Catecholamine depletion in mice upon reexposure to stress: mediation of the escape deficits produced by inescapable shock

Immediately following exposure to 60 inescapable shocks, Swiss-Webster mice had significantly reduced hypothalamic norepinephrine (NE). Within 24 hr NE levels returned to control values. Reexposure to as few as 10 shocks 24 hr after initial stress exposure resulted in a significant decline of hypothalamic NE. Moreover, at this interval after inescapable shock, escape performance was severely disrupted, with a large proportion of mice exhibiting numerous failures to escape shock. Increasing brain dopamine (DA) and NE by L-dopa treatment prior to inescapable shock prevented the escape deficits. Conversely, pairing five inescapable shocks with NE depletion by FLA-63, or both DA and NE depletion by alpha-methyl-p-tyrosine, disrupted escape performance 24 hr later. Residual drug effects, state dependence, or sustained amine turnover could not account for the behavioral changes observed. Data are discussed in terms of catecholamine mediation of escape performance through variations in response maintenance abilities. Furthermore, it is suggested that the long-term effects of inescapable shock may be due to sensitization effects or conditioned amine depletion.     

Exposure to inescapable shock produces both activity and associative deficits in the rat

Interference with shuttle-box escape learning following exposure to inescapable shock is often difficult to obtain in rats. The first experiment investigated the role of shock intensity during escape training in the apparent fragility of the effect. Experiment 1A demonstrated that the magnitude of the interference effect was systematically related to shock intensity during shuttle-box testing. At .6 mA, a robust effect was obtained, whereas at .8 mA and 1.0, little or no deficit in the escape performance of inescapably shocked rats was observed. Experiment 1B demonstrated that the deficit observed in Experiment 1A depended upon whether or not rats could control shock offset. Experiment 2 suggested that preshock may suppress activity and that higher shock levels may overcome this deficit. Experiment 3 tested this as the sole cause of the escape deficit by requiring an escape response which exceeded the level of activity readily elicited by a 1.0-mA shock in both restrained and preshocked rats. In such a task, preshocked rats performed more poorly than did restrained controls. These results are consistent with the possibility that inescapable shock may, in addition to reducing activity, produce an associative deficit. Experiment 4 more clearly demonstrated that inescapable shock produces deficits in performance which cannot be expleined by activity deficits and which appear to be associative in nature. It was shown that inescapable shock interfered with the acquisition of signaled punishment suppression but not CER suppression. The theoretical implications of these data for explanations of the manner in which prior exposure to inescapable shock interferes with escape learning were discussed.     

Effects of signaling inescapable shock on subsequent escape learning: implications for theories of coping and "learned helplessness"

The present experiments reveal that shuttle-escape performance deficits are eliminated when exteroceptive cues are paired with inescapable shock. Experiment 1 indicated that, as in instrumental control, a signal following inescapable shock eliminated later escape performance deficits. Subsequent experiments revealed that both forward and backward pairings between signals and inescapable shock attenuated performance deficits. However, the data also suggest that the impact of these temporal relations may be modulated by qualitative aspects of the cues because the effects of these relations depended upon whether an increase or decrease in illumination (Experiment 2) or a compound auditory cue (Experiment 4) was used. Preliminary evidence suggests that the ability of illumination cues to block escape learning deficits may be related to their to reduce contextual fear (Experiment 3). The implications of these data for conceptions of instrumental control and the role of fear in the etiology of effects of inescapable shock exposure are discussed.     

The time course of learned helplessness, inactivity, and nociceptive deficits in rats

Four experiments are reported which explore the nature of the effects of inescapable shock on subsequent shuttlebox escape learning. The first experiment demonstrated that shuttle escape deficits dissipate within 48 hr after treatment with inescapable shock. Experiment 2 showed that exposure to inescapable shock suppressed unlearned activity in the shuttlebox and that this activity deficit recovered within 48 hr. Experiment 2A demonstrated that this shuttlebox crossing decrement was at least partly attributable to the inescapability of the shocks. These results suggested that activity factors might partly mediate the shuttle escape learning deficit reported in Experiment 1. Experiment 3 explored the possibility that activity and shuttle escape learning deficits are subserved by the effects of inescapable shock on pain sensitivity. The results supported this notion. It was found that rats were less sensitive to painful stimulation 24 hr after inescapable shock and that this analgesic tendency also dissipated within 48 hr after pretreatment. The implications of these results were discussed.     

