases. We then offer evidence that the combined effects of IGF-I and TNFalpha on neuronal survival can be vastly different when both receptors are stimulated simultaneously, as is likely to occur in vivo. We propose the framework of a molecular model of hormone-cytokine receptor cross talk in which disparate cell surface receptors share intracellular substrates that regulate neuronal survival.

Expression and localization of p80 and p68 interleukin-1 receptor proteins in the brain of adult mice.

The biological effects of interleukin-1 (IL-1) are mediated by two distinct receptors, the p80 type I IL-1 and p68 type II IL-1 receptor proteins (IL-1RI and IL-1RII, respectively), both of which have been recently co-localized to the growth hormone synthesizing cells of the adenohypophysis. Previous studies have shown that IL-1 can bind to specific structures in the central nervous system, but the distribution of IL-1RI and IL-1RII proteins in the adult mouse brain has not been reported. Here we have used immunohistochemistry to study the expression, distribution and cellular localization of both isoforms of the IL-1 receptor proteins in the adult mouse brain. Using a combination of processing techniques (AMeX fixation and cryosectioning), we have immunolabeled brain sections for each isoform of the IL-1R. Both isoforms are expressed in the CNS, particularly in neuronal soma of the granular layer of the dentate gyrus and pyramidal cells of fields CA1-CA4 of Ammon's horn of the hippocampus, in epithelial cells of the choroid plexus and ependymal layer, and in neuronal soma of Purkinje cells of the cerebellum. The IL-1RII isoform, but not IL-1RI, is expressed in specific neuronal soma and proximal cell processes of neurons of the paraventricular gray matter of the hypothalamus. These immunohistochemical data directly demonstrate the neuronal expression of both IL-1R proteins in situ. The distribution and cellular localization of IL-1R proteins in the CNS provide a molecular basis for understanding reciprocal interactions between the immune system and the brain.

Vasopressin involvement in antipyresis, social communication, and social recognition: a synthesis.

This review concentrates on the sexually dimorphic neuronal cells and fibers that contain arginine-vasopressin (AVP) and are present in several extrahypothalamic brain areas besides the neurohypophyseal system. Of particular interest are the vasopressinergic neurons that project from the bed nucleus of the stria terminalis and the medial amygdala to the lateral septum because their content of vasopressin is a positive function of circulating levels of testosterone. Physiological and behavioral data suggest that androgen-dependent vasopressin plays an important role in antipyresis and social recognition. In addition, there is evidence that extrahypothalamic AVP-sensitive neurons and hypothalamic AVP-containing neurons control scent marking, a form of social communication in hamsters, in a sex-dependent manner. The interrelationships of these different functions of brain vasopressin are discussed.

Central mediation of the effects of interleukin-1 on social exploration and body weight in mice.

To study the role of central IL-1 receptors in the effects of recombinant human IL-1 beta (IL-1 beta) on behavior and body weight, intracerebroventricular (i.c.v.) injection of the specific antagonist of IL-1 receptors, IL-1ra, was administered to mice injected intraperitoneally (i.p.) and i.c.v. with various doses of IL-1 beta. Doses of 500 ng i.p. IL-1 beta and 900 pg i.c.v. IL-1 beta induced a comparable decrease in social behavior and loss of body weight. Pretreatment with IL-1ra (1.8 micrograms/mouse, i.c.v.) blocked the effects of i.c.v. IL-1 beta (900 pg/mouse) on social behavior. i.c.v. IL-1ra (3.6 micrograms/mouse) also attenuated the effects of i.p. IL-1 beta (500 ng/mouse) on social behavior and change in body weight, suggesting that the effects of peripheral IL-1 beta are centrally mediated.

Gonadal steroids influence the involvement of arginine vasopressin in social recognition in mice.

