Acute experimental changes in mood state regulate immune function in relation to central opioid neurotransmission: a model of human CNS-peripheral inflammatory interaction.

Although evidence shows depressed moods enhance risk for somatic diseases, molecular mechanisms underlying enhanced somatic susceptibility are ill-defined. Knowledge of these molecular mechanisms will inform development of treatment and prevention strategies across comorbid depressive and somatic illnesses. Existing evidence suggests that interleukin-18 (IL-18; an IL-1 family cytokine) is elevated in depression and implicated in pathophysiology underlying comorbid medical illnesses. We previously identified strong associations between baseline IL-18 and µ-opioid receptor availability in major depressive disorder (MDD) volunteers. Combined with the evidence in animal models, we hypothesized that experimental mood induction would change IL-18, the extent proportional to opioid neurotransmitter release. Using the Velten technique in a [(11)C]carfentanil positron emission tomography neuroimaging study, we examined the impact of experimentally induced mood (sad, neutral) on plasma IL-18 and relationships with concurrent changes in the central opioid neurotransmission in 28 volunteers (healthy, MDD). Results showed mood induction impacted IL-18 (F2,25=12.2, P<0.001), sadness increasing IL-18 (T27=2.6, P=0.01) and neutral mood reducing IL-18 (T27=-4.1, P<0.001). In depressed volunteers, changes in IL-18 were more pronounced (F2,25=3.6, P=0.03) and linearly proportional to sadness-induced µ-opioid activation (left ventral pallidum, bilateral anterior cingulate cortices, right hypothalamus and bilateral amygdala). These data demonstrate that dynamic changes of a pro-inflammatory IL-1 superfamily cytokine, IL-18, and its relationship to µ-opioid neurotransmission in response to experimentally induced sadness. Further testing is warranted to delineate the role of neuroimmune interactions involving IL-18 in enhancing susceptibility to medical illness (that is, diabetes, heart disease and persistent pain states) in depressed individuals.

Gestational flu exposure induces changes in neurochemicals, affiliative hormones and brainstem inflammation, in addition to autism-like behaviors in mice.

The prevalence of neurodevelopmental disorders such as autism is increasing, however the etiology of these disorders is unclear and thought to involve a combination of genetic, environmental and immune factors. A recent epidemiological study found that gestational viral exposure during the first trimester increases risk of autism in offspring by twofold. In mice gestational viral exposures alter behavior of offspring, but the biological mechanisms which underpin these behavioral changes are unclear. We hypothesized that gestational viral exposure induces changes in affiliative hormones, brainstem autonomic nuclei and neurotransmitters which are associated with behavioral alterations in offspring. To address this hypothesis, we exposed pregnant mice to influenza A virus (H3N2) on gestational day 9 and determined behavioral, hormonal and brainstem changes in male and female offspring. We found that gestational flu exposure induced dose-dependent alterations in social and aggressive behaviors (p≤0.05) in male and female offspring and increases in locomotor behaviors particularly in male offspring (p≤0.05). We found that flu exposure was also associated with reductions in oxytocin and serotonin (p≤0.05) levels in male and female offspring and sex-specific changes in dopamine metabolism. In addition we found changes in catecholaminergic and microglia density in brainstem tissues of male flu exposed offspring only (p≤0.05). This study demonstrates that gestational viral exposure induces behavioral changes in mice, which are associated with alterations in affiliative hormones. In addition we found sex-specific changes in locomotor behavior, which may be associated with sex-specific alterations in dopamine metabolism and brainstem inflammation. Further investigations into maternal immune responses are necessary to unravel the molecular mechanisms which underpin abnormal hormonal, immune and behavioral responses in offspring after gestational viral exposure.

Peripheral and central mediators of lipopolysaccharide induced suppression of defensive rage behavior in the cat.

