Robert M. Zacharko

Depression: The predisposing influence of stress

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 organisms 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.

Multiple neurochemical and behavioral consequences of stressors: Implications for depression

Animal models of clinical depression have frequently focused on the contribution of stressors to the induction of behavioral impairments and pharmacological intervention in the amelioration of these disturbances. Stressors provoke various behavioral disturbances and influence the activity of central neurotransmitters implicated in depression. It is our contention that those variables which favor the provocation of amine depletions or prevent the development of a neurochemical adaptation will increase vulnerability to behavioral disturbances. It is essential to consider, however, that marked interindividual and interstrain differences exist in the behavioral and neurochemical response to stressors, and in the effectiveness of antidepressant treatments.

Region-specific reductions of intracranial self-stimulation after uncontrollable stress: Possible effects on reward processes

Rates of responding for intracranial self-stimulation from the medial forebrain bundle, nucleus accumbens and substantia nigra were evaluated in mice that had been exposed to either escapable shock, yoked inescapable shock or no shock treatment. Whereas performance was unaffected by escapable shock, marked reductions of responding from the medial forebrain bundle and nucleus accumbens were evident following the uncontrollable shock treatment. Responding from the substantia nigra was unaffected by the stress treatment. Uncontrollable shock is thought to reduce the rewarding value of responding for electrical brain stimulation from those brain regions in which stressors are known to influence dopamine activity.

Synergistic effects of interleukin-1β, interleukin-6, and tumor necrosis factor-α : Central monoamine, corticosterone, and behavioral variations

The proinflammatory cytokines interleukin-1β (IL-1β), IL-6, and tumor necrosis factor-alpha (TNF-α) influence neuroendocrine activity, promote central neurotransmitter alterations, and induce a constellation of symptoms collectively referred to as sickness behaviors. These cytokines may also elicit anxiety and anhedonia, and have been associated with psychological disturbances in humans. In the present investigation, systemic IL-1β and TNF-α dose-dependently and synergistically disrupted consumption of a highly palatable food source (chocolate milk), possibly reflecting anorexia or anhedonia engendered by the treatments. As well, these cytokines synergistically increased plasma corticosterone levels. Although IL-1β and TNF-α provoked variations of amine turnover in the hypothalamus, locus coeruleus, and central amygdala, synergistic effects were not evident in this respect. Nevertheless, in view of the central amine variations induced by the cytokines, it is suggested that immune activation may come to influence complex behavioral processes, as well as affective state.

Mouse strain differences in plasma corticosterone following uncontrollable footshock

Exposure to acute inescapable footshock provoked marked increases of plasma corticosterone concentrations in six strains of mice (A/J, Balb/cByJ, C57BL/6J, C3H/HeJ, DBA/2J and CD-1). However, the magnitude of the increase, as well as the time required for corticosterone to return to control values, varied appreciably across strains. Moreover, it appeared that the strain-specific corticoid increases ordinarily observed after acute shock were also evidence following a chronic stressor regimen. The data were related to previously observed strain differences in stressor-induced alterations of brain norepinephrine, dopamine and serotonin, as well as variations in performance in several behavioral paradigms.

Stressor-induced anhedonia in the mesocorticolimbic system

It has been suggested that uncontrollable stressors induce motivational changes in animals which are reminiscent of reward alteration in human depression. Although there is considerable support for this position, most animal models of depression do not adequately address this issue. The present review suggests that stressor-induced reductions in the rewarding value of electrical brain stimulation (ICSS) from the mesocorticolimbic system may simulate the anhedonia of human depression. The magnitude, severity and the site of these stressor-induced reward alterations within the mesocorticolimbic system vary with the strain of animal employed. The anhedonic effects of stressors are attenuated by treatments which influence mesocorticolimbic DA turnover, including systemic antidepressant and intraventricular neuropeptide administration. Although the diverse symptom profile of depression should be addressed by consideration of the constellation of behavioral disturbances induced by stressors, considerable emphasis should be devoted to an assessment of reward loss in depression. The implications of these data to the stressor depression topography and the potential role of mesocorticolimbic DA in depression and anhedonia are discussed.

Brief exposure to predator odor and resultant anxiety enhances mesocorticolimbic activity and enkephalin expression in CD-1 mice

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.

Alterations of central norepinephrine, dopamine and serotonin in several strains of mice following acute stressor exposure

Exposure to inescapable footshock provoked region-specific alterations of norepinephrine (NE), dopamine (DA) and serotonin (5-HT) activity across six strains of mice (A/J, BALB/cByJ, C3H/HeJ, C57BL/6J, DBA/2J and CD-1). The stressor provoked reductions of hypothalamic NE and increased MHPG accumulation in all strains. In contrast, the effects of the stressor on NE activity in the hippocampus and locus coeruleus varied appreciably across strains. In the mesocortex and nucleus accumbens shock induced an increase of DOPAC accumulation and pronounced reductions of DA in some strains, while in others these variations were less pronounced or entirely absent. Stressor-provoked alterations of 5-HT and 5-HIAA were most evident in the mesocortex. Strain-specific neurochemical alterations following footshock are discussed relative to stressor-induced behavioral disturbances and animal models of depression.

Strain-specific effects of inescapable shock on intracranial self-stimulation from the nucleus accumbens

Responding for electrical stimulation from the nucleus accumbens was assessed in 3 inbred strains of mice (DBA/2J, C57BL/6J and BALB/cByJ) following exposure to uncontrollable footshock. While the operant response was most readily acquired in the DBA/2J strain, exposure to inescapable shock in this strain induced a marked deterioration of self-stimulation responding, which tended to dissipate over a 168-h period. In contrast to these mice, the stressor did not affect self-stimulation responding in the C57BL/6J strain, and produced a transient enhancement of responding in BALB/cByJ mice. It appears that although uncontrollable aversive events may engender an anhedonic effect, such an outcome is strain-dependent. These data suggest the importance of considering individual and genetic differences in the development of animal models of depression.

The Impact of Stressors on Immune and Central Neurotransmitter Activity: Bidirectional Communication

Antigenic challenge may have broad ranging effects which include not only immunological changes, but also endocrine and central neurotransmitter repercussions, and may thus elicit profound behavioral sequelae. Commensurate with the notion that bidirectional communication exists between the immune and central nervous systems it has been demonstrated that manipulations which influence central neurotransmitter or endocrine activity provoke alterations of immune functioning, and conversely immunological alterations will affect central neurotransmitter and endocrine activity. It seems, as well, that environmental stressors may provoke marked alterations of the activity of each of these systems. Indeed, in several respects the variables that influence vulnerability to stressor-provoked neurotransmitter changes, likewise affect the immunological alterations engendered by stressors. Moreover, immunological challenges will affect central neurotransmitter functioning in much the same way as stressors provoke such effects. It is thought that immune derived products (including cytokines as well as peptide hormones) may act directly or indirectly to moderate neurotransmitter functioning, and centrally derived neurotransmitters and hormones may affect receptors present on lymphocytes. In accordance with earlier suggestions, it is maintained that the immune system may be acting as a sensory organ informing the brain of the presence of antigenic challenges, and the brain may interpret such challenge as a stressor, hence leading to behavioral alterations.