Dynamic interactions between plasma IL-1 family cytokines and central endogenous opioid neurotransmitter function in humans.

Evidence in animal models suggests IL-1 family cytokines interact with central endogenous opioid neurotransmitter systems, inducing or perpetuating pathological states such as persistent pain syndromes, depression, substance use disorders, and their comorbidity. Understanding these interactions in humans is particularly relevant to understanding pathological states wherein this neurotransmitter system is implicated (ie, persistent pain, mood disorders, substance use disorders, etc). Here, we examined relationships between IL-1ß, IL-1ra, and functional measures of the endogenous opioid system in 34 healthy volunteers, in the absence and presence of a standardized sustained muscular pain challenge, a psychophysical challenge with emotionally and physically stressful components. Mu-opioid receptor availability in vivo was examined with [(11)C]carfentanil positron emission tomography (PET) scanning. Sex and neuroticism impacted IL-1 family cytokines; higher baseline IL-1ß and IL-1ra was identified in females with lower neuroticism. Higher baseline IL-1ß was also associated with reduced µ-opioid receptor availability (amygdala) and greater pain sensitivity. The pain challenge increased IL-1ß in females with high neuroticism. Strong associations between IL-1ra (an anti-nociceptive cytokine) and µ-opioid receptor activation (VP/NAcc) were identified during the pain challenge and the resulting analgesic effect of µ-opioid receptor activation was moderated by changes in IL-1ß whereby volunteers with greater pain induced increase in IL-1ß experienced less endogenous opioid analgesia. This study demonstrates the presence of relationships between inflammatory factors and a specific central neurotransmitter system and circuitry, of relevance to understanding interindividual variations in regulation of responses to pain and other physical and emotional stressors.

Short- and long-term effects of interleukin-2 treatment on the sensitivity of periadolescent female mice to interleukin-2 and dopamine uptake inhibitor.

Interleukin (IL)-2, a T-helper 1 (Th1) cell-derived cytokine, which potently modulates dopamine activity and neuronal excitability in mesolimbic structures, is linked with pathological outcomes (e.g., schizophrenia, depression, etc.) that at least partly reflect alterations in central dopaminergic processes. It has been suggested that dopamine neurons undergo pruning during adolescence and abnormalities in pruning predispose individuals to behavioral disorders. Since IL-2 is known as a neurodevelopmental factor affecting associated behavioral processes, the present study tested whether IL-2 can modulate stereotypic behaviors in both the periadolescent and adult periods. This study determined whether IL-2 treatment would produce long-lasting changes in sensitivity to a later challenge with IL-2 or GBR 12909, a highly selective dopamine uptake inhibitor. Four experiments were conducted. Firstly, a decrease in novelty-induced stereotypic behavior was observed in BALB/c periadolescent mice (38 days of age) following IL-2 administration (0.4 µg/2 ml) relative to vehicle control. In the second experiment, an initial dose of IL-2 was given in the periadolescent period, but did not affect rearing responses. A second dose of IL-2 given to the animals 30 days later as adults, resulted in a significant increase in rearing behaviors relative to control animals. In the third experiment, separate groups of experimental and control mice were administered GBR 12909, a highly selective dopamine reuptake inhibitor, 30 days following treatment with either IL-2 or vehicle. It was noted that this experimental group, which initially received IL-2, exhibited stereotypy, as evidenced by increased sniffing behavior. A fourth experiment revealed that IL-2 administered in periadolesecence and adulthood had no effect on other motor responses, indicating that IL-2 selectively modulates selective stereotypic behaviors. The results provide evidence, for the first time, that long-term changes in stereotypy in periadolescent mice are linked to an IL-2 mechanism, possibly utilizing dopamine.

A pilot study investigating tumor necrosis factor-α as a potential intervening variable of atypical antipsychotic-associated metabolic syndrome in bipolar disorder.

