Escapable Shock Research Articles

Can Mind Affect Body Defenses Against Disease? Nascent Specialty Offers a Host of Tantalizing Clues

PSYCHONEUROIMMUNOLOGY, the synthesis of data from psychiatry and immunology, provides an interesting perspective on human illness. Investigators hope that it also may uncover clues to the pathogenesis of acquired immunodeficiency syndrome (AIDS). "This field of behavioral immunology is one of the most exciting developments in recent years and promises to yield great insight into the relationships between psychological factors... and the disease process," says Steven F. Maier, PhD, professor and chair of experimental psychology at the University of Colorado, Boulder. Maier and coworkers have performed animal experiments that suggest a link between stress and immune function and indicate the importance of the subject's sense of control in a stressful situation. In one experiment, three groups of laboratory rats were given a series of inescapable electric shocks, escapable shocks, or no shocks, respectively (<i>Science</i>1983;221:568-570). Lymphocyte proliferation, in response to phytohemagglutinin and concanavalin A (in vitro stimuli), was then measured. Those

Scopolamine disrupts leverpress shock escape learning in rats.

Five groups of rats were tested on a discrete-trial leverpress shock escape task 30 min following an intraperitoneal injection of either 0 (saline), 0.2, 1.0, or 5.0 mg/kg scopolamine hydrobromide, or 5.0 mg/kg methylscopolamine hydrobromide. The results indicated that scopolamine, but not methylscopolamine, disrupted escape performance and this disruption was dose-related. These findings are consistent with both disinhibition and reduced freezing explanations of anticholinergic effects and support the view that reduced acetylcholine is involved in the behavioral effects of septal lesions.

Interaction of Pavlovian conditioning with a zero operant contingency: Chronic exposure to signaled inescapable shock maintains learned helplessness effects.

In four experiments we used triads, consisting of escapable-shock (ES), yoked inescapable-shock (IS), and no-shock (NS) rats, to investigate the effect of the interaction between Pavlovian contingencies and a zero operant contingency (i.e., uncontrollability) upon subsequent shock-escape acquisition in the shuttle box. After exposure to 50 signals and shocks per session for nine sessions, interference with shuttle box escape acquisition for IS rats was a monotonically increasing function of the percentage of signal-shock pairings during training (Experiment 1), with 50% pairings producing little or no impairment. Without regard to signaling, ES rats performed as well as NS rats. Experiment 2 demonstrated that our training and test conditions led to substantial and equal impairment in IS rats preexposed for one session to 100% or 50% signal-shock pairings or to unsignaled shocks. In Experiment 3, chronic exposure to 100% signaled inescapable shocks resulted in impairment only if the signal (light) was present during the shuttle box test. The continuous presence of the signal during the test contrasted with its discrete (5-s) presentation during training and suggested that an antagonistic physiological reaction rather than a specific competing motor response had been conditioned. Experiment 4 provided evidence for possible conditioned opioid mediation by demonstrating contemporaneous stress-induced analgesia and shock-escape impairment in IS rats chronically exposed to 100%, but not to 50%, signal-shock pairings, and the elimination of both analgesia and escape interference by the opiate antagonist naltrexone. Thus, chronic exposure to uncontrollable shocks appears to maintain the impairment produced by acute exposure only if the shocks are adequately signaled.

Stressor controllability and the pituitary-adrenal system.

Stressor controllability can alter both behavior and pituitary-adrenal activity. Potential mediation of these behavioral effects by differential pituitary-adrenal output requires that the precise conditions that lead to differential behavioral consequences also produce differential pituitary-adrenal activity. Both plasma ACTH and corticosterone levels were measured at various times following escapable and yoked inescapable electric shock conditions known to produce differential behavioral outcomes. The escapable and inescapable shock procedures did not produce a detectable differential effect. Both shock conditions produced equivalent elevation of ACTH and corticosterone. Neither decay rates nor the ACTH and corticosterone response to shock reexposure differed among shocked groups.

Safety signals can mimic responses in reducing the ulcerogenic effects of prior shock

The severity of restraint-induced gastric ulcerations in rats may be influenced by proactive effects of earlier shock experience. Earlier experience with escapable shock offers some protection against the ulcerogenic effects of restraint stress. In this experiment, we tested the hypothesis that providing animals with safety signals during a Pavlovian conditioning session would also provide a proactive protection against restraint ulceration similar to that provided by escape responses. Animals were subjected to five daily sessions of 20 shocks before they were subjected to a single 23-h restraint stress procedure. The animals given safety signals during the conditioning sessions developed less ulceration than those subjected to random tone-shock pairings and those that were not shocked. This complements other reports of the similar properties shared by escape conditioning and safety-signal (backward) conditioning. In contrast, postrestraint corticosterone levels were higher in animals provided earlier with safety signals than they were in other groups.

