Somatic effects of predictable and unpredictable shock.
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Biomedical subjects
J M Weiss
Publications and source records attributed to J M Weiss.
Effects of acute exposure to stressors on subsequent avoidance-escape behavior.
This paper attempts to show that severely stressful conditions can lead to a deficit in avoidance-escape responding by reducing noradrenergic activity in the brain. It is argued that this stress-induced neurochemical change explains more adequately an avoidance-excape deficit seen previously in dogs after severe inescapable shock than does the "learned helplessness" explanation originally offered for this effect. A series of six experiments are described that test the stress-neurochemical change explanation, which is called the "motor activation deficit" hypothesis. The first experiment showed that a brief exposure to cold swim, which reduced central noradrenergic activity but did not induce "learned helplessness," produced an avoidance-escape deficit similar to that observed after inescapable shock in the original "learned helplessness" studies. Subsequent experiments demonstrated that the deficit induced by cold swim was also similar to the original deficit in that it too dissipated with the passage of time and was reduced by pretraining animals in the correct response. Further experiments then showed that the deficit induced by cold swim was (a) aggravated by raising the height of the barrier between compartments in the shuttle box, and (b) did not occur if the avoidance-escape task used required little motor activity, both of the findings being predicted by the "motor activation deficit" hypothesis. Finally, an avoidance-escape deficit was produced by inescapable shock, and it was found that this stressor likewise did not impair avoidance-escape responding if the task required little skeletal activity, a result not predicted by the "learned helplessness" hypothesis. The paper concludes by discussing how the results presented in this paper, as well as in succeeding papers, support the "motor activation deficit" explanation for certain avoidance-escape deficits, defining the cases to which the explanation applies and discussing the neurotransmitters involved.
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Effects of chronic exposure to stressors on avoidance-escape behavior and on brain norepinephrine.
A single exposure to a severe stressor (either cold swim or inescapable shock) impairs subsequent performance in a shuttle avoidance-escape task (1), a deficit attributed to reduction in brain noradrenergic activity produced by these stressors. In the present paper, two experiments are described which examine how repeated exposure to such stressors affects (a) shuttle avoidance-escape performance (Experiment 1), and (b) aspects of brain norepinephrine metabolism (Experiment 2). Experiment 1 showed that, whereas subjects receiving the single exposure to cold swim or shock showed a large avoidance-escape deficit, subjects that received repeated exposure to these stressors for 14 days performed similarly to the control group that received no stressor. Experiment 2 showed that, whereas subjects that received one session of the inescapable shock stressor showed a lower level of norepinephrine in hypothalamus and cortex than did subjects that received no shock, subjects that received repeated exposure to inescapable shock or cold swim showed neurochemical "habituation." Subjects that received repeated shock showed elevated tyrosine hydroxylase activity and no depletion of norepinephrine level, and both repeated shock and cold swim caused a decrease in uptake of 3H-norepinephrine by slices of cortex in vitro. Thus, it is concluded that the behavioral and neurochemical changes that were observed after the stressful conditions studied are consistent with the hypothesis that changes in avoidance-escape responding following exposure to these stressful events are due to changes in brain noradrenergic activity.
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Monamines as mediators of avoidance-escape behavior.
A series of three experiments were carried out to test the hypothesis ("motor activation deficit" hypothesis) that the avoidance-escape deficits observed following certain highly stressful conditions result from changes in activity of noradrenergic (or other monominergic) neural systems. These studies indicate that: (1) Depletion of monamines by a single injection of tetrabenazine produces an active avoidance-escape deficit when the avoidance-escape response involves a relatively high degree of motor activity but not when a minimum of motor activity is required. This parallels results found when animals are acutely exposed to a stressor prior to avoidance-escape testing. (2) Daily injections of tetrabenazine for a period of two weeks, like daily exposure to inescapable shock for the same period of time, markedly attenuates the magnitude of the avoidance-escape deficit produced by either a single injection of tetrabenazine or single session of inescapable shock. (3) Decreasing the stress-induced depletion of monamines by the use of an MAO inhibitor serves to protect the animals from the effects of inescapable shock, markedly reducing the avoidance-escape deficit produced by such shock. It is concluded that these results are consistent with the motor activation deficit hypothesis.
