Neural plasticity, neuropeptides and anxiety in animals--implications for understanding and treating affective disorder following traumatic stress in humans.

Exposure of rats to cats (predator stress) lastingly increases rodent anxiety-like behavior (ALB) in the elevated plus-maze. Previous work shows that lasting changes in ALB following predator stress depend on NMDA and CCKB receptors. In this paper we describe the effects of differing degrees of predator exposure on behavior.

Lipopolysaccharide, central in vivo biogenic amine variations, and anhedonia.

Systemic administration of lipopolysaccharide (LPS), a non-specific activator of proinflammatory cytokine release from macrophages, provokes sickness characterized by anorexia, soporific effects, and disturbances of locomotor activity and exploration. In addition, endotoxin treatment may provoke an anhedonic response. Assessment of anhedonia in appetitive paradigms, however, is compromised by the anorexia provoked by the treatment.

Efficacy and tolerability of venlafaxine in the treatment of primary dysthymia.

Objective: Currently, there is no documentation of the efficacy of venlafaxine (a serotonin norepinephrine reuptake inhibitor) in the treatment of dysthymia. This open-label pilot investigation examined the efficacy and tolerability of venlafaxine in patients with primary dysthymia without concomitant major depression.

Methods: Fifteen patients were treated with venlafaxine for 12 weeks, with a dose range of 75 mg to 225 mg daily (taken orally), and symptom changes were measured using standard instruments including the Hamilton Depression Rating Scale (HAM-D).

Stressor-induced corticotropin-releasing hormone, bombesin, ACTH and corticosterone variations in strains of mice differentially responsive to stressors.

The effects of brief stressor exposure on hypothalamic-pituitary-adrenal (HPA) functioning was assessed in two strains of mice shown to be differentially responsive to stressors. Mild stress (1 min of cold swim, 20 C) led to marked elevations of plasma ACTH and corticosterone concentrations in the stress-reactive BALB/cByJ and the stress-resistant C57Bl/6ByJ mice. Moreover, it was observed that the strains differed in basal CRH content within the amygdala and the paraventricullar nucleus (PVN).

Do early-life events permanently alter behavioral and hormonal responses to stressors?

Early-life stimulation (e.g., brief handling) attenuates the behavioral and neuroendocrine responses to stressors encountered in adulthood, particularly with respect to activation of hypothalamic-pituitary-adrenal (HPA) activity.

Influence of interleukin-1beta on exploratory behaviors, plasma ACTH, corticosterone, and central biogenic amines in mice.

Systemic administration of interleukin-1beta (IL-1beta) promoted behavioral changes in an open-field exploratory test. In particular, while the cytokine suppressed locomotor activities, these behaviors were not particularly sensitive to dosage differences. In contrast, dose-dependent biphasic variations that varied over time were evident with respect to the exploration of a novel container.

Circulating lymphocyte subsets in major depression and dysthymia with typical or atypical features.

Objective: Inconsistent results have been reported concerning circulating lymphocyte subsets in depression. To establish whether the immune alterations in depression could be related to neurovegetative symptoms, lymphocyte subsets were assessed in major depressive and dysthymic patients who exhibited either typical or atypical features (ie, the latter characterized by mood reactivity and reversed neurovegetative features).

Method: Blood was collected from major depressive, atypical depressive, typical dysthymic, or atypical dysthymic patients and from nondepressed control subjects.

Aversive and appetitive events evoke the release of corticotropin-releasing hormone and bombesin-like peptides at the central nucleus of the amygdala.

There is wide agreement that corticotropin-releasing hormone (CRH) systems within the brain are activated by stressful stimuli. There is also mounting evidence for the role of bombesin (BN)-like peptides in the mediation of the stress response. To date, however, the extent to which other stimuli increase the activity of these peptidergic systems has received little attention.

An assessment of the effects of central interleukin-1beta, -2, -6, and tumor necrosis factor-alpha administration on some behavioural, neurochemical, endocrine and immune parameters in the rat.