Modeling signal features of escape response: effects of cessation conditioning in "learned helplessness" paradigm

Six experiments examined the effects of signaling the termination of inescapable shock (cessation conditioning) or shock-free periods (backward conditioning) on later escape deficits in the learned helplessness paradigm, using rats (Sprague-Dawley and Bantin-Kingman). A cessation signal prevented later performance deficits when highly variable inescapable shock durations were used during pretreatment. The inclusion of short minimum intertrial intervals during pretreatment did not alter the benefits of cessation conditioning but eliminated the protection afforded by a safety signal. The beneficial effects of both cessation and backward signals were eliminated when a single stimulus signaled shock termination and a shock-free period. Finally, a combination of cessation and backward signals was found to be most effective in immunizing against the effects of subsequent unsignaled, inescapable shock on later escape performance. These data suggest that cessation conditioning may be crucial to the prophylactic action of an escape response.     

The role of norepinephrine and acetylcholine in mediating escape deficits produced by inescapable shocks

This study examined the role of neurochemical changes produced by inescapable shock, specifically the depletion of norepinephrine (NE) and enhancement of acetylcholine (ACh), in mediating subsequent inescapable shock-induced deficits in escape acquisition in rats. Enhancement of these neurochemical changes by injections of the NE synthesis inhibitor, FLA-63 (10 mg/kg), or the anticholinesterase, eserine sulphate (3 X 0.5 mg/kg), during the inescapable shock enhanced the subsequent escape deficits observed 3 days later. In contrast, these drugs had no effect on the subsequent escape behavior of rats that were not exposed to inescapable shock. Since these effects could not be attributed to carry-over or state-dependent effects of the drugs, these data suggest that the magnitude of the escape deficit produced by prior inescapable shock is dependent on the magnitude of the initial inescapable shock-induced changes in NE and ACh.     

Analgesic and opioid involvement in the shock-elicited activity and escape deficits produced by inescapable shock

Three experiments examined the involvement of analgesic processes and endogenous opioids in the production of the shuttlebox escape acquisition and unconditioned activity deficits which follow exposure to inescapable shock. Experiment 1 found that the opiate antagonist naltrexone administered before the inescapable shock session interfered with the shuttlebox escape acquisition deficit which would normally follow. Experiment 2 found naltrexone to completely prevent the unconditioned activity deficit. The final experiment revealed that dexamethasone, a synthetic glucocorticoid which abolishes the analgesia produced by inescapable shock, reversed the activity deficit. These results indicate that endogenous opioids may be involved in the production of both the escape acquisition and activity deficits. They also suggest that the analgesia produced by these opioids may participate in the mediation of the activity deficit, even though analgesia is not involved in producing the shuttlebox acquisition deficit.     

The effects of escape conditioning and shock intensity on responding during inescapable shock

Eight albino rats, conditioned to press a lever to escape shock, continued to lever press during short inescapable shocks presented subsequently. The rate of this behavior was found to be higher for higher shock intensities regardless of the order in which shock values were presented. Relative to the immediately preceding escape rate, responding during inescapable shock was higher following conditioning at higher fixed-ratio escape requirements. Four subjects not conditioned to escape shock pressed the lever very infrequently during inescapable shock and showed little change with changes in shock intensity. The escape conditioning effects suggest that responding during inescapable shock is superstitious escape behavior. The effects of shock intensity on this behavior appear to be similar to reported effects of shock intensity on escape behavior.     

Learned helplessness in the rat: time course, immunization, and reversibility.

Rats, like dogs, fail to escape following exposure to inescapable shock. This failure to escape does not dissipate in time; rats fail to escape 5 min, 1 hr., 4 hr., 24 hr., and 1 wk. after receiving inescapable shock. Rats that first learned to jump up to escape were not retarded later at bar pressing to escape following inescapable shock. Failure to escape can be broken up by forcibly exposing the rat to an escape contingency. Therefore, the effects of inescapable shock in the rat parallel learned helplessness effects in the dog.     