BACKGROUND: Strong associations exist between tumor necrosis factor-α (TNF-α) and metabolic syndrome (MetS). Although TNF-α is associated with bipolar depression (BD), its role in atypical antipsychotic (AAP)-associated MetS in BD is unclear. Here, we investigate the potential intervening role of TNF-α in the indirect relationship between AAP treatment and MetS in BD. MATERIALS AND METHODS: Using a cross-sectional design, 99 euthymic BD volunteers were stratified by the presence or the absence of MetS (National Cholesterol Education Program Adult Treatment Panel III). Serum TNF-α concentration, determined via chemiluminescent immunometric assays, was compared between groups (ie, MetS or no MetS). We investigated the intervening effect of TNF-α on the relation between AAP treatment and MetS in BD using regression techniques. RESULTS: Treatment with those antipsychotics believed associated with a higher risk for MetS (ie, AAPs: olanzapine, quetiapine, risperidone, paliperidone, clozapine) was found to be associated with significantly greater TNF-α (F 1,88 = 11.2, P = 0.001, mean difference of 1.7 ± 0.51) and a higher likelihood of MetS (F 1,88 = 4.5, P = 0.036) than in those not receiving treatment with an AAP. Additionally, TNF-α was greater (trending toward significance; T 52 = 2.0, P = 0.05) in BD volunteers with MetS and was found to have a statistically significant effect on the indirect relationship between AAP treatment and elevated waist circumference in these BD volunteers. DISCUSSION: These results identify TNF-α as a potential intervening variable of AAP-associated MetS in BD, not previously identified in this population. Future prospective studies could assess the predictive potential of TNF-α in determining risk of AAP-associated MetS in BD. Given previous evidence relating TNF-α and mood state in BD, this study increases the importance in understanding the role of TNF-α in "mind-body" interactions and renews discussions of the utility of research into the clinical efficacy of TNF-α antagonist treatment in mood disorders.

Pharmacokinetics and modeling of immune cell trafficking: quantifying differential influences of target tissues versus lymphocytes in SJL and lipopolysaccharide-treated mice.

BACKGROUND: Immune cell trafficking into the CNS and other tissues plays important roles in health and disease. Rapid quantitative methods are not available that could be used to study many of the dynamic aspects of immune cell-tissue interactions. METHODS: We used pharmacokinetics and modeling to quantify and characterize the trafficking of radioactively labeled lymphocytes into brain and peripheral tissues. We used variance from two-way ANOVAs with 2 × 2 experimental designs to model the relative influences of lymphocytes and target tissues in trafficking. RESULTS: We found that in male CD-1 mice, about 1 in 5,000 intravenously injected lymphocytes entered each gram of brain. Uptake by brain was 2 to 3 times higher in naïve SJL females, but uptake by spleen and clearance from blood was lower, demonstrating a dichotomy in immune cell distribution. Treatment of CD-1 mice with lipopolysaccharide (LPS) increased immune cell uptake into brain but decreased uptake by spleen and axillary nodes. CONCLUSIONS: Differences in brain uptake and in uptake by spleen between SJL and CD-1 mice were primarily determined by lymphocytes, whereas differences in uptake with LPS were primarily determined by lymphocytes for the brain but by the tissues for the spleen and the axillary lymph node. These results show that immune cells normally enter the CNS and that tissues and immune cells interact in ways that can be quantified by pharmacokinetic models.

Soluble interleukin-6 receptor induces motor stereotypies and co-localizes with gp130 in regions linked to cortico-striato-thalamo-cortical circuits.

Soluble cytokine receptors are normal constituents of body fluids that regulate peripheral cytokine and lymphoid activity and whose levels are increased in states of immune activation. Soluble interleukin-6 receptor (sIL-6R) levels positively correlate with disease progression in some autoimmune conditions and psychiatric disorders. Particularly strong links between levels of sIL-6R and the severity of psychotic symptoms occur in schizophrenia, raising the possibility that sIL-6R is involved in this disease. However, there is no evidence that peripheral sIL-6R induces relevant behavioral disturbances. We showed that single subcutaneous injections of sIL-6R (0-1 µg), stimulated novelty stress-induced exploratory motor behaviors in male Balb/c mice within 20-40-min of injection. A progressive increase in vertical stereotypies was observed 40-80 min post injection, persisting for the remainder of the test session. Paralleling these stimulant-like effects, sIL-6R pre-treatment significantly enhanced stereotypy scores following challenge with GBR 12909. We found that peripherally administered sIL-6R crossed the blood-brain barrier, localizing in brain regions associated with cortico-striatal-thalamo-cortical (CSTC) circuits, which are putative neuroanatomical substrates of disorders associated with repetitive stereotypies. Peripherally administered sIL-6R co-localized with gp130, a transmembrane protein involved in IL-6 trans-signaling, in the nucleus accumbens, caudate-putamen, motor and infralimbic cortices, and thalamic nuclei, but not with gp130 in the ventral tegmental area, substantia nigra, or sensorimotor cortex,. The results suggest that peripheral sIL-6R can act as a neuroimmune messenger, crossing the blood brain barrier (BBB) to selectively target CSTC circuits rich in IL-6 trans-signaling protein, and inducing repetitive stereotypies. As such sIL-6R may represent a novel therapeutic agent for relevant psychiatric disorders.