Gonadal steroids have been shown to modulate the involvement of vasopressinergic neurotransmission in social recognition in rats. To assess whether the same phenomenon occurs in another species showing sexual dimorphism of vasopressinergic neurons, social recognition was studied in DBA2 male mice. Social recognition was inferred from the reduction in investigation time of a juvenile conspecific when this social stimulus was presented for the second time at different intervening intervals after the initial exposure. Such a reduction occurred when the interval was 20 min or 1 hr but not 2 hr. This effect was stimulus-specific, because it did not occur when a different juvenile was presented on the second exposure. AVP (0.4 micrograms/mouse, SC) injected immediately after the first exposure to the juvenile prolonged social recognition, whereas SC injection of an antagonist of the vasopressor receptors of AVP, dPTyr(Me)AVP (2 micrograms/mouse) impaired it. Compared with intact males, castrated mice spent less time investigating juveniles but were still able to recognize them after a 2-hr interval. However, this recognition was no longer sensitive to dPTyr(Me)AVP. These results confirm that androgen-dependent vasopressinergic transmission modulates social recognition in mice.

Synergy between tumor necrosis factor alpha and interleukin-1 in the induction of sickness behavior in mice.

Like interleukin-1, recombinant human tumor necrosis factor alpha (TNF alpha) has been found to decrease social exploration and induce weight loss in mice in a dose and time-dependent manner. The present study was carried out to study the interaction between these two cytokines. Mice were injected IP with subthreshold doses of TNF alpha (2.5 micrograms/mouse) and IL-1 beta (50 ng/mouse). Social exploration was decreased 2 and 4 h after injection of TNF and IL-1, but body weight was not affected. Subthreshold doses of TNF alpha (90 ng/mouse) and IL-1 beta (100 pg/mouse) were also injected intracerebroventricularly (ICV). Social exploration was decreased 1.5 and 3 h after injections of the two cytokines and body weight was decreased for 6 h. To test the possibility of central induction of IL-1 by TNF alpha, mice pretreated with IL-1 receptor antagonist (IL-1ra, 1.8 micrograms/mouse, ICV) were injected with 90 ng TNF alpha. Pretreatment with IL-1ra antagonized the depressive effect of TNF alpha on behavior, but had no effect on weight loss induced by this cytokine. These results suggest that TNF alpha-induced behavioral alterations are mediated by endogenously released IL-1, whereas metabolic changes are dependent on the release of other cytokines.

Central injection of IL-10 antagonizes the behavioural effects of lipopolysaccharide in rats.

Peripheral (i.p.) and central (i.c.v.) injections of lipopolysaccharide (LPS) have been shown to induce brain expression of proinflammatory cytokines and to depress social behaviour in rats, increase duration of immobility and induce body weight loss. To determine if the anti-inflammatory cytokine, interleukin-10 (IL-10) is able to modulate these effects, recombinant rat IL-10 was injected in the lateral ventricle of the brain (30, 100, 300 ng/rat) prior to i.p. or i.c.v. injection of LPS (250 micrograms/kg or 60 ng/rat, respectively). Social exploration was depressed for 6 h after i.p. LPS injection. This effect was attenuated by IL-10 (30 and 100 ng) 2 h after injection, whereas the highest dose of IL-10 blocked the depression of social interaction for 6 h after LPS injection. IL-10 produced the same effects on the increase of immobility although the results did not reach significance. Social exploration was depressed 3 h after i.c.v. LPS injection, and this was accompanied by increased immobility. These effects were totally blocked by i.c.v. IL-10 (300 ng/rat). Rats lost body weight after i.c.v. LPS, and this effect was attenuated by i.c.v. IL-10. These results indicate that IL-10 is able to modulate the production and/or action of central proinflammatory cytokines.

Chronic treatment with the atypical antidepressant tianeptine attenuates sickness behavior induced by peripheral but not central lipopolysaccharide and interleukin-1beta in the rat.