Despite a vast amount of research into the actions of cytokines within the central nervous system, the pharmacological role and/or physiological function of the various cytokines within the central nervous system is still not fully understood. The present study evaluated the effects of intracerebroventricular administration of interleukin-1beta, -2, -6 (20 ng) and tumour necrosis factor-alpha (40 ng) on elevated plus maze behaviour, monoamine levels in the hypothalamus, hippocampus and amygdala, plasma corticosterone and catecholamine concentrations and Concanavalin A-induced splenic lymphocyte proliferation in the rat. Both interleukin-1beta and tumour necrosis factor-alpha induced "anxiogenic-like" effects on the elevated plus maze, whereas interleukin-2 and interleukin-6 did not.

Influence of a psychogenic and a neurogenic stressor on several indices of immune functioning in different strains of mice.

It is demonstrated that cell proliferation in response to mitogens, natural killer cell (NK) activity, and macrophage functioning of mice may be influenced by either a neurogenic stressor (footshock) or a psychogenic stressor (exposing the mouse to a predator, namely a rat). The nature and magnitude of the immune changes, however, varied across three strains of mice (BALB/cByJ, C57BL/6ByJ, and CD-1), differing in reactivity to stressors and also as a function of the type of stressor employed. While footshock reduced mitogen-stimulated B-cell proliferation in BALB/cByJ mice, it had the opposite effect in the CD-1 strain.

Self-stimulation from the mesencephalon following intraventricular interleukin-2 administration.

Intracranial self-stimulation was evaluated among CD-1 mice responding for brain stimulation from the dorsal and ventral aspects of the ventral tegmental area (VTA). Intraventricular interleukin-2 (IL-2) administration (5 ng) in a 1-microl volume elevated the stimulation frequency required to effect half-maximal responding for brain stimulation from the dorsal A10 region 15 min, 24 h, 48 h, and 1 week following drug administration relative to vehicle-treated animals. Intraventricular IL-2 administration did not influence responding for brain stimulation from the ventral A10 area, and performance of these animals was indistinguishable from the performance of vehicle-challenged animals implanted with a stimulating electrode in the ventral A10 area.

Are bombesin-like peptides involved in the mediation of stress response?

The neurochemical mechanisms underlying the coincident activation of the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system in response to stress remain unclear. Central injection of the neuropeptide bombesin (BN) potently stimulates the release of epinephrine from the adrenal medulla, adrenocorticotropic hormone (ACTH) from the pituitary gland, and elicits behaviors typically associated with increased emotionality and arousal. The current studies assessed whether stress is associated with 1) fluctuations in the endogenous regional levels of BN-like peptides and/or 2) changes in BN receptor density.

Differential effects of interleukin (IL)-1beta, IL-2 and IL-6 on responding for rewarding lateral hypothalamic stimulation.

Bacterial endotoxin and interleukin-1 (IL-1) challenge induce a constellation of symptoms associated with illness. While such treatment may result in anhedonia, it is often difficult to dissociate this effect from the anorexia induced by these agents, particularly in paradigms that involve appetitive motivation. The present investigation assessed the effects of several systemically administered cytokines (IL-1beta, IL-2 and IL-6) on reward processes by evaluating responding for rewarding intracranial self-stimulation (ICSS) from the lateral hypothalamus.

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.

Effects of interleukin-1beta and mild stress on alterations of norepinephrine, dopamine and serotonin neurotransmission: a regional microdialysis study.

The effects of systemically administered interleukin-1beta (1.0 microg) on in vivo variations of monoamines was assessed in several brain regions. Administration of the cytokine provoked a modest increase of extracellular 5-HIAA and HVA from the nucleus accumbens, and 5-HIAA from the hippocampus.

Neuroendocrine measures and lymphocyte subsets in depressive illness: influence of a clinical interview concerning life experiences.

The effects of a clinical interview concerning either positive or negative day-to-day events on lymphocyte subpopulations, and on plasma cortisol, ACTH and norepinephrine, were determined in depressive patients (major depressive and dysthymic) and in normal controls. Irrespective of its content, the interview provoked an elevation of circulating natural killer (NK) cells, suggesting that this effect was related to either a change in mood state (regardless of its valence) or to the stress associated with the interview procedure. Since the interview did not influence plasma cortisol, ACTH or norepinephrine, it is likely that the NK cell variations were independent of these endocrines.

Influence of psychogenic and neurogenic stressors on endocrine and immune activity: differential effects in fast and slow seizing rat strains.