Coping and seizure susceptibility: Control over shock protects against bicuculline-induced seizures

Rats were either given 80 escapable shocks, yoked inescapable shocks, restraint or given no treatment. Two hours later all subjects received i.p. injection of bicuculline (4, 6 or 8 mg/kg) and were immediately tested for latency to initial myoclonic jerk and clonus. The latency to clonic convulsion was dramatically affected by prior shock treatment, and the direction of this change depended upon the escapability/inescapability of the shock. Subjects that were given escapable shock a delay of onset to seizure, while subjects inescapably shocked demonstrated a decreased latency to clonus in comparison to restrained and naive controls. It was also demonstrated that if the subjects were tested immediately following a stress experience, both the 80 escapable and inescapable shock condition protected against bicuculline-induced seizures in comparison to the control condition. Finally Experiment 2 confirmed a previous finding that less stress, i.e., 20 inescapable shocks, protects against seizures when the animals are challenged with bicuculline either immediately or 2 h later. Our suggestion is that control over stress may facilitate GABAergic transmission, and this may be the mechanism whereby coping protects against the behavioral and physiological disruption produced by exposure to a stressor.

Stimulus perseveration in a water maze following exposure to controllable and uncontrollable shock

When placed in a water-filled maze, mice display a pronounced preference for the illuminated over the nonilluminated arm of the maze. Exposure to inescapable shock increased the time spent in the illuminated arm of the maze, and decreased the frequency of entries into the nonilluminated arm. When animals that had received shock entered the nonilluminated arm they exhibited more activity per second than nonstressed animals. Controllability over the stressor enhanced the preference for the illuminated arm; however, the contribution of this variable was dependent on the number of shock trials mice received. Following 180 escapable or inescapable shock presentations the preference for the illuminated arm was enhanced. The propensity to approach the illuminated arm declined following a greater number (360) of escapable shock trials, while the preference for the illuminated arm did not decline in mice that received inescapable shock. Both escapable and inescapable shock were also found to produce a transient disruption of discrimination performance in a task where animals were required to emit a contraprepared response (swim to dark), whereas these treatments were without effect on performance of the highly prepared response of approaching the illuminated arm. It is provisionally suggested that enhancement of the perseveration represents an innate response to stressful stimuli, but as animals learn mastery over the response contingencies, the persistence in adopting such a response strategy wanes. Moreover, despite the differential effects of escapable and inescapable shock on the perseverative tendency, discrimination accuracy may not be differentially affected by these treatments in a task where acquisition progresses quickly and where explicit cues are associated with the correct and incorrect arms of the maze.

Shock controllability and the nature of stress-induced analgesia.

Three experiments were conducted to examine the impact of the escapability of shock on the nature of the analgesia produced by shock. In Experiment 1, rats were exposed to 0, 20, 40, or 80 escapable or yoked inescapable shocks. Tail-flick testing revealed a "double-peak" pattern in which analgesia was present after 20 and 80 shocks. This was true for both escapable and inescapable shock. Analgesia after 20 escapable or inescapable shocks was insensitive to naltrexone, as was the analgesia after 80 escapable shocks. However, the analgesia after 80 inescapable shocks was completely blocked by naltrexone. Moreover, in Experiment 2 the analgesia following 80 inescapable shocks persisted for at least 2 hr, whereas it dissipated rapidly following 80 escapable shocks. Further, the analgesia produced by escapable shock even dissipated with the continued occurrence of escapable shock. Finally, shock controllability was shown to alter the analgesia produced by subsequent exposure to shock. Prior experience with controllable shock completely blocked the late-appearing naltrexone reversible analgesia; prior experience with uncontrollable shock led it to appear sooner.

Shock controllability and opioid substrates of escape performance and nociception: differential effects of peripherally and centrally acting naltrexone.