Soluble cytokine receptors (sIL-2Rα, sIL-2Rß) induce subunit-specific behavioral responses and accumulate in the cerebral cortex and basal forebrain.

Soluble cytokine receptors are normal constituents of body fluids that regulate peripheral cytokine and lymphoid activity. Levels of soluble IL-2 receptors (sIL-2R) are elevated in psychiatric disorders linked with autoimmune processes, including ones in which repetitive stereotypic behaviors and motor disturbances are present. However, there is no evidence that sIL-2Rs (or any peripheral soluble receptor) induce such behavioral changes, or that they localize in relevant brain regions. Here, we determined in male Balb/c mice the effects of single peripheral injections of sIL-2Rα or sIL-2Rß (0-2 µg/male Balb/c mouse; s.c.) on novelty-induced ambulatory activity and stereotypic motor behaviors. We discovered that sIL-2Rα increased the incidence of in-place stereotypic motor behaviors, including head up head bobbing, rearing/sniffing, turning, and grooming behavior. A wider spectrum of behavioral changes was evident in sIL-2Rß-treated mice, including increases in vertical and horizontal ambulatory activity and stereotypic motor movements. To our knowledge, this is the first demonstration that soluble receptors induce such behavioral disturbances. In contrast, soluble IL-1 Type-1 receptors (0-4 µg, s.c.) didn't appreciably affect these behaviors. We further demonstrated that sIL-2Rα and sIL-2Rß induced marked increases in c-Fos in caudate-putamen, nucleus accumbens and prefrontal cortex. Anatomical specificity was supported by the presence of increased activity in lateral caudate in sIL-2Rα treated mice, while sIL-2Rß treated mice induced greater c-Fos activity in prepyriform cortex. Moreover, injected sIL-2Rs were widely distributed in regions that showed increased c-Fos expression. Thus, sIL-2Rα and sIL-2Rß induce marked subunit- and soluble cytokine receptor-specific behavioral disturbances, which included increases in the expression of ambulatory activity and stereotypic motor behaviors, while inducing increased neuronal activity localized to cortex and striatum. These findings suggest that sIL-2Rs act as novel immune-to- brain messengers and raise the possibility that they contribute to the disease process in psychiatric disorders in which marked increases in these receptors have been reported.

Anti-streptococcus IgM antibodies induce repetitive stereotyped movements: cell activation and co-localization with Fcα/µ receptors in the striatum and motor cortex.

Group A beta-hemolytic streptococcus (GABHS) infections are implicated in neuropsychiatric disorders associated with an increased expression of repetitive stereotyped movements. Anti-streptococcus IgG presumably cross-reacts with elements on basal ganglia cells, modifies their function, and triggers symptoms. IgM may play a unique role in precipitating behavioral disturbances since variations in cortico-striatal activity occur in temporal congruity with peak IgM titers during an orchestrated immune response. We discovered in Balb/c mice that single subcutaneous injections of mouse monoclonal IgM antibodies to streptococcus group A bacteria induce marked dose-dependent increases in repetitive stereotyped movements, including head bobbing, sniffing, and intense grooming. Effects were antibody- and antigen-specific: anti-streptococcus IgG stimulated ambulatory activity and vertical activity but not these stereotypies, while anti-KLH IgM reduced activity. We suggest that anti-streptococcus IgM and IgG play unique roles in provoking GABHS-related behavioral disturbances. Paralleling its stereotypy-inducing effects, anti-streptococcus IgM stimulated Fos-like immunoreactivity in regions linked to cortico-striatal projections involved in motor control, including subregions of the caudate, nucleus accumbens, and motor cortex. This is the first evidence that anti-streptococcus IgM antibodies induce in vivo functional changes in these structures. Moreover, there was a striking similarity in the distributions of anti-streptococcus IgM deposits and Fos-like immunoreactivity in these regions. Of further importance, Fcα/µ receptors, which bind IgM, were present- and co-localized with anti-streptococcus IgM in these structures. We suggest that anti-streptococcus IgM-induced alterations of cell activity reflect local actions of IgM that involve Fcα/µ receptors. These findings support the use of anti-streptococcus monoclonal antibody administration in Balb/c mice to model GABHS-related behavioral disturbances and identify underlying mechanisms.