Based upon recent findings in our laboratory that cytokines microinjected into the medial hypothalamus or periaqueductal gray (PAG) powerfully modulate defensive rage behavior in cat, the present study determined the effects of peripherally released cytokines following lipopolysaccharide (LPS) challenge upon defensive rage. The study involved initial identification of the effects of peripheral administration of LPS upon defensive rage by electrical stimulation from PAG and subsequent determination of the peripheral and central mechanisms governing this process. The results revealed significant elevation in response latencies for defensive rage from 60 to 300 min, post LPS injection, with no detectable signs of sickness behavior present at 60 min. In contrast, head turning behavior elicited by stimulation of adjoining midbrain sites was not affected by LPS administration, suggesting a specificity of the effects of LPS upon defensive rage. Direct administration of LPS into the medial hypothalamus had no effect on defensive rage, suggesting that the effects of LPS were mediated by peripheral cytokines rather than by any direct actions upon hypothalamic neurons. Complete blockade of the suppressive effects of LPS by peripheral pretreatment with an Anti-tumor necrosis factor-alpha (TNFalpha) antibody but not with an anti- interleukin-1 (IL-1) antibody demonstrated that the effects of LPS were mediated through TNF-alpha rather than through an IL-1 mechanism. A determination of the central mechanisms governing LPS suppression revealed that pretreatment of the medial hypothalamus with PGE(2) or 5-HT(1A) receptor antagonists each completely blocked the suppressive effects of LPS, while microinjections of a TNF-alpha antibody into the medial hypothalamus were ineffective. Microinjections of -Iodo-N-[2-[4-(methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) benzamide monohydrochloride (p-MPPI) into lateral hypothalamus (to test for anatomical specificity) had no effect upon LPS induced suppression of defensive rage. The results demonstrate that LPS suppresses defensive rage by acting through peripheral TNF-alpha in periphery and that central effects of LPS suppression of defensive rage are mediated through PGE(2) and 5-HT(1A) receptors in the medial hypothalamus.

Cytokine modulation of defensive rage behavior in the cat: role of GABAA and interleukin-2 receptors in the medial hypothalamus.

Defensive rage behavior is a form of aggressive behavior occurring in nature in response to a threatening stimulus. It is also elicited by stimulation of the medial hypothalamus and midbrain periaqueductal gray (PAG) and mediated through specific neurotransmitter-receptor mechanisms within these regions. Since interleukin (IL)-2 modulates the release of neurotransmitters linked to aggression and rage, we sought to determine whether IL-2 microinjected into the medial hypothalamus would modulate defensive rage. Microinjections of relatively low doses of IL-2 into the medial hypothalamus significantly suppressed defensive rage elicited from the PAG in a dose-dependent manner and in the absence of signs of sickness behavior. Pre-treatment with an antibody directed against IL-2Ralpha or a GABA(A) receptor antagonist blocked IL-2's suppressive effects upon defensive rage. Since the suppression of defensive rage is also mediated by 5-HT(1) receptors in the medial hypothalamus, a 5-HT(1) antagonist was microinjected into this region as a pretreatment for IL-2; however, it did not block IL-2's suppressive effects. Immunocytochemical data provided anatomical support for these findings by revealing extensive labeling of IL-2Ralpha on neurons in the medial hypothalamus. IL-2 microinjected into the medial hypothalamus did not modulate predatory attack elicited from the lateral hypothalamus. In summary, we provide evidence for a novel role for IL-2 in the medial hypothalamus as a potent suppressor of defensive rage behavior. These effects are mediated through an IL-2-GABA(A) receptor mechanism.

Potentiating role of interleukin-1beta (IL-1beta) and IL-1beta type 1 receptors in the medial hypothalamus in defensive rage behavior in the cat.