Rats exposed to inescapable shock exhibited analgesia and a significant impairment of shock-escape learning in a shuttle box situation 24 hr later. In contrast, rats exposed to escapable shock or to no shock displayed neither effect. Naltrexone (10 mg/kg) significantly reduced the analgesia and completely eliminated the escape deficit in inescapably shocked rats but induced hyperalgesia, coupled with a marked deterioration of escape performance, in escapably shocked and nonshocked rats. The same dose of quaternary naltrexone, which has low ability to cross the blood-brain barrier, had no effect on either the antinociception or the escape deficit produced by inescapable shock, although it also induced escape impairment and hyperalgesia in rats preexposed to escapable shock or to no shock. A second experiment demonstrated that both the escape interference and the antinociceptive consequences of prior inescapable shock could be reduced partially by a much lower dose (1 mg/kg) of naltrexone but 50 times this amount of quaternary naltrexone was still without effect. These results imply that the consequences of exposure to inescapable shock are mediated by activation of central opioid processes whereas naltrexone-induced effects in escapably shocked and nonshocked animals may be peripherally mediated. The relevance of these findings to the possible role of nociception in escape performance is discussed.

Feedback during exposure to inescapable shocks and subsequent shock-escape performance

In two experiments, we assessed the ability of a feedback stimulus during helplessness training to reduce the performance deficits common to inescapable shock. In each experiment, four groups of rats were exposed to either escapable shock (E), inescapable shock with a feedback stimulus following shock termination (Y-FS), inescapable shock with no feedback stimulus (Y-NFS), or no shock (N). The feedback stimulus eliminated the interference effects of inescapable shock when tested with an FR-3 lever press escape task (Experiment 1) or on an FR-1 task with a 3-s delay between the response and shock termination (Experiment 2). These results suggest that stress-induced biochemical changes may mediate the interference effects seen in inescapably shocked rats.

Influence of postpartum shock controllability on subsequent maternal behavior in rats

Responses of mother rats were observed 24 h before and 24 and 72 h after exposure to one of three 8-day postpartum treatments: shock escape training, yoked inescapable shock, or restrained with no shock. In contrast to those in the other two groups, the dams given inescapable shock showed slower speed to approach the nest, shorter durations of being on the nest, and lower frequency and shorter total duration of oral contact with their pups. These dams also retrieved their pups less frequently, but this measure, as well as the frequency of leaving the nest, did not result in significant differences between groups. Since the traditional interpretations of the learned-helplessness effect were not entirely able to account for these findings, the observed uncontrollable-stress-produced changes in maternal behavior were examined from an ethological perspective.

Responding for brain stimulation: Stress and desmethylimipramine

1. Stressors influence the activity of biogenic amines and provoke a variety of behavioral disturbances which have been considered as models of human depression. 2. To evaluate the effects of Stressors on reward processes, responding for electrical brain stimulation was assessed after acute or chronic shock, and the modification of performance by desmethylimipramine was determined. 3. While escapable shock did not affect performance, inescapable shock reduced responding from the nucleus accumbens and medial forebrain bundle, but not from the substantia nigra. These deficits were were antagonized by repeated Stressor application or by desmethylimipramine. 4. Uncontrollable Stressors may influence motivational processes subserved by some brain regions, and may thus influence affective state. Chronic stress or desmethylimipramine may Induce adaptive neurochemical changes, thereby preventing the behavioral disturbances otherwise produced by Stressors.

Fear conditioned with escapable and inescapable shock: Effects of a feedback stimulus.

Fear conditioned with escapable and inescapable shock: Effects of a feedback stimulus.

Exposure to uncontrollable stress alters withdrawal from morphine.

Prior exposure to uncontrollable stress potentiates morphine analgesia. This study was designed to examine the influence of the controllability/uncontrollability of shock as a stressor on the severity of subsequent morphine withdrawal. In Experiment 1, rats that received two daily sessions of 80 yoked-inescapable shocks, in contrast to those given 80 escapable shocks or restrained without shock, showed an enhanced series of correlated withdrawal behaviors (i.e., mouthing, teeth chattering, and head/body shakes) 24 hr later when injected with morphine (5 mg/kg) followed by a naloxone (5 mg/kg) challenge. In Experiment 2, this finding was replicated with escape-yoked-restrained groups of rats given saline injections during the pretreatment phase, but the impact that only inescapable shock had on later precipitated withdrawal was completely blocked when subjects were administered naltrexone (14 mg/kg) before each shock session. These findings are discussed in terms of the capability of inescapable shock to activate an endogenous opiate system(s) and thereby lead to a sensitization of release or receptor processes which could potentiate later morphine withdrawal.

Coping and immunosuppression: inescapable but not escapable shock suppresses lymphocyte proliferation.