Association of plasma interleukin-18 levels with emotion regulation and µ-opioid neurotransmitter function in major depression and healthy volunteers.

BACKGROUND: Alterations in central neurotransmission and immune function have been documented in major depression (MDD). Central and peripheral endogenous opioids are linked to immune functioning in animal models, stress-activated, and dysregulated in MDD. We examined the relationship between µ-opioid receptor (OR)-mediated neurotransmission and a proinflammatory cytokine (interleukin [IL]-18). METHODS: We studied 28 female subjects (14 MDDs, 14 control subjects) with positron emission tomography and [(11)C] carfentanil (µ-OR selective) during neutral and sadness states. With a simple regression model in SPM2 (Wellcome Trust, London, England) we identified brain regions where baseline µ-OR availability (nondisplaceable binding potential [BP(ND)]) and sadness-induced changes in µ-OR BP(ND) were associated with baseline IL-18. RESULTS: Baseline IL-18 was greater in MDDs than control subjects [t(25) = 2.13, p = .04]. In control subjects IL-18 was correlated with negative emotional ratings at baseline and during sadness induction. In MDDs, IL-18 was positively correlated with baseline regional µ-OR BP(ND) and with sadness-induced µ-opioid system activation in the subgenual anterior cingulate, ventral basal ganglia, and amygdala. CONCLUSIONS: This study links plasma IL-18 with sadness-induced emotional responses in healthy subjects, the diagnosis of MDD, and µ-opioid functioning, itself involved in stress adaptation, emotion regulation, and reward. This suggests that IL-18 represents a marker associated with emotion regulation/dysregulation at least in part through central opioid mechanisms.

Lack of aggression and anxiolytic-like behavior in TNF receptor (TNF-R1 and TNF-R2) deficient mice.

The mechanisms underlying violence and aggression and its control remain poorly understood. Using the resident-intruder paradigm, we have discovered that resident mice with combined deletion of TNF receptor type 1 (TNF-R1) and type 2 (TNF-R2) genes show a striking absence of aggressive behavior, which includes fighting, sideways postures, and tail rattling. In parallel, resident TNF-R1 and TNF-R2 knockout mice show an increase in non-aggressive exploration of the intruder mice. Given the relationship between aggression and anxiety, we also measured anxiety-related behavior, as reflected by performance in the Open Field and the Light-Dark Choice Test. Compared with wild type mice, TNF-R1 and TNF-R2 deficient mice spent significantly more time and showed increased movement in the center of the Open Field and in the illuminated compartment of the light-dark box, suggesting an anxiolytic-like profile. Together, these data show that combined deletion of TNF-R1 and TNF-R2 results in a striking absence of aggressive behavior, an increase in non-aggressive exploration, and anxiolytic-like effects. These findings identify potent roles for TNF in regulating aggression and anxiety-related behavior, and suggest that TNF receptor signaling tonically modulates activity in brain regions underlying these behaviors.

The MATRICS Consensus Cognitive Battery, part 1: test selection, reliability, and validity.