Recently, this laboratory provided evidence that interleukin-1beta (IL-1beta), an immune and brain-derived cytokine, microinjected into the medial hypothalamus, potentiates defensive rage behavior in the cat elicited from the midbrain periaqueductal gray (PAG), and that such effects are blocked by a 5-HT2 receptor antagonist. Since this finding represents the first time that a brain cytokine has been shown to affect defensive rage behavior, the present study replicated and extended these findings by documenting the specific potentiating role played by IL-1beta Type 1 receptor (IL-1RI), and the anatomical relationship between IL-1beta and 5-HT2 receptors in the medial hypothalamus. IL-1beta (10 ng) microinjected into the medial hypothalamus induced two separate phases of facilitation, one at 60 min and another at 180 min, post-injection. In turn, these effects were blocked with pretreatment of the selective IL-1 Type I receptor antagonist (IL-1ra) (10 ng), demonstrating the selectivity of the effects of IL-1beta on medial hypothalamic neurons upon PAG-elicited defensive rage behavior. The next stage of the study utilized immunohistochemical methods to demonstrate that IL-1beta and 5-HT2 receptors were present on the same neurons within regions of the medial hypothalamus where IL-1beta and the IL-1beta receptor antagonists were administered. This provided anatomical evidence suggesting a relationship between IL-1RI and 5-HT2 receptors in the medial hypothalamus that is consistent with the previous pharmacological observations in our laboratory. The overall findings show that activation of IL-1RI in the medial hypothalamus potentiates defensive rage behavior in the cat and that these effects may also be linked to the presence of 5-HT2 receptors on the same groups of neurons in this region of hypothalamus.

Interleukin-1 beta in the hypothalamus potentiates feline defensive rage: role of serotonin-2 receptors.

The neurochemistry of aggression and rage has largely focused on the roles played by neurotransmitters and their receptor mechanisms. In contrast, little attention has been given to the possible functions of other substances. Interleukin-1beta is an immune and brain-derived cytokine that is present in the hypothalamus. Functionally, interleukin-1 has been shown to induce the release of serotonin (5-HT), a neurotransmitter known to potently affect aggression and rage behavior. Thus, the goal of the present study was to test the hypothesis that interleukin-1beta in the medial hypothalamus could modulate defensive rage behavior in the cat. In the first experiment, electrical stimulation of sites in the medial hypothalamus from which defensive rage could be elicited and where microinjections of specific compounds were later placed, facilitated defensive rage elicited from the periaqueductal gray (PAG), thus demonstrating the functional relationship between these two regions. In the second experiment, microinjections of relatively low doses of interleukin-1beta into the medial hypothalamus potentiated defensive rage behavior elicited from the midbrain periaqueductal gray in a dose-related manner. In the third experiment, pretreatment with a selective 5-HT2 receptor antagonist, LY-53857, blocked the facilitating effects of interleukin-1beta upon defensive rage. These findings reveal for the first time that brain cytokines can dramatically alter aggressive behavior. In particular, interleukin-1beta in the medial hypothalamus potentiates defensive rage behavior elicited from the periaqueductal gray in the cat, and the potentiating effects of interleukin-1beta on this form of emotional behavior are mediated via a 5-HT2 receptor mechanism.

Interleukin-2 potentiates novelty- and GBR 12909-induced exploratory activity.

Interleukin (IL)-2 is a cytokine that influences exploratory behavior and central dopamine activity in rodents, and induces schizophrenic-like behavior and cognitive deficits in humans. We presently report that a single i.p. injection of murine IL-2 (0.05-0.80 microg/mouse) induced significant increases in novelty-induced locomotion and exploration in BALB/c mice. These measures were not significantly altered in mice that were pre-exposed to the test cage prior to cytokine injection. The IL-2-induced behavioral changes were not further augmented by repeated intermittent injections (five daily i.p. injections; 0.4 microg/mouse), however. Nonetheless, during the treatment period, activity scores of IL-2-treated mice significantly exceeded those of mice receiving saline; hence, repeated injections of IL-2 induced a persistent behavioral activation. IL-2 treatment also increased sensitivity to the behavior-stimulating effects of GBR 12909, a highly selective dopamine uptake inhibitor. This effect was a very long-lasting one since the dopamine agonist was administered 6 weeks after cessation of IL-2 treatment. The latter finding indicates that IL-2 interacts with the mesolimbic dopamine system, changing its sensitivity to seemingly different substances. Based on these data, and those of Zalcman and colleagues (S. Zalcman, I. Savina, R.A. Wise, Interleukin-6 increases sensitivity to the locomotor-stimulating effects of amphetamine in rats, Brain Res. 847 (1999) 276-283), it is suggested that cytokines can influence the development of behavioral abnormalities that are characteristic of aberrant mesolimbic dopamine activity via sensitization-like processes.