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Physiologic doses of urocanic acid do not alter the allostimulatory function or the development of murine dendritic cells in vitro.
Exposure to UVB results in the isomerization of trans-urocanic acid (UCA), localized in the stratum corneum, to cis-UCA. Cis-UCA can mediate at least some of the immunosuppressive effects of UVB, though the mechanism of cis-UCA action remains incompletely defined. Alterations in Langerhans cells, and other dendritic antigen presenting cell populations in the skin, may contribute to the loss of skin immune function following UVB exposure. Hence, this study was designed to investigate whether cis-UCA directly can induce changes in the immunostimulatory capacity of dendritic cells (DC) and the development of DC from precursor cells. Murine DC were generated from C57BL/6 bone marrow (BM) using granulocyte-macrophage colony-stimulating factor (GM-CSF), and were used as stimulator cells in mixed lymphocyte reactions (MLR) using BALB/c lymph node cells (LNC) as responders. The addition of cis- and trans-UCA at concentrations ranging from 0.1-500 micrograms/ml to the MLR did not affect proliferative responses. Cis- or trans-UCA (100 micrograms/ml) was added to GM-CSF stimulated mouse BM cells on day 0, day 3 or day 5 of culture, and the phenotype and allo-stimulatory function of the DC were analysed on day 7. Treatment with cis- or trans-UCA did not affect the numbers or the viability of cells in the BM cultures. In addition, the expression on DC of Iab, CD11c or the costimulatory molecules ICAM-1, B7-1, B7-2 and CD40 was not altered by the addition of cis-UCA to BM cultures. The inability of cis-UCA to alter the development of DC in vitro was confirmed by analysing the functional capacity of DC in MLR. DC generated in the presence of cis-UCA were equally efficient in the induction of allo-stimulation, when compared with control DC. These results suggest that cis-UCA does not exert its immunosuppressive activity through direct effects on DC. Such activity may be independent of DC, or alternatively, cis-UCA may influence DC function indirectly, through the induction of secondary mediators.
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Detection of interleukin-1 bioactivity in various brain regions of normal healthy rats.
Although interleukin-1 (IL-1) has been implicated in an array of brain functions, past studies usually have failed to detect IL-1 bioactivity in the brain of normal healthy animals. However, in view of the potency of IL-1 in brain, small amounts of this cytokine may normally act in brain, and such quantities can escape detection by assay methods usually employed. Although bioassays are highly sensitive for detecting IL-1, these can be compromised by molecules in brain tissue other than IL-1, and attempts to purify IL-1 from brain tissue can result in significant loss of IL-1 from samples. In this study, we have refined our method of assessing brain IL-1 bioactivity by first semi-isolating IL-1 with a Sephadex minicolumn and then measuring IL-1 activity with a sensitive D10 cell assay. To confirm that our assay was specific for IL-1, a monoclonal antibody against IL-1 receptor was used to block any observed IL-1 activity. We report here that IL-1 bioactivity can be reliably detected in both the cell-free supernatant and cell lysate of brainstem, cortex, diencephalon, and hippocampus of normal rat brain. These results lend support to some recent studies that found IL-1 may play important roles in the functions of normal brain.
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In vivo induction of interleukin-1 bioactivity in brain tissue after intracerebral infusion of native gp 120 and gp 160.
We have previously reported that intracerebral infusion of recombinant human immunodeficiency virus envelope protein gp 120 induced interleukin-1 (IL-1) bioactivity in rat brain. In this study, we tested the ability of native gp 120 and gp 160 to induce IL-1 activity in rat brain and also examined whether altering the secondary and tertiary structures of these proteins by carboxymethylation could influence the IL-1-inducing effect of these peptides. Results showed that both native gp 120 and gp 160 can induce IL-1 activity in rat brain in vivo, and that intact secondary and tertiary structures of these proteins appear critical for this effect.
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