OBJECTIVE: The lack of an accepted standard for measuring cognitive change in schizophrenia has been a major obstacle to regulatory approval of cognition-enhancing treatments. A primary mandate of the National Institute of Mental Health's Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) initiative was to develop a consensus cognitive battery for clinical trials of cognition-enhancing treatments for schizophrenia through a broadly based scientific evaluation of measures. METHOD: The MATRICS Neurocognition Committee evaluated more than 90 tests in seven cognitive domains to identify the 36 most promising measures. A separate expert panel evaluated the degree to which each test met specific selection criteria. Twenty tests were selected as a beta battery. The beta battery was administered to 176 individuals with schizophrenia and readministered to 167 of them 4 weeks later so that the 20 tests could be compared directly. RESULTS: The expert panel ratings are presented for the initially selected 36 tests. For the beta battery tests, data on test-retest reliability, practice effects, relationships to functional status, practicality, and tolerability are presented. Based on these data, 10 tests were selected to represent seven cognitive domains in the MATRICS Consensus Cognitive Battery. CONCLUSIONS: The structured consensus method was a feasible and fair mechanism for choosing candidate tests, and direct comparison of beta battery tests in a common sample allowed selection of a final consensus battery. The MATRICS Consensus Cognitive Battery is expected to be the standard tool for assessing cognitive change in clinical trials of cognition-enhancing drugs for schizophrenia. It may also aid evaluation of cognitive remediation strategies.

Role of IL-1 beta and 5-HT2 receptors in midbrain periaqueductal gray (PAG) in potentiating defensive rage behavior in cat.

Feline defensive rage, a form of aggressive behavior that occurs in response to a threat can be elicited by electrical stimulation of the medial hypothalamus or midbrain periaqueductal gray (PAG). Our laboratory has recently begun a systematic examination of the role of cytokines in the regulation of rage and aggressive behavior. It was shown that the cytokine, interleukin-2 (IL-2), differentially modulates defensive rage when microinjected into the medial hypothalamus and PAG by acting through separate neurotransmitter systems. The present study sought to determine whether a similar relationship exists with respect to interleukin 1-beta (IL-1 beta), whose receptor activation in the medial hypothalamus potentiates defensive rage. Thus, the present study identified the effects of administration of IL-1 beta into the PAG upon defensive rage elicited from the medial hypothalamus. Microinjections of IL-1 beta into the dorsal PAG significantly facilitated defensive rage behavior elicited from the medial hypothalamus in a dose and time dependent manner. In addition, the facilitative effects of IL-1 beta were blocked by pre-treatment with anti-IL-1 beta receptor antibody, while IL-1 beta administration into the PAG had no effect upon predatory attack elicited from the lateral hypothalamus. The findings further demonstrated that IL-1 beta's effects were mediated through 5-HT(2) receptors since pretreatment with a 5-HT(2C) receptors antagonist blocked the facilitating effects of IL-1 beta. An extensive pattern of labeling of IL-1 beta and 5-HT(2C) receptors in the dorsal PAG supported these findings. The present study demonstrates that IL-beta in the dorsal PAG, similar to the medial hypothalamus, potentiates defensive rage behavior and is mediated through a 5-HT(2C) receptor mechanism.

The neurobiological bases for development of pharmacological treatments of aggressive disorders.

Violence and aggression are major causes of death and injury, thus constituting primary public health problems throughout much of the world costing billions of dollars to society. The present review relates our understanding of the neurobiology of aggression and rage to pharmacological treatment strategies that have been utilized and those which may be applied in the future. Knowledge of the neural mechanisms governing aggression and rage is derived from studies in cat and rodents. The primary brain structures involved in the expression of rage behavior include the hypothalamus and midbrain periaqueductal gray. Limbic structures, which include amygdala, hippocampal formation, septal area, prefrontal cortex and anterior cingulate gyrus serve important modulating functions. Excitatory neurotransmitters that potentiate rage behavior include excitatory amino acids, substance P, catecholamines, cholecystokinin, vasopressin, and serotonin that act through 5-HT(2) receptors. Inhibitory neurotransmitters include GABA, enkephalins, and serotonin that act through 5-HT(1) receptors. Recent studies have demonstrated that brain cytokines, including IL-1beta and IL-2, powerfully modulate rage behavior. IL-1-beta exerts its actions by acting through 5-HT(2) receptors, while IL-2 acts through GABAA or NK(1) receptors. Pharmacological treatment strategies utilized for control of violent behavior have met with varying degrees of success. The most common approach has been to apply serotonergic compounds. Others included the application of antipsychotic, GABAergic (anti-epileptic) and dopaminergic drugs. Present and futures studies on the neurobiology of aggression may provide the basis for new and novel treatment strategies for the control of aggression and violence as well as the continuation of existing pharmacological approaches.