Interleukin-2 modulates N-methyl-D-aspartate receptors of native mesolimbic neurons.

Interleukin (IL)-2 is a brain-derived cytokine that influences mesocorticolimbic dopamine release, and is associated with pathological outcomes that are mediated, at least in part, by aberrations in mesolimbic neurotransmission. The mechanisms by which IL-2 modulates mesolimbic transmission, however, are not known. The NMDA receptor/channel (NMDAR) plays an essential role in neuronal excitability of mesolimbic neurons; we thus examined in neonatal rats the effects of IL-2 on NMDA-activated current (I(NMDA)) in voltage-clamped neurons freshly isolated from the ventral tegmental area (VTA), the site of origin of the mesolimbic system. IL-2 (0.01-500 ng/ml) alone had no effect on membrane conductance. When co-applied with NMDA, IL-2 (50-500 ng/ml) significantly potentiated I(NMDA). In contrast, doses as low as 0.01 ng/ml markedly decreased the NMDA response. Dose-response analysis showed that IL-2 ( > 50 ng/ml) increased the maximal I(NMDA), without changing the EC(50), indicating that IL-2 potentiates I(NMDA) by increasing the efficacy of the NMDAR. Moreover, current-voltage analysis revealed that IL-2 potentiation of I(NMDA) was voltage-dependent, being greater at negative potentials. In contrast, IL-2 inhibition of I(NMDA) was voltage-independent, and IL-2 did not alter the reversal potential. Additionally, IL-2 (1 ng/ml) shifted the NMDA concentration-response curve to the right, significantly increasing the EC(50) for NMDA without changing the maximal I(NMDA), suggesting that IL-2 inhibits the NMDAR by a competitive mechanism. IL-2 thus acts as a potent modulator of the NMDAR. IL-2-induced alterations of responses to NMDAR activation may contribute to synaptic plasticity in the mesolimbic system and to pathological outcomes associated with this system.

Interleukin-6 increases sensitivity to the locomotor-stimulating effects of amphetamine in rats.

Interleukin (IL)-6 mediates brain-immune interactions, influences the survival of postnatal mesencephalic and basal forebrain cells, influences mesocorticolimbic dopamine and serotonin neurotransmission, and is linked with various central nervous system disorders. In the present study, single injections of IL-6 (1 or 2 microg/Long-Evans rat, i.p.) induced modest elevations of locomotor activity. The locomotor increases were not augmented by repeated intermittent injections of IL-6 (five daily injections; 1 microg/rat), however. Nonetheless, repeated IL-6 treatment increased sensitivity to the locomotor-stimulating effects of 1.0 and 0.5 mg/kg amphetamine, when tested 5, 7, or 14 days following interruption of the cytokine treatment. The ability of acute IL-6 injections to alter locomotor activity and the ability of repeated IL-6 injections to produce long-lasting sensitization to the locomotor-stimulating effects of amphetamine suggest an interaction of this cytokine with the mesolimbic dopamine system, a system implicated in aspects of schizophrenia, addiction, and movement disorders. The fact that IL-6 caused a lasting change in responsiveness to amphetamine implies a mechanism by which immunogenic stimuli can alter brain circuitry, changing its sensitivity to seemingly unrelated subsequent stimuli or events.

Interleukin-2 and -6 induce behavioral-activating effects in mice.