Reconsideration of the role of competing responses in demonstrations of the interference effect (learned helplessness)

In Experiment 1a, rats trained to escape shock by performing a 2-s inactive response were less impaired on a subsequent 2-way shuttle response than their yoked counterparts that received inescapable shock. In contrast, in Experiment 1b, rats trained to escape shock by performing a longer duration inactive response were more impaired on the subsequent escape task than their inescapably shocked counterparts. In Experiment 2, the results of Experiments 1a and 1b were replicated, and the inactive responses performed during pretreatment by both the escapable and inescapable shock groups were assessed and correlated with test stage 2-way shuttle escape performance. These activity data indicate that inactivity during pretreatment shock in both escapable and inescapable shock groups was a highly reliable predictor of subsequent 2-way shuttle performance, irrespective of the pretreatment shock contingency to which these Ss were exposed.     

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.     

Factors affecting the measurement of classically conditioned fear in rats following exposure to escapable versus inescapable signaled shock.

Three experiments are reported in which rats first received 50 escapable or inescapable signaled-shock trials. Experiment 1 (n = 22) employed an acquired-drive paradigm and found inescapable shock subjects learned a hurdle-jump response to escape the signal less rapidly than did escapable-shock subjects. Experiment 2 (n = 24) employed a conditioned emotional response paradigm and found inescapable-shock subjects suppressed more when the signal was introduced in the appetitive bar-pressing task. Both experiments measured spontaneous activity immediately following conditioning and found no group differences. Experiment 3 (n = 39) employed the same activity task and found no difference between escapable- and inescapable-shock groups when the signal was introduced into the activity task. Both groups displayed less activity than a nonshock control group during the signal. The results suggest that lack of control over the shock in the conditioning phase did not result in an increase of conditioned fear. The results are discussed in terms of a learned active-inactive predisposition to respond.     

Prior exposure to inescapable electric shock in rats affects extinction behavior after the successful acquisition of an escape response

In Expt 1, rats exposed to 64 inescapable electric shocks in a restrainer or merely restrained were later given either 0, 5, 15 or 30 escape/avoidance training trials with a two-way shuttlebox procedure that does not lead to interference with escape acquisition due to prior exposure to inescapable shock. After escape training all rats were given an escape/avoidance extinction procedure in which shock was inescapable. The rats which had received prior exposure to inescapable shock responded less often and with longer latencies in extinction than did the restrained rats. Experiment 2 demonstrated that this effect is caused by the inescapability of the initial shock treatment. These results were explained in terms of (a) associative interference which minimized the effect of shuttlebox escape training for the preshocked subjects, and (b) a stronger tendency to recognize the presence of an inescapable shock situation during extinction for the preshocked subjects. The relationship between these results and previous work demonstrating that exposure to the escape contingency mitigates the effects of inescapable shock exposure was also discussed.     

The Effects of Intra-amygdala Infusion of the AMPA Receptor Antagonist CNQX on Retention Performance Following Aversive Training

The aim of these experiments was to determine whether impaired retention performance in aversively motivated tasks, induced by blockade of amygdala AMPA receptors, is due to influences on mechanisms underlying memory retrieval or to other influences on performance. Rats received either footshock escape training (1 or 10 trials), or no foot shock, in a two-compartment straight alley and bilateral intra-amygdala infusions of the AMPA receptor antagonist CNQX (0.5 μg) were subsequently administered prior to inhibitory avoidance retention testing 8 days later. The CNQX impaired, but did not block, inhibitory avoidance retention performance as indicated by the initial latencies to enter the shock compartment. The animals were then retained in the alley until they remained in the starting compartment for 100 consecutive s and entries into the shock compartment were recorded as errors. In both the controls and CNQX-treated groups, increases in amount of original training resulted in fewer errors, indicating memory for the escape training. Furthermore, regardless of the amount of original training (i.e., 0, 1, or 10 trials), CNQX-treated groups made more errors. Other experiments examined intra-amygdala CNQX effects on reactivity to footshock, locomotor activity, and anxiety. CNQX decreased reactivity to footshock, blocked shock-induced decreases in locomotor activity, and had an anxiolytic effect in an elevated plus maze comparable to that induced by midazolam (0.5 μg). These findings suggest that intra-amygdala infusions of CNQX prior to retention testing affect inhibitory avoidance retention performance following aversive training by altering locomotor activity, reducing sensitivity to footshock, and reducing anxiety. The implications of these findings for hypotheses concerning amygdala function in aversively motivated learning and memory is discussed.     