RATIONALE: The hypothesis that proinflammatory cytokines play a causative role in the pathophysiology of depression has been recently tested by studying the effect of antidepressants on production of endogenous cytokines, and on sickness behavior induced by exogenous cytokines. In this last case, however, the effect of antidepressants has been only studied on the effect of peripherally administered cytokines. OBJECTIVES: The aim of the present study was to determine whether the antidepressant tianeptine can attenuate both peripheral and central cytokine actions. METHODS: Rats were injected IP with acute (10 mg/kg) or chronic (10 mg/kg, 2 times/day, 17 days) tianeptine. The effects of this treatment were assessed on the behavioral (social exploration, locomotion) and metabolic (food intake, body weight) alterations induced by peripheral or central administration of the cytokine inducer lipopolysaccharide (LPS) (250 microg/kg IP; 100 ng/rat ICV) or the prototypical proinflammatory cytokine interleukin-1 (IL-1)beta (15 microg/rat IP; 90 ng/rat ICV). RESULTS: Chronic, but not acute, treatment with tianeptine attenuated the behavioral signs of sickness behavior induced by peripheral, but not central, LPS or IL-1beta. CONCLUSIONS: This work, which is the first in vivo study assessing the effect of an antidepressant on centrally induced immune activation, shows a clear dissociation between peripheral and central cytokine effects, and suggests a peripheral site of action of tianeptine. It also provides the first evidence that the protective effects of classical antidepressants on LPS-induced sickness behavior extend to an atypical antidepressant, and that the protective effect of antidepressants also applies to IL-1beta.

Specificity of aversive stimulus properties of vasopressin.

Rats injected SC with arginine vasopressin (AVP) following consumption of a milk solution developed a marked aversion to the taste of this solution. An analog of vasopressin devoid of pressor activity, dDAVP, was unable to induce conditioned taste aversion. The aversive stimulus properties of AVP were blocked by the vasopressor antagonist dPTyr(Me)AVP. This antagonist did not block apomorphine-mediated conditioned taste aversion. These results demonstrate that AVP induces conditioned taste aversion by interacting with vasopressor-like receptors.

Modulation of social memory in male rats by neurohypophyseal peptides.

Adult male rats spend a great amount of time investigating novel juveniles. In contrast, rats re-exposed to the same juvenile 30 min after the initial exposure display little investigatory behavior. If the re-exposure occurs 2 h later, the juvenile is thoroughly investigated. These results have been interpreted to mean that rats form a transient memory for a particular juvenile. In the present study, memory was enhanced when the initial exposure to the juvenile was followed by another exposure to the same juvenile (retroactive facilitation) and impaired when exposure to the original juvenile was followed by exposure to another juvenile (retroactive interference). Arginine vasopressin had retroactive facilitating effects on social memory and these effects were blocked by the vasopressor antagonist dPTyr(Me)AVP. Moreover, the antagonist had retroactive interfering effects, since it impaired the recognition of a familiar juvenile. Oxytocin shared the same inhibitory pattern of action. These results suggest that neurohypophyseal peptides may have a prepotent role in modulating the mnemonic processing of chemosensory information associated with social interactions.

Ethological study of the effects of tetrahydroaminoacridine (THA) on social recognition in rats.

Two major difficulties confront ethopharmacological investigations on cognitive abilities such as social recognition in drug-treated animals involved in free social interactions. The first concerns the choice of the most relevant behaviours, those reflecting the cognitive abilities attributed to the animals and assessing the specificity of the drug activity, and those reflecting non-specific drug effects. The second refers to the experimenter's awareness that in contrast to physical objects, social stimuli respond to drug-treated subjects and that their own level of responsiveness may influence the changes of drug-treated subjects' social interest. In addition, their contribution may vary according to the different treatments the drug-treated subjects receive. In examining the effects of tetrahydroaminoacridine (THA) at doses of 0.3, 1 and 3 mg/kg on the ability of adult male rats to recognize previously encountered conspecifics, we attempted to take into consideration such difficulties. A detailed behavioural profile of drug-treated rats was reported to separate specific from non-specific effects of THA. In addition, rats were assigned an index of responsibility for contact which takes into account the interactive dimension of each dyad and allows relevant comparisons between different treatments. The doses of THA which were found to decrease the duration of exploration of a familiar juvenile were also found to decrease the number of contacts initiated by the drug-treated subjects. THA induced a relative increase in body care by comparison to saline treatment. However, it had no effect of locomotor activity and rearing of the subjects. These findings enable dissociation of the effects of THA on cognitive versus non-cognitive processes.