Interleukin (IL)-1, IL-2 and IL-6 influence central monoamine activity in a cytokine-specific manner. We demonstrated that whereas IL-2 increased hypothalamic and hippocampal norepinephrine (NE) utilization, and DA turnover in the prefrontal cortex, IL-6 induced profound elevations of serotonin (5-HT) and mesocortical dopamine (DA) activity in the hippocampus and prefrontal cortex [S. Zalcman, J.M. Green-Johnson, L. Murray, D.M. Nance, D.G. Dyck, H. Anisman, A. H. Greenberg, Cytokine-specific central monoamine alterations following IL-1, -2 and -6 administration, Brain Res. 643 (1994) 40-49]. IL-1, in contrast, induced a wide range of central monoamine alterations. We presently report that these cytokines also differentially influence behavior. Profound reductions in non-ambulatory and ambulatory exploration were induced in BALB/c mice following IL-1 administration. In contrast, IL-2-treated mice displayed significant increases in the time spent engaged in non-ambulatory exploration, digging, rearing (particularly the number of free rears), and in the investigation of a novel stimulus (i.e., increased number and duration of stimulus contacts). IL-6-treated mice, moreover, exhibited significant increases in the time spent engaged in ambulatory exploration, digging and rearing (particularly the number of free rears, which tended to be of short duration). Modest increases in locomotion and grooming were also observed in IL-6-treated animals. Plasma corticosterone levels did not vary significantly as a function of IL-6 treatment. Hence, cytokine-specific behavioral-activating effects were induced following administration of IL-2 and IL-6. We suggest that these effects have adaptive significance and relevance to sickness behavior; however, pathological outcomes (e.g., schizophrenia, anxious-like states, anxious depression, motor abnormalities) could develop should these cytokines be overproduced or dysregulated.

Differential effects of immunologic challenge on self-stimulation from the nucleus accumbens and the substantia nigra.

Paralleling the effects of uncontrollable stressors, systemic administration of sheep red blood cells (SRBC) provokes brain neurotransmitter alterations, including DA variations within mesocorticolimbic regions, coinciding with or slightly preceding the peak immune response. Inasmuch as stressors disrupt responding for brain stimulation from the nucleus accumbens, possibly reflecting the anhedonic consequences of stressors, the present investigation assessed whether antigenic challenge would also influence responding for brain stimulation. Sheep red blood cell administration was found to reduce responding for brain stimulation from the nucleus accumbens, without affecting performance from the substantia nigra. The alterations of self-stimulation from the nucleus accumbens occurred at times that approximated the peak immune response. These data suggest that antigenic challenge may induce anhedonic-like effects that may be secondary to central neurochemical alterations engendered by the treatment. The possibility is also entertained that antigenic challenge may be interpreted as a stressor and contribute to alterations of affect.

Role of norepinephrine in suppressed IgG production in epilepsy-prone mice.

The responses of two substrains of Balb/c mice (Epilepsy Prone and Epilepsy Resistant) to immunization with sheep red blood cells (SRBC) were examined to determine whether chronic neurochemical differences between the two strains could influence B cell function. Anti-SRBC IgG production in the Epilepsy Prone (EP) strain was reduced relative to the Epilepsy Resistant (ER) strain, while anti-SRBC IgM production was unaffected. No differences were found in in vitro antibody (Ab) production or T lymphocyte function between the EP and ER strains, suggesting that in vivo conditions rather than an intrinsic cellular defect are responsible for reduced IgG production by EP mice. Basal splenic norepinephrine (NE) levels were significantly higher in EP mice than those in ER mice, and remained significantly higher following immunization. ER mice treated with the beta 2 adrenergic agonist terbutaline on days 4, 5 and 6 after immunization produced significantly lower numbers of IgG PFC than did saline treated controls. Addition of NE during later stages of in vitro immunization suppressed both anti-SRBC IgM and IgG production by splenic lymphocytes from Balb/c mice, and NE was found to decrease IFN gamma production. These observations suggest that dysregulation of splenic NE can have an impact on the immune response.

Suppressed T cell and macrophage function in the "reeler" (rl/rl) mutant, a murine strain with elevated cerebellar norepinephrine concentration.

The effects of neurochemical alterations in specific brain regions on the immune system were examined in reeler (rl/rl) mice, a neurologic mutant strain having an abnormally high concentration of cerebellar norepinephrine (NE). Following immunization with sheep red blood cells, lower numbers of IgM-producing B cells were found in rl/rl mice than in B6C3Fea/a controls. Interleukin-1 (IL-1) production by splenic macrophages from rl/rl mice was reduced compared to B6C3F3a/a controls, as was the proliferative response of splenic T lymphocytes from rl/rl mice activated with an anti-CD3 monoclonal antibody. Levels of IL-4, interferon-gamma and IL-2 produced by splenic T lymphocytes from rl/rl mice were also lower than those of B6C3Fea/a controls. Rl/rl mice do not have an intrinsic defect in the ability to produce IgM, as lipopolysaccharide activated splenic lymphocytes from rl/rl mice produced levels of IgM similar to those of controls. This suggests that defective function in the T lymphocyte and/or macrophage population rather than in the B cell population may underlie the defect in IgM production. No significant alterations were observed in basal splenic levels of NE or neuropeptides in rl/rl mice relative to controls. The reeler mouse model shows that alterations in immune function are present in a strain with inherited alterations in cerebellar noradrenergic innervation and NE concentration.