The neurobiology of aggression and rage: role of cytokines.

Recent studies have suggested an important relationship linking cytokines, immunity and aggressive behavior. Clinical reports describe increasing levels of hostility, anger, and irritability in patients who receive cytokine immunotherapy, and there are reports of a positive correlation between cytokine levels and aggressive behavior in non-patient populations. On the basis of these reports and others describing the presence or actions of different cytokines in regions of the brain associated with aggressive behavior, our laboratory embarked upon a program of research designed to identify and characterize the role of IL-1 and IL-2 in the hypothalamus and midbrain periaqueductal gray (PAG)--two regions functionally linked through reciprocal anatomical connections--in the regulation of feline defensive rage. A paradigm involved cytokine microinjections into either medial hypothalamus and elicitation of defensive rage behavior from the PAG or vice versa. These studies have revealed that both cytokines have potent effects in modulating defensive rage behavior. With respect to IL-1, this cytokine facilitates defensive rage when microinjected into either the medial hypothalamus or PAG and these potentiating effects are mediated through 5-HT2 receptors. In contrast, the effects of IL-2 are dependent upon the anatomical locus. IL-2 microinjected into the medial hypothalamus suppresses defensive rage and this suppression is mediated through GABA(A) receptors, while microinjections of IL-2 in the PAG potentiate defensive rage, in which these effects are mediated through NK-1 receptors. Present research is designed to further delineate the roles of cytokines in aggressive behavior and to begin to unravel the possible signaling pathways involved this process.

Kainate-activated currents in the ventral tegmental area of neonatal rats are modulated by interleukin-2.

Interleukin (IL)-2 is a potent modulator of neurotransmission and neuronal development in the mesolimbic and mesostriatal systems. It is also implicated in pathologies (including schizophrenia, Parkinson's disease, autism, cognitive disorders) that are linked with abnormalities in these systems. Since the kainate receptor plays an essential role in mesolimbic neuronal development and excitability, we examined the effects of physiologically relevant concentrations of IL-2 on kainate-activated current (I(KA)) in voltage-clamped neurons freshly isolated from the ventral tegmental area (VTA) of 3- to 14-day-old rats. IL-2 (0.01-10 ng/ml) alone had no effect on membrane conductance. When co-applied with kainate, IL-2 significantly decreased I(KA). IL-2 (2 ng/ml) shifted the kainate concentration-response curve to the right in a parallel manner, significantly increasing the EC(50) without changing the maximal I(KA). IL-2 inhibition of I(KA) was voltage-dependent, being greater at negative potentials. IL-2 did not alter the reversal potential. These findings suggest that IL-2 potently modulates kainate receptors of developing mesolimbic neurons. We suggest that IL-2 plays a role in the excitability of developing neurons in the mesolimbic system. Inasmuch as increased I(KA) is associated with excitotoxicity, coupled with the present observation that IL-2 inhibits I(KA), we suggest an adaptive role for IL-2 in limiting excitotoxicity in the developing brain. IL-2 might thus be required for normal cell development in the mesolimbic and mesostriatal systems.

Approaching a consensus cognitive battery for clinical trials in schizophrenia: the NIMH-MATRICS conference to select cognitive domains and test criteria.

To stimulate the development of new drugs for the cognitive deficits of schizophrenia, the National Institute of Mental Health (NIMH) established the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) initiative. This article presents an overview of decisions from the first MATRICS consensus conference. The goals of the meeting were to 1) identify the cognitive domains that should be represented in a consensus cognitive battery and 2) prioritize key criteria for selection of tests for the battery. Seven cognitive domains were selected based on a review of the literature and input from experts: working memory, attention/vigilance, verbal learning and memory, visual learning and memory, reasoning and problem solving, speed of processing, and social cognition. Based on discussions at this meeting, five criteria were considered essential for test selection: good test-retest reliability, high utility as a repeated measure, relationship to functional outcome, potential response to pharmacologic agents, and practicality/tolerability. The results from this meeting constitute the initial steps for reaching a consensus cognitive battery for clinical trials in schizophrenia.

Permeability of the mouse blood-brain barrier to murine interleukin-2: predominance of a saturable efflux system.