Rats were given series of escapable shocks, identical inescapable shocks, or no shock. The subjects were reexposed to a small amount of shock 24 hours later, after which an in vitro measure of the cellular immune response was examined. Lymphocyte proliferation in response to the mitogens phytohemagglutinin and concanavalin A was suppressed in the inescapable shock group but not in the escapable shock group. This suggests that the controllability of stressors is critical in modulating immune functioning.

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.

The reversal effect of antidepressants on the escape deficit induced by inescapable shock in rats.

This experiment investigated the effect of antidepressants on the escape deficit induced by inescapable shock. Following exposure to escapable shock, rats received a single injection of either tricyclic antidepressants (imipramine, desipramine), an atypical antidepressant (nomifensine), or saline. In a subsequent two-way shuttle test, treatments with these antidepressants reversed the escape deficit of the "inescapable-shock" groups without affecting performance of the "escapable-shock" groups. It is suggested that catecholamine re-uptake inhibition of the acute actions of antidepressants contributed to this reversal effect. The findings are discussed in relation to the neurochemical hypothesis of the escape deficit induced by inescapable shock and to an animal model of depression.

Immunization of opioid analgesia: Effects of prior escapable shock on subsequent shock-induced and morphine-induced antinociception

In Experiment 1, it was shown that experience with escapable foot shock 4 hr prior to a session of 80 inescapable tail shocks prevented the occurrence of an analgesic response normally observed immediately following the tail shock. It has been suggested by J. W. Grau, R. L. Hyson, S. F. Maier, J. Madden, and J. D. Barchas ( Science, 1981 , 213, 1409–1411) that the analgesia that occurs following this number of inescapable tail shocks is mediated by endogenous opioid systems. To further explore the influence of escapable shock on opiate-mediated analgesia, Experiment 2 examined the effects of prior escapable shock on the long-term analgesia reaction that occurs upon brief exposure to shock 20 hr after morphine administration. Rats were given escapable shock, inescapable shock, or no shock 4 hr prior to a morphine injection. Twenty hours following the injection, all subjects received 5 brief foot shocks and were then immediately given tail-flick analgesia tests. Subjects which received inescapable shock or no shock prior to the morphine injection displayed a significant analgesic response. However, subjects which received escapable shock prior to morphine were not analgesic following brief exposure to shock. Thus, escapable shock seems to directly influence the activation of opioid analgesia systems.

Learned mastery in the rat

In a series of five experiments, we investigated the bidirectional effects of prior experience with both control or lack of control over shock on subsequent shock-motivated activity and escape learning. Rats were tested with inescapable shock rather than escapable shock as is used in typical helplessness experiments. Naive rats initially shuttled frequently during shock but decreased activity as testing continued. Pretraining with inescapable shock reduced shuttle responding throughout testing. Unexpectedly, rats which first learned to lever press to escape shock continued unabated shuttling through 200 trials of 10-sec duration inescapable shocks (Experiment 1). These bidirectional effects were replicated using a shuttle escape response for pretreatment and lever pressing as the test response. During two uninterrupted 1000-sec duration inescapable shocks (Experiment 2), escape rats continued to lever press through the 2000-sec of shock. In the third experiment, escapable shock facilitated and inescapable shock hindered later learning when the escape contingency was degraded by a 3-sec delay of shock termination. The fourth and fifth experiments demonstrated that (1) this associative facilitation effect is not simply due to an increase in active responding by escape animals (Experiment 4), and (2) no associative facilitation is observed if the contingency is not initially degraded by a 3-sec delay (Experiment 5). Taken together, these results are the first demonstration of bidirectional effects of control on aversively motivated behavior in animals. In addition to typical helplessness effects, a “mastery” phenomenon is observed. This mastery induced by experience with escape learning is characterized by (1) a motivational effect: persistent general active behavior in the face of inescapable shock, and (2) an associative effect: facilitation in learning degraded response-shock contingencies. These are the opposite of helplessness effects, operationally and descriptively, and may be opposite in process as well.

Opiate antagonists overcome the learned helplessness effect but impair competent escape performance

Rats exposed to inescapable shocks exhibited deficiencies in learning to escape shock in a novel situation 24 hours later (learned helplessness). Opiate antagonists (naloxone or naltrexone) blocked the learned helplessness effect, allowing efficient escape performance on the subsequent test. In contrast, these drugs impaired the performance of rats pretrained with escapable shocks and animals with no previous exposure to shock. Both effects occurred at small doses and increased substantially with higher doses. The results suggest a significant role for endogenous opiates in the induction of learned helplessness as well as in the acquisition of efficient escape behavior.