Donald T. Lysle

Evidence that shock-induced immune suppression is mediated by adrenal hormones and peripheral β-adrenergic receptors

Our previous work has demonstrated that presentations of mild foot-shock to Lewis rats induces a suppression of splenic and peripheral blood lymphocyte responses to nonspecific T-cell mitogens. The present study demonstrated that adrenalectomy prevented the shock-induced suppression of the mitogenic response of peripheral blood T-cells but did not attenuate the suppression of splenic T-cells. Conversely, the beta-adrenergic receptor antagonists, propranolol and nadolol, attenuated the shock-induced suppression of splenic T-cells in a dose-dependent manner but did not attenuate suppression of the blood mitogen response. These data indicate that distinct mechanisms mediate the shock-induced suppression of T-cell responsiveness to mitogens in the spleen and the peripheral blood. The results indicate that the peripheral release of catecholamines is responsible for splenic immune suppression and that adrenal hormones, which do not interact with beta-adrenergic receptors, are responsible for shock-induced suppression of blood mitogenic responses.

Shock-induced modulation of lymphocyte reactivity: suppression, habituation, and recovery

The present study was designed to evaluate the suppressive effect of different frequencies of signaled-shock presentations on mitogenic reactivity of lymphocytes in Lewis rats, and to assess the recovery of that reactivity at varying times after the shocks. The results showed that the magnitude of decreased reactivity in both the spleen and whole-blood lymphocytes, as determined by mitogenic reactivity to Concanavalin A (Con A), was directly related to the number of shock presentations within a daily session. However, the suppressed reactivity for the spleen cells diminished with repeated sessions of frequent shocks, in contrast to the whole-blood lymphocytes which did not show any habituation. Furthermore, the imposition of different periods of recovery following a single session of frequent shocks showed that the decreased reactivity for the whole-blood lymphocytes extended beyond the immediate period of the shock experience, and took 48 to 96 hours to recover completely. In contrast, the spleen lymphocytes showed complete recovery within 24 hours following the administration of shock. These results establish that the rate of habituation to and recovery from a shock-induced decrease in mitogen reactivity is more rapid for the spleen than whole-blood lymphocytes.

Shock-induced modulation of lymphocyte responsiveness and natural killer activity: Differential mechanisms of induction

The present study was designed to determine the influence of signaled shock on splenic natural killer (NK) activity and nonspecific T-lymphocyte mitogenic responsiveness. Furthermore, experiments were conducted to examine possible mechanisms mediating this suppression. The results demonstrate that a single session of signaled shock induces suppression of splenic NK activity and T-cell response to the mitogens concanavalin A (Con A) and phytohemagglutinin (PHA). However, the suppression of mitogenic responsiveness was attenuated after five daily sessions of shock, while NK activity remained suppressed. The suppression of NK function was prevented by administration of naltrexone prior to the shock session indicating mediation by opiate receptors. However, naltrexone did not prevent the shock induced suppression of mitogenic responsiveness to Con A or PHA. Diazepam was not effective in preventing the shock-induced suppression of mitogenic responses or NK activity. Collectively, these results demonstrate that mononuclear cell populations in the spleen are differentially affected by the same stressor and that the immune alterations are mediated via different pathways.

Pavlovian conditioning of shock-induced supression of lymphocyte reactivity: Acquisition, extinction, and preexposure effects

Recent research has indicated that physical stressors, such as electric shock, can suppress immune function in rats. The present study investigated whether a nonaversive stimulus that had been associated with electric shock would also impair immune function. Presentation of that conditioned stimulus (CS) by itself produced a pronounced suppression of lymphocyte proliferation in response to the nonspecific mitogens, Concanavalin-A (ConA) and Phytohemagglutinin (PHA). In further evidence of a conditioning effect, the suppression was attenuated by extinction and preexposure manipulations that degraded the associative value of the CS. These results indicate that a psychological or learned stressor can suppress immune reactivity independently of the direct effect of physically aversive stimulation or of ancillary changes in dietary and health-related habits.

2-deoxy-D-glucose modulation of T-lymphocyte reactivity: differential effects on lymphoid compartments.

This study was designed to evaluate the effect of glucoprivation, as induced by 2-deoxy-D-glucose (2-DG) administration, on lymphocyte mitogen reactivity in Sprague-Dawley rats. The results showed that a single injection of 2-DG decreased reactivity in both whole-blood and spleen lymphocytes, as determined by mitogenic stimulation to concanavalin A (Con A) and phytohemagglutinin (PHA). However, the suppressed reactivity for the spleen lymphocytes attenuated with repeated injections, but the whole-blood lymphocytes did not show attenuation. Mitogen assessments of lymphocytes obtained from the thymus indicated that a single injection did not induce suppressed reactivity, but repeated injections induced a pronounced suppression of responsiveness. Furthermore, mitogen assessments of mesentery lymph nodes did not show any effect of 2-DG injections. These results corroborate other findings using electric shock as the stressor, namely that different compartments of the immune system are differentially affected by a stressor.

Characterization of immune alterations induced by a conditioned aversive stimulus

In this study, we investigated the immune alterations induced in rats by an aversive conditioned stimulus that had been developed through pairings with electric shock. The results showed that the conditioned stimulus induced a pronounced suppression of the mitogenic responsiveness of splenic and blood lymphocytes and a reduction in splenic natural killer cell activity. In contrast, the conditioned stimulus did not induce any alteration in the mitogenic responsiveness of lymphocytes from the mesenteric lymph nodes. The reduction in the mitogenic responsiveness of splenic lymphocytes was not related to a reduction in the level of interleukin-2 (IL-2) production, as splenic lymphocytes from subjects exposed to the conditioned stimulus showed normal levels of IL-2. Plasma corticosterone measurements showed that glucocorticoid secretion was related to the alteration of the mitogenic responsiveness of blood lymphocytes. However, plasma corticosterone levels were not related to any of the other immune measures. These findings establish that a signal for an aversive event can have a pronounced effect on immune function, but that such an effect is dependent on the particular compartment of the immune system studied. These results support the claim that glucocorticoids can induce immune alterations, but they suggest that additional pathways must be involved in the immune alterations induced by a conditioned aversive stimulus.