Interleukin (IL)-2, a T helper (TH)1 cell-derived glycoprotein with potent neuromodulatory effects, is implicated in the etiology and pathogenesis of various psychiatric and neurological disorders. Paralleling these findings, chronic IL-2 intravenous immunotherapy may induce similar psychopathological outcomes. The findings that acute or repeated injections of IL-2 induce motor and cognitive abnormalities in rodents are consistent with these clinical findings, and raise the possibility that IL-2 crosses the blood-brain barrier (BBB) to alter brain function. However, little is known about the ability of IL-2 to enter the brain or whether its effects vary with the chronicity of IL-2 treatment. Here, we found that radioactively labeled mouse IL-2 (I-IL-2) given intravenously entered the brain at a low rate (Ki=0.142+/-0.044microl/g-min) by a non-saturable process. Repeated injections of either IL-2 or vehicle altered the kinetics of entry without producing a net effect on IL-2 entry. When I-IL-2 was given by brain perfusion, the entry rate greatly increased over 10-fold to 2.2+/-0.805microl/g-min. This suggests a circulating factor is retarding the entry of IL-2 into the brain. A paradoxic increase in the rate of I-IL-2 entry into brain occurred when an excess of unlabeled IL-2 was included in the brain perfusate, suggesting a saturable CNS-to-blood efflux system. Intracerebroventricular injection of I-IL-2 with and without unlabeled IL-2 confirmed the presence of a saturable efflux system. We conclude that IL-2 entry into the brain is low because of the absence of a blood-to-brain transporter and further retarded by circulating factors and a CNS-to-blood efflux system. This is the first description of a saturable CNS-to-blood efflux system for a cytokine. We postulate that this efflux system may protect the brain from circulating IL-2.

Effects of hemispheric lateralization and site specificity on immune alterations induced by kindled temporal lobe seizures.

The effects of kindled seizures elicited from sites in the left and right temporal lobes on mitogen-induced proliferation (LPS, Con A, PHA) and induction of representative TH1 (IFN-gamma) and TH2 (IL-10, IL-4) cytokines were determined in activated rat splenocytes. With reference to cell proliferation, the changes depended on the hemispheric side and location of kindling. Kindling of the left side mediated significant increase in cell proliferation by LPS. Left side kindling resulted in decreased cell proliferation by PHA. Although right side kindling showed no change when taken together, further analysis showed that the reduced proliferation by PHA was mediated when the pyriform cortex was kindled with no change from amygdaloid nuclei. Similar hemispheric polarization was observed in the production of IL-10 and IFN-gamma by Con A-stimulated splenocytes in left side kindled rats. Hence, kindled temporal lobe seizures induced changes in specific immune functions. These effects are not only lateralized but are also specific with respect to the particular region kindled. Since epileptic patients have altered immune functions, this report contributes to our understanding of this complex immune-brain cross-talk in epilepsy.

Interleukin-2-induced increases in climbing behavior: inhibition by dopamine D-1 and D-2 receptor antagonists.

Interleukin (IL)-2 is a potent modulator of dopamine activity in the mesocorticolimbic and mesostriatal systems. It is also associated with behavioral changes (increased motor activity) and psychopathological outcomes (schizophrenia, Parkinson's Disease, cognitive deficits) that at least partly reflect aberrations in central dopaminergic transmission. Nonetheless, there is no evidence that a functional link exists between IL-2, dopaminergic processes, and related behavioral changes. We thus determined if IL-2 treatment increases the expression of climbing behavior, a behavior that is linked with dopamine D-1 and/or D-2 receptors and one used to test the efficacy of neuroleptics. IL-2 treatment (5-daily i.p. injections; 0.4 microg/BALB/c mouse) induced a marked 2-fold increase in climbing scores; a single injection had no effect. IL-2-induced increases in climbing behavior were completely blocked by a selective dopamine D-1 receptor antagonist (SCH 23390; 0.05 or 0.2 mg/kg; i.p.), or by a relatively high dose of a D-2 antagonist (sulpiride; 80 mg/kg; i.p.). In contrast, MK-801, a noncompetitive NMDA receptor antagonist, had no effect. This is the first demonstration of a functional link between IL-2, dopaminergic receptors, and behavior. These findings could shed light on the mechanisms by which IL-2 increases vulnerability to psychiatric abnormalities associated with aberrations in central dopaminergic processes.