The proinflammatory cytokines interleukin-1 ␤ (IL-1 ␤ ), IL-6, and tumor necrosis factor-alpha (TNF-␣ Dopamine; Monoamines; Neurochemical; Norepinephrine; Serotonin; Synergism; It is clear that interactions occur between the immune, endocrine, central, and autonomic nervous systems. Immunological manipulations (or products of an activated immune system, e.g., cytokines) may affect neuroendocrine and central neurotransmitter processes, and conversely, neuroendocrine and central neurotransmitter alterations may impact on immune activity (Blalock 1994;Dunn 1990;Rivier 1993;Rothwell et al. 1997). It has been posited that, among other things, the immune system acts like a sensory organ informing the brain of antigenic challenge (Blalock 1994) and that immune activation may be interpreted by the CNS as a stressor Dunn 1990). Further, cytokines may be part of a regulatory loop that, by virtue of effects on CNS functioning, might influence behavioral outputs and may even contribute to the symptoms of behavioral pathologies, including mood and anxietyrelated disorders . Indeed, in humans, depression was associated with variations of plasma cytokines, including interleukin-1 ␤ (IL-1 ␤ ), IL-1 receptor antagonist (IL-1Ra), IL-2, soluble IL-2 receptors, IL-6, and soluble IL-6 receptors Maes 1995;Maes et al. 1995;Muller and Ackenheil 1998).From the Institute of Neuroscience, Carleton University, Ottawa, Ontario, Canada (KB, SH, RZ, HA); and School of Psychology and Department of Cellular and Molecular Medicine (ZM), University of Ottawa, Ottawa, Ontario, Canada.Address correspondence to: Hymie Anisman, Ph.D., Life Sciences Research Building, Carleton University. Ottawa, Ontario K1S 5B6, Canada.Received January 28, 1999; revised May 10, 1999; accepted December 6, 1999. N EUROPSYCHOPHARMACOLOGY 2000 -VOL . 22 , NO . 6 Synergistic Effects of Cytokines 567Cytokines and bacterial endotoxins, such as lipopolysaccharide (LPS), induce a constellation of apparently adaptive behavioral changes, collectively referred to as "sickness behaviors" . For instance, these agents induce fever, reduce social exploration, sexual behaviors, and food consumption (Bluthe et al. 1992;Johnson et al. 1996;Plata-Salaman 1988;Plata-Salaman et al. 1988;O'Reilly et al. 1987). In addition, endotoxins may induce anxiogenic-like effects ) and disrupt responding for rewarding brain stimulation (Borowski et al. 1998), possibly reflecting anhedonic effects elicited by the immune challenge. The behavioral effects of endotoxin and cytokine treatment are paralleled by increased hypothalamic-pituitary-adrenal (HPA) activity, as reflected by increased activity of corticotropin releasing hormone (CRH) and elevated plasma ACTH and corticosterone levels (Kakucksa et al. 1993;Tilders et al. 1993). Inasmuch as cytokines elicit several effects similar to those of LPS, it has been assumed that at least some of the endotoxin effects involve IL-1 ␤ , or this cytokine acting conjointly or synergistically with IL-6 and/or TNF-␣ (Dunn 1992a; Ebisui et al. 1994;Long et...

Aversive experiences have been thought to provoke or exacerbate clinical depression. The present review provides a brief survey of the stress-depression literature and suggests that the effects of stressful experiences on affective state may be related to depletion of several neurotransmitters, including norepinephrine, dopamine, and serotonin. A major element in determining the neurochemical changes is the organism's ability to cope with the aversive stimuli through behavioral means. Aversive experiences give rise to behavioral attempts to cope with the stressor, coupled with increased utilization and synthesis of brain amines to contend with environmental demands. When behavioral coping is possible, neurochemical systems are not overly taxed, and behavioral pathology will not ensue. However, when there can be no behavioral control over the stressful stimuli, or when the aversive experience is perceived as uncontrollable, increased emphasis is placed on coping through endogenous neurochemical mechanisms. Amine utilization increases appreciably and may exceed synthesis, resulting in a net reduction of amine stores, which in turn promotes or exacerbates affective disorder. The processes governing the depletions may be subject to sensitization or conditioning, such that exposure to traumatic experiences may have long-term repercussions when the organism subsequently encounters related stressful stimuli. With continued uncontrollable stimulation, adaptation occurs in the form of increased activity of synthetic enzymes, and levels of amines approach basal values. It is suggested that either the initial amine depletion provoked by aversive experiences or a dysfunction of the adaptive processes, resulting in persistent amine depletion, contributes to behavioral depression. Aside from the contribution of behavioral coping, several organismic, experiential, and environmental variables will influence the effects of aversive experiences on neurochemical activity, and may thus influence vulnerability to depression.