Variations of plasma ACTH and corticosterone, as well as splenic macrophage activity and mitogen-induced cell proliferation, were determined in rats following 15 min of either the neurogenic stressor of restraint or by a purely psychogenic stressor consisting of exposure to a ferret. The effects of these stressors were assessed in two strains of rats that were selectively bred for either Fast or Slow kindling epileptogenesis triggered in response to amygdala stimulation. The stressors differentially influenced behavioral responses, endocrine activity, and immune functioning, and these effects varied with the strain of rat.

The effects of early postnatal stimulation on Morris water-maze acquisition in adult mice: genetic and maternal factors.

Following stressor exposure BALB/cByJ mice exhibit hypersecretion of corticosterone and marked brain catecholamine alterations. In addition, mice of this strain exhibit impairments of performance in a Morris water-maze, which may be exacerbated by footshock application. In the present investigation it was demonstrated that early-life handling of mouse pups (coupled with brief separation periods from the dam over the course of 21 days postpartum) reduced the learning impairments seen when mice were tested in the Morris water-maze at 120 days of age and also prevented stress-induced disturbances in this task.

Variations of lymphocyte subsets associated with stress in depressive populations.

Major depression and dysthymia have been associated with increased perception of day-to-day stressors, greater reliance on emotion-focused coping efforts, and reduced perception of uplifting events. Moreover, it has been observed that levels of circulating natural killer (NK) cells were elevated in depressed patients. Given that mild stressors may increase circulating NK cells, it is conceivable that the elevated NK cells in depression may be secondary to the increased stress perception associated with the illness.

Neuroimmune mechanisms in health and disease: 2. Disease.

In the second part of their article on the emerging field of neuroimmunology, the authors present an overview of the role of neuroimmune mechanisms in defence against infectious diseases and in immune disorders. During acute febrile illness, immune-derived cytokines initiate an acute phase response, which is characterized by fever, inactivity, fatigue, anorexia and catabolism. Profound neuroendocrine and metabolic changes take place: acute phase proteins are produced in the liver, bone marrow function and the metabolic activity of leukocytes are greatly increased, and specific immune reactivity is suppressed.

Neuroimmune mechanisms in health and disease: 1. Health.

A novel scientific discipline that examines the complex interdependence of the neural, endocrine and immune systems in health and disease has emerged in recent years. In health, the neuroimmunoregulatory network is fundamental to host defence and to the transfer of immunity to offspring; the network also plays important roles in intestinal physiology and in tissue regeneration, healing and reproduction. The proliferation of lymphocytes in primary lymphoid organs (bone marrow, bursa of Fabricius [in birds] and thymus) and in secondary lymphoid organs (spleen, lymph nodes and mucosal lymphoid tissue) depends on prolactin and growth hormone.

Primary dysthymia: a study of several psychosocial, endocrine and immune correlates.

The relationship between primary dysthymia (chronic, low grade depression) and indices of major and minor life stresses, uplifts and coping styles was examined. Additionally, circulating lymphocyte subsets were assessed in dysthymic patients to determine their relationship to stress/coping factors or plasma levels of cortisol, ACTH or norepinephrine. Primary dysthymia was found to be associated with increased minor stressors (daily hassles), reduced uplifts, as well as particular reliance on emotion-focused rather than problem-oriented coping strategies.

Interleukin-2 decreases accumbal dopamine efflux and responding for rewarding lateral hypothalamic stimulation.

Systemic administration of interleukin-2 (IL-2) provoked marked alterations of responding for rewarding brain stimulation from the medial forebrain bundle (MFB). In particular, when animals were tested for ICSS immediately following IL-2 treatment only a modest disturbance of responding was evident. However, if animals were subsequently exposed to repeated daily ICSS sessions (24-168 h) in the drug-free state, rightward shifts in the rate intensity functions and significant increases in reward thresholds were apparent.

Stressor-induced alterations of the splenic plaque-forming cell response: strain differences and modification by propranolol.

The effects of stressor application on the splenic plaque-forming cell (PFC) response was assessed in two strains of mice: the BALB/cByJ strain, which is highly responsive to stressors; and the more hardy DBA/2J strain. Both strains exhibited a peak PFC response 120 h following administration of sheep red blood cells (SRBC; 5 x 106 cells). Stressor exposure reduced the immune response; however, the appearance of such an outcome was dependent upon the time at which the stressor was applied relative to SRBC inoculation.