Stress and Enhanced Dopamine Utilization in the Frontal Cortex: The Myth and the Reality

Fashions are seen in science as they are in other arenas of society. Some findings, as certain areas of research, are “in” and others are not. Unfortunately, those results that fit in with the zeitgeist are often subject to less scrutiny than they might otherwise be and perhaps than they ought to be. One such example relates to the currently fashionable and widespread belief that mild stress causes a “selective activation of the mesocortical dopaminergic system.”’ There is no question that there have been a number of reports suggesting an increase in dopamine (DA) utilization in the frontal cortical terminal region of the mescortical DA pathway following several different stressors.l-lo However, questions can and should be raised regarding the issues of (1) whether this is true of all stressors, (2) whether the stressors employed to induce this effect can truly be considered “mild,” and (3) whether the effects of stressors are selective for the mesocortical DA system. Interest in some of these issues began as a result of experiments designed to determine whether prior exposure to a benzodiazepine (BZD) could sensitize the response to a subsequent encounter with the same agent. Our initial finding was that the ability of diazepam (0.5 mg/kg, ip) to antagonize convulsions induced by pentylenetetrazole (PTZ) was significantly enhanced when the same dose of this BZD had been administered once, weeks earlier.I1 We next inquired whether the demonstrated antistress effects of diazepam on DA metabolism in the nucleus accumben~~ and frontal and would show similar evidence of sensitization over tirne.l3 Since PTZ produces stresslike effects, including anxiogenic actions in rats”

Immobilization 12 days (but not one hour) earlier enhanced 2-deoxy-d-glucose-induced immunosuppression: Evidence for stressorinduced time-dependent sensitization of the immune system

1. Prior exposure to a stressor can either increase or decrease subsequent behavioral, neurochemical, and endocrine reactivity to stress, depending on the pattern of stress exposure. 2. Massed or frequent exposures typically induce a reduction in reactivity whereas intermittent or widely spaced exposures increase subsequent reactivity. 3. In the present study, the authors examined whether a single presentation of a temporally remote stressor would increase the immunosuppressive effects of a subsequent stressor. Specifically, the authors investigated the effectiveness of 2-deoxy-D-glucose (2-DG) in suppressing the responsiveness of splenic lymphocytes in male, Sprague-Dawley rats that received either no prior treatment, or immobilization either one hour or 12 days earlier. 4. Splenic lymphocyte responsiveness to the T-cell mitogens, Concanavalin A (Con-A) and phytohemagglutinin (PHA) was suppressed following a single injection of 2-DG. 5. The group exposed to the stress of immobilization one hour prior to 2-DG demonstrated a comparable level of immune suppression. 6. In contrast, animals immobilized 12 days prior to the administration of 2-DG showed a more pronounced suppression of immune responsiveness which was significantly greater than the other groups injected with 2-DG. 7. Neither the stress-induced elevation in corticosterone, nor the suppression of blood lymphocyte reactivity to Con-A and PHA was enhanced by prior immobilization. 8. The results indicate that the immunosuppressive effects of an acute stressor can sensitize with the passage of time.

Stressor-induced changes in mitogenic activity are not associated with decreased interleukin 2 production or changes in lymphocyte subsets

Splenic lymphocytes from Lewis rats that received presentations of physically aversive electric shock demonstrated a marked reduction in responsiveness to T-cell mitogens such as concanavalin A. This study examined cellular mechanisms which may be responsible for this functional alteration. There was no difference in distribution of T-cell subsets from shocked and nonshocked rats. There was no difference in the production of interleukin 2 (IL-2) nor was there a difference in the percentage of IL-2 receptor positive T cells or T-cell subsets after culture for 24 hr. However, there was a marked lack of mitogenic stimulation in splenocytes from shocked rats when stimulated with the calcium ionophore A23187. This indicates a defect in the biochemical pathways necessary to activate T-cell mitogenesis.

Changes in pain reactivity induced by unconditioned and conditioned excitatory and inhibitory stimuli.

In three experiments we investigated the effects of aversive-conditioning components on the reactivity of rats to pain. After training in Experiment 1 with a discrete conditioned stimulus (CS) for a shock unconditioned stimulus (US), different groups were exposed to the CS, US, CS/Us compound, just the training context, or none of those immediately prior to a hot-plate test assessing the latency of a paw-lick response. Relative to no exposure and context alone, the CS produced a shorter latency--that is, an apparent sensitization effect--whereas the US produced a longer latency--that is, a hypoalgesic effect--that was actually augmented by the CS/US compound. Furthermore, whereas the US-induced hypoalgesia was unaffected by the opiate antagonist, naloxone, hypoalgesia produced by the CS/US compound was appreciably decremented by the drug. Experiment 2 showed the same effects with parameters more typical of conditioning research. Experiment 3 compared signals for the presence (CS+) and absence (CS-) of the US. The CS- did not itself affect pain reactivity, but in inhibited the effects of the CS+, US, and CS+/US compound. Collectively, the results suggest that a CS+sensitizes the animal to imminent events and also potentiates an opioid reaction that supplants the less effective nonopioid hypoalgesia induced by the US. In contrast, a CS- functions as a general moderator of excitation, inhibiting both sensitization and hypoalgesic effects, whether opioid or nonopioid.