Learned helplessness in the cockroach (Periplaneta americana)

For 3 consecutive days cockroaches (Periplaneta americana) were exposed to either escapable, inescapable, or no shock in an escape task. Twenty-four hours later they were tested in a shuttlebox escape task. There were reliable differences between escapable and inescapable animals and between inescapable and control animals in both escape latencies and the number of failures to escape.     

Acute and chronic stress effects on performance in a forced-swim task

The effects of uncontrollable stressors on performance in a subsequent forced-swim paradigm were assessed in mice. Uncontrollable shock initially induced behavioral invigoration; however, within 24 h of stressor application, swimming behavior was depressed relative to nonstressed mice. The controllability of the stressor did not influence the initial invigoration, being present among escapably shocked mice as well as among mice that received (yoked) inescapable shock. In contrast, the depression of responding evident 24 h after stressor application was related to the availability of behavioral coping methods. Finally, following repeated exposure to footshock there was no indication of adaptation to the behavioral changes ordinarily induced by acute shock stress. The data were related to the effects of uncontrollable stressors on escape performance, and with respect to the use of this preparation as an animal model of human depression.     

Role of fear in mediating shuttle escape learning deficit produced by inescapable shock

The relation between the shuttlebox escape deficit produced by prior inescapable shock (IS) and fear during shuttlebox testing as assessed by freezing was investigated in rats. IS rats learned to escape poorly and were more fearful than either escapably shocked subjects or controls, both before and after receiving shock in the shuttlebox. However, fear and poor escape performance did not covary with the manipulation of variables designed to modulate the amount of fear and the occurrence of the escape deficit. A 72-hr interval between IS and testing eliminated the escape deficit but did not reduce preshock freezing. Diazepam before testing reduced both preshock and postshock fear in the shuttlebox but had no effect on the escape deficit. Naltrexone had no effect on fear but eliminated the escape deficit. This independence of outcomes suggests that the shuttlebox escape deficit is not caused by high levels of fear in IS subjects.     

Emotionality in selectively bred strains of rats mediates prior shock effects on escape-avoidance conditioning.

Rats of the Maudsley Reactive and Maudsley Non-reactive strains were given 25 trials of escape-avoidance conditioning after exposure to inescapable shock. Prior shock exposure (PSE) did not affect avoidance or escape latencies, but decreased the number of avoidances made by the Maudsley non-reactive animals and increased the number of their failures to escape. The results are interpreted as demonstrating an interference with the classical conditioning of a conditioned emotional response, through a reduction in the information content of the CS following PSE. The strain differences are interpreted as due to the non-reactive animals being especially sensitive to PSE.     

The debilitating effect of exposure to noncontingent escape: A test of the learned helplessness model

Two studies were conducted to test the hypothesis that exposure to non-contingent escape leads to performance deficits similar to those observed when subjects are exposed to noncontingent aversive outcomes from which there is no escape, and that causal attributions mediate these deficits. Previous attempts to produce “appetitive helplessness” (deficits resulting from exposure to noncontingent positive events) have been plagued by subjects' tendency to believe that they are responsible for positive events. In Experiment 1, 40 subjects were exposed to contingent or noncontingent noise escape trials. As predicted by the learned helplessness model, subjects who received inescapable noise performed less well on a subsequent anagram task than subjects exposed to escapable noise. Similarly, subjects who escaped from the noise owing to the benevolence of a powerful other rather than because of their own efforts, showed performance deficits paralleling those of the inescapable noise subjects. In Experiment 2, subjects who escaped an aversive tone through no effort of their own showed subsequent performance deficits, but globality of their self-reported attributions did not predict subsequent anagram performance. The results of these studies provide support for the hypothesis that uncontrollability, independent of the valence of a particular outcome, is responsible for helplessness deficits, but do not support the mediational role of attributions, at least in the laboratory.