Specific modulation of social memory in rats by cholinomimetic and nootropic drugs, by benzodiazepine inverse agonists, but not by psychostimulants.

The recognition of an unfamiliar juvenile rat by an adult rat has been shown to imply short-term memory processes. In this study the effect of various psychotropic drugs on this investigatory behaviour was examined. The procedure was as follows: an unfamiliar juvenile rat was placed in the home cage of an adult rat for 5 min. The time spent by the adult rat in investigating the juvenile was recorded. The adult rat was then immediately treated with vehicle or test compounds, and was again exposed for 5 min to the same juvenile 2 h later. At this time point vehicle-treated rats no longer recognized the juvenile rat, i.e. the time of investigation was similar to that observed during the first presentation. Arecoline (1 and 3 mg/kg IP), physostigmine (0.05 and 0.1 mg/kg SC), RS86 (0.5 mg/IP) and nicotine (0.125 and 0.5 mg/kg IP) reduced in a dose-dependent fashion the time spent in investigating the juvenile during the second exposure. This result cannot be attributed to nonspecific effects, since it was not observed when a different juvenile was used for the second exposure. The effect of arecoline was reversed by scopolamine, but not by methylscopolamine. Aniracetam reduced investigatory behaviour at the dose of 50 mg/kg IP. FG 7142 (5 mg/kg IP) and beta-CCM (0.4 mg/kg IP) were also active and their effect was reversed by Ro 15-1788. DL-Amphetamine (0.5 and 1 mg/kg IP), nomifensine (1.25-10 mg/kg IP) and strychnine (0.25 and 0.5 mg/kg IP) were ineffective or reduced this behaviour unspecifically.(ABSTRACT TRUNCATED AT 250 WORDS)

Mechanisms of the behavioral effects of interleukin 1. Role of prostaglandins and CRF.

Sickness behavior induced by IL-1 can be assessed quantitatively by measuring disruption of schedule-controlled behavior and loss of interest in social activities displayed by rats or mice injected peripherally or centrally with this monokine. These effects are mediated via the release of prostaglandins since they are blocked by the prostaglandin synthesis inhibitors indomethacin and piroxicam. They do not depend, however, on the central release of CRF, since they are not altered by central administration of either CRF or the specific antagonist of CRF receptors.

Cytokines and sickness behavior.

Peripheral and central injections of interleukin-1 (IL-1) and lipopolysaccharide (LPS) induce the expression of proinflammatory cytokines in the brain and have profound depressing effects on spontaneous and learned behaviors. These effects are mediated by vagal afferents, because they are abrogated by section of the vagus nerves at the subdiaphragmatic level in rats and mice. Vagotomy does not interfere with the synthesis and release of proinflammatory cytokines at the periphery, because plasma and tissue levels of interleukin-1 of vagotomized animals are similar to those of sham-operated animals. Furthermore, the consequences of vagotomy on the host behavioral response to peripheral cytokines are specific to the intraperitoneal route of administration of cytokines because vagotomized animals are still able to respond to IL-1 injected intravenously, subcutaneously, and into the lateral ventricle of the brain. Finally, substance P and cholecystokinin do not appear to play a key role in the transmission of the immune message to the brain because pretreatment by capsaicin or by specific antagonists of CCKA and CCKB receptors does not alter the behavioral effects of LPS and IL-1. All these findings point to the role of neural afferents for transmitting the immune message from the periphery to the brain.