Alterations in central catecholamines associated with immune responding in adult and aged mice.

Central catecholamine alterations associated with immune activity are similar to those seen following stressor exposure. Inasmuch as aged animals exhibit more pronounced stressor-provoked alterations of central amines relative to younger animals, it was of interest to determine whether immune challenge would similarly induce more pronounced central amine variations in older animals. Fifteen-month old CD-1 mice challenged with 10(7) sheep red blood cells (SRBC) revealed an equivalent peak splenic plaque-forming cell response (4 days after antigen challenge) to that of 3-month-old mice challenged with 10(6) cells. Neither plasma adrenocorticotropic hormone (ACTH) nor corticosterone levels varied over days following immunization, although ACTH levels were generally higher in the older mice. In both age groups reductions of hypothalamic and locus coeruleus norepinephrine (NE) and increased accumulation of the metabolite MHPG coincided with (or preceded by 24 h) the peak immune response. However, increased accumulation of MHPG in the hypothalamus was greater and occurred earlier in the locus coeruleus of the aged mice. Likewise, at or about the time of peak immune responses nucleus accumbens dopamine (DA) levels were reduced and metabolites elevated in both age groups, while in the prefrontal cortex only DA metabolite levels were elevated. These data are commensurate with previous findings showing that SRBC inoculation may influence central neurotransmitters and that such effects correspond with the time of the peak immune responses. Moreover, in so far as hypothalamic NE utilization is concerned, it seems that the effects of SRBC inoculation are more pronounced in aged animals.

Interleukin-2-induced enhancement of an antigen-specific IgM plaque-forming cell response is mediated by the sympathetic nervous system.

Interleukin (IL)-2, a lymphokine produced by activated T-cells, stimulates T-cell proliferation and differentiation and potentiates B-cell production of antigen-specific immunoglobulins. IL-2 also increases hypothalamic norepinephrine turnover without affecting plasma corticosterone levels, which suggests that it selectively impacts on central sites that mediate sympathetic outflow to lymphoid organs. Because sympathetic stimulation during the early phases of an immunoglobulin (Ig)M plaque-forming cell (PFC) response to sheep red blood cells results in an increase in the subsequent number of antibody-forming cells, we assessed whether the enhancing effects of IL-2 on the PFC response are mediated by the sympathetic nervous system. The peak splenic IgM PFC response was increased in male Sprague-Dawley rats and BALB/c mice administered recombinant human IL-2 (50, 100 or 200 ng i.p.) in close temporal congruity with sheep red blood cell administration (i.e., 1 day before or immediately before immunization), compared with vehicle-treated controls. IL-2 administered at a later interval after immunization (i.e., 2 days) did not increase the number of antibody-forming cells. Intact sympathetic innervation of the spleen was required for the IL-2-induced immunoenhancement to occur because cutting the splenic nerve 10 days prior to IL-2 administration blocked the lymphokine's potentiation of the IgM PFC response. The immunostimulatory effects of IL-2 were also blocked in mice administered the beta adrenergic antagonist propranolol (5 mg/kg) immediately and 1 day after IL-2 administration. The alpha adrenergic antagonist phentolamine (5 mg/kg) had no effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Time-dependent in vivo mesolimbic dopamine variations following antigenic challenge.