A series of neurochemical changes occur in response to stressors that may permit the organism to contend with environmental demands. When the organism is exposed to a stressor the utilization and synthesis of brain NE and DA increases. Under conditions where utilization exceeds synthesis, owing either to the nature of the stressor (uncontrollability), experiential factors (e.g., prior exposure to acute stressors), or organismic variables (e.g., strain, age), reductions of the amine may be incurred. It is suggested that the reduced amine concentrations leave the organism less well prepared to deal with the demands placed upon it, and ultimately increase vulnerability to psychological disturbances. It follows that the more persistent the amine reduction, the greater the probability of pathology being engendered. In effect, in our analyses of stressor effects it is not sufficient merely to determine whether amine reductions occur, but also to assess the ability of the system to re-establish adequate levels and turnover. Additionally, since stressors may result in the conditioning or sensitization of neurochemical processes, it is essential not only to assess the immediate impact of the stressor, but also the neurochemical variations that occur upon re-exposure to stressors or cues associated with the stressor. In considering the consequences of stressors and the potential implications for human pathology, it is important to consider the impact of chronic stressors. After all, many stressors encountered by humans are chronic in nature, particularly if one considers ruminations associated with the aversive event. It seems that with repeated stressor application a further series of adaptive neurochemical changes occur. The activity of tyrosine hydroxylase is increased, and concentrations of NE and DA approach those of nonstressed animals. Indeed, it appears that after stressor termination the increased amine synthesis may persist for some time leading to a further increase of amine concentrations, which may enable the organism to deal with environmental demands. In addition, receptor variations may occur, including down-regulation of beta-NE receptors, and possibly alterations of alpha-1 and alpha-2 receptors as well. It is believed that the receptor variations may be the essential element in maintaining the integrity of the organism. It is our contention that where such adaptive changes do not occur or are slow in occurring, pharmacological intervention may be necessary to engender such neuronal variations.

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The present study assessed alterations in mesolimbic enkephalin (ENK) mRNA levels after predator [2,5-dihydro-2,4,5-trimethylethiazoline (TMT)] and non-predator (butyric acid) odor encounter and/or light-dark (LD) testing in CD-1 mice immediately, 24, 48 and 168 h after the initial odor encounter and/or LD testing. The nucleus accumbens, ventral tegmental area, basolateral (BLA), central (CEA) and medial amygdaloid nuclei, prelimbic and infralimbic cortex were assessed for fos-related antigen (FRA) and/or ENK mRNA as well as neuronal activation of ENK neurons (FRA/ENK). Mice exposed to TMT displayed enhanced freezing and spent less time in the light of the immediate LD test relative to saline- or butyric acid-treated mice. Among mice exposed to TMT, LD anxiety-like behavior was associated with increased FRA in the prelimbic cortex and accumbal shell and decreased ENK-positive neurons in the accumbal core. Mice displaying high TMT-induced LD anxiety exhibited increased ENK-positive neurons in the BLA, CEA and medial amygdaloid nuclei relative to mice that displayed low anxiety-like behavior in the LD test after TMT exposure. In the BLA and CEA, 'high-anxiety' mice also displayed increased FRA/ENK after TMT exposure and LD testing. In contrast to neural cell counts, the level of ENK transcript was decreased in the BLA and CEA of 'high-anxiety' mice after TMT exposure and LD testing. These data suggest that increased FRA may regulate stressor-responsive genes and mediate long-term behavioral changes. Indeed, increased ENK availability in mesolimbic sites may promote behavioral responses that detract from the aversiveness of the stressor experience.