Central interleukin-1 receptors as mediators of sickness.

These data establish that cytokines, such as IL-1, can act on specific receptors within the brain to induce many symptoms of sickness. A number of inflammatory stimuli in the periphery can activate both the transcription and translation of IL-1 within the central nervous system. It will now be important to determine if similar central IL-1 pathways are activated during SLE and whether these central inflammatory cytokines are involved in the neurologic complications that often accompany this disease.

Modulation of the behavioural effects of interleukin-1 in mice by nitric oxide.

Interleukin-1 is a cytokine which mediates the host response to infection and inflammation and is responsible for sickness behaviour. Inhibition of nitric oxide synthase activity by N omega nitro-L-Arginine-Methyl-ester (30 mg kg-1, i.p.) potentiated the depressive effects of interleukin-1 (375 ng, i.p.) on social investigation in mice. This effect was attenuated by L-arginine (180 mg kg-1, i.p.) but not by D-arginine. The same treatment did not alter the body weight loss induced by interleukin-1. These results suggest that nitric oxide plays a protective role in the neural effects of interleukin-1.

Vagotomy blocks behavioural effects of interleukin-1 injected via the intraperitoneal route but not via other systemic routes.

To test specificity of the involvement of vagal afferents in the communication between the immune system and the brain, sham-operated and vagotomized mice were injected i.p., s.c. or i.v. with physiological saline or interleukin-1 beta (IL-1 beta [symbol: see text] 4 weeks after surgery. Vagotomy attenuated the decrease in social exploration induced by i.p. injection of 300 ng recombinant human IL-1 beta but had no effect when IL-1 beta was injected s.c. (300 ng) or i.v. (500 ng). Vagotomy also attenuated the depression in social investigation induced by i.p. injection of recombinant rat IL-1 beta (IL-1 beta, 1 microgram) but was without effect when 1 microgram IL-1 beta was injected i.v. These results confirm the role of vagal afferent nerves in the transmission of an immune message from the periphery to the brain and show that the vagus nerve only conveys information concerning cytokines injected into the abdominal cavity.

Central injection of interleukin-13 potentiates LPS-induced sickness behavior in rats.

Systemic administration of the bacterial endotoxin lipopolysaccharide (LPS) has profound depressive effects on behavior that are mediated by the inducible expression of proinflammatory cytokines such as interleukin-1 (IL-1), IL-6 and tumor necrosis factor-alpha (TNF-alpha) in the brain. To assess the regulatory effects of the anti-inflammatory cytokine IL-13 on LPS-induced sickness behavior, rats injected i.p. with LPS were administered rat recombinant IL-13 i.c.v. IL-13 (300 ng) potentiated the behavioral effects of LPS (125 microg/kg) when both molecules were co-injected. Administration of IL-13 (300 ng) 12 h prior to LPS (150 microg/kg) did not block the depressing effects of LPS on social exploration. These results indicate that IL-13 acts as a proinflammatory cytokine in the brain.

Vagotomy attenuates behavioural effects of interleukin-1 injected peripherally but not centrally.

Peripheral and central injections of recombinant rat interleukin-1 beta (IL-1 beta) have been shown to decrease social exploration in rats. To test the involvement of vagal afferents in the communication between the immune system and the brain, sham-operated and vagotomized rats were injected peripherally or centrally with physiological saline or IL-1 beta 4 weeks after surgery. Vagotomy attenuated the depression in social exploration induced by i.p. administration of IL-1 beta (15 micrograms) but did not alter the behaviour-depressing effects of an intracerebroventricular (i.c.v.) injection of IL-1 beta (45 ng). These results confirm the role of vagal afferent nerves in the transmission of an immune message from the periphery to the brain, and show that vagotomy does not impair the direct sensitivity of the brain itself to immune signals.