Administration of sheep red blood cells (SRBC: 5 x 10(6)) to rats provoked an immune response which peaked 4 days following inoculation. Immune activation elicited an increase of in vivo extracellular dopamine (DA) in the nucleus accumbens, indicating increased release of DA from neurons. The DA alterations coincided with the time of the peak immune response, being significantly altered 4 days after inoculation, and declining to control levels thereafter. In contrast, the levels of serotonin metabolite, 5-hydroxyindoleacetic acid (5HIAA), were not affected by SRBC inoculation. These data are consistent with the supposition that antigenic challenge influences central neurotransmitters, and indicates that such effects are not restricted to the hypothalamus, but are apparent in mesolimbic regions. It is suggested that the antigenic challenge leads to effects comparable to those induced by stressors. As such, it might be expected that immune activation may come to produce behavioral alterations much like those engendered by stressors.

Cytokine-specific central monoamine alterations induced by interleukin-1, -2 and -6.

Cytokine-specific alterations of monoamine activity were evident in the hypothalamus, hippocampus and prefrontal cortex 2 h following peripheral administration of recombinant interleukin (IL)-1 beta, IL-2 and IL-6 (200 ng, i.p.) in male, BALB/c mice. IL-1 induced the broadest range of neurochemical changes, affecting central norepinephrine (NE), serotonin (5-HT) and dopamine (DA) activity. In particular, IL-1 enhanced NE turnover in the hypothalamus and hippocampus, 5-HT turnover in the hippocampus and prefrontal cortex (owing to increased utilization and reduced content of the transmitters in these brain regions), and enhanced DA utilization in the prefrontal cortex. IL-6 increased 5-HT and DA activity in the hippocampus and prefrontal cortex in a manner similar to IL-1, but failed to affect central NE activity. Moreover, IL-2 increased hypothalamic NE turnover (reflecting a profound increase in NE utilization) and enhanced DA turnover in the prefrontal cortex, but did not influence central 5-HT activity. Hence, these cytokines differentially altered neurochemical activity in brain regions that mediate neuroimmune interactions and that are influenced by physical and psychological stressors. In addition to the neurochemical changes, plasma corticosterone concentrations were profoundly enhanced in IL-1-treated animals, but not significantly altered by IL-2 or IL-6 treatment. The IL-1-induced corticosterone elevations did not significantly correlate with alterations of hypothalamic NE activity.

Influence of change from grouped to individual housing on a T-cell-dependent immune response in mice: antagonism by diazepam.

Transferring CD-1 mice from grouped to individual housing and then maintaining them individually resulted in a decline in the peak IgM plaque-forming cell (PFC) response to sheep red blood cells (SRBCs). However, the immunosuppression was dependent on the amount of time mice were maintained individually. In particular, individual housing for 5-10 days prior to SRBC inoculation and for 4 days following inoculation resulted in a suppression of the splenic PFC response and serum antibody titers. Shorter periods of individual housing (4 days following inoculation) did not provoke the immunosuppression. Likewise, following more protracted individual housing (15-30 days prior to inoculation) the immunosuppression was not evident. Inasmuch as daily treatment with an anxiolytic, diazepam (1.0 mg/kg), antagonized the suppression induced by 5 days of individual housing, it was suggested that the change from group to individual housing and then maintenance of animals individually acted much like a stressor to induce the immunosuppression.

Acute and chronic stressor effects on the antibody response to sheep red blood cells.

Exposure to inescapable foot-shock 72 h following immunization with sheep red blood cells resulted in a marked suppression of the peak splenic immunoglobulin (Ig)M plaque-forming cell response and plasma antibody titers in CD-1 mice. However, the nature of this effect was influenced by the animal's stressor history. In particular, if mice were initially exposed to a single stressor session immediately or 24 h following antigen treatment subsequent reexposure to the stressor (72 h following inoculation) did not provoke the immunosuppression. Moreover, reexposure to the stressor-related cues elicited a marked immunoenhancement. In contrast, if animals were exposed to a single stressor session 48 h prior to inoculation then later reexposure to the stressor-related cues provoked an immunosuppression. Among mice that had been exposed to a repeated stressor regimen on successive days prior to inoculation, the immunosuppression ordinarily elicited by an acute stressor was absent. Indeed, chronic stressor exposure typically favored potentiation of the immune response. However, the immunofacilitation elicited by the chronic stressor treatment likely was unrelated to the immunoenhancing effects of pairing a stressor with antigenic challenge.