Temporal parameters of post-stress prophylactic glucose treatment in rats.

Acute trauma can lead to life-long changes in susceptibility to psychiatric disease, such as post-traumatic stress disorder (PTSD). Rats given free access to a concentrated glucose solution for 24 h beginning immediately after trauma failed to show stress-related pathology in the learned helplessness model of PTSD and comorbid major depression. We assessed effective dosing and temporal constraints of the glucose intervention in three experiments. We exposed 120 male Sprague-Dawley rats to 100, 1 mA, 3-15 s, inescapable and unpredictable electric tail shocks (over a 110-min period) or simple restraint in the learned helplessness procedure. Rats in each stress condition had access to a 40% glucose solution or water. We measured fluid consumption under 18-h free access conditions, or limited access (1, 3, 6, 18 h) beginning immediately after trauma, or 3-h access with delayed availability of the glucose solution (0, 1, 3, 6 h). We hypothesized that longer and earlier access following acute stress would improve shuttle-escape performance. Rats exposed to traumatic shock and given 18-h access to glucose failed to show exaggerated fearfulness and showed normal reactivity to foot shock during testing as compared to their water-treated counterparts. At least 3 h of immediate post-stress access to glucose were necessary to see these improvements in test performance. Moreover, delaying access to glucose for more than 3 h post-trauma yielded no beneficial effects. These data clearly identify limits on the post-stress glucose intervention. In conclusion, glucose should be administered almost immediately and at the highest dose after trauma.

Rapid avoidance acquisition in Wistar-Kyoto rats.

The relationship between trait stress-sensitivity, avoidance acquisition and perseveration of avoidance was examined using male Wistar-Kyoto (WKY) and Sprague-Dawley (SD) rats. Behavior in an open field was measured prior to escape/avoidance (E/A) acquisition and extinction. E/A was assessed in a discrete trial lever-press protocol. The signal-shock interval was 60s with subsequent shocks delivered every 3s until a lever-press occurred. A 3-min flashing light safety signal was delivered contingent upon a lever-press (or failure to respond in 5 min). WKY rats displayed phenotypic low open field activity, but were clearly superior to SD rats in E/A performance. As avoidance responses were acquired and reached asymptotic performance, SD rats exhibited "warm up", that is, SD rats rarely made avoidance responses on the initial trial of a session, even though later trials were consistently accompanied with avoidance responses. In contrast, WKY rats did not show the "warm up" pattern and avoided on nearly all trials of a session including the initial trial. In addition to the superior acquisition of E/A, WKY rats demonstrated several other avoidance features that were different from SD rats. Although the rates of nonreinforced intertrial responses (ITRs) were relatively low and selective to the early safety period, WKY displayed more ITRs than SD rats. With removal of the shocks extinction was delayed in WKY rats, likely reflecting their nearly perfect avoidance performance. Even after extensive extinction, first trial avoidance and ITRs were evident in WKY rats. Thus, WKY rats have a unique combination of trait behavioral inhibition (low open field activity and stress sensitivity) and superior avoidance acquisition and response perseveration making this strain a good model to understand anxiety disorders.

Escape deficits induced by inescapable shock and metabolic stress are reversed by adenosine receptor antagonists.

We examined the relationship between metabolic stress, brain adenosine regulation, and the learned helplessness effect in four experiments in rats. Glucoprivation and metabolic inhibition were induced by treating previously restrained (nonshocked) rats with 2-deoxy-D-glucose (2DG) shortly before escape testing. Experiment 1 demonstrated that 2-deoxy-D-glucose impairs escape performance in a dose-dependent manner. Experiment 2 showed that 2-deoxy-D-glucose and shock induced escape deficits are completely reversed by peripheral administration of the adenosine receptor antagonist caffeine. This result indicates that both inescapable shock and 2-deoxy-D-glucose result in compensatory adenosine regulation which, in turn, mediates the behavioral impairment. Experiment 3 determined that 8-[p-sulfophenyl]-theophylline, a peripheral adenosine receptor antagonist, fails to reverse the escape deficit resulting from metabolic stress, whereas centrally acting theophylline does. Experiment 4 showed that the behavioral impairments from both 2-deoxy-D-glucose and inescapable shock are reversed by intracranial ventricular (icv) caffeine treatment. The results of Experiments 3 and 4 indicate that the enhanced adenosine regulation and the ensuing performance deficit resulting from 2-deoxy-D-glucose treatment occurred in the central nervous system. These data are discussed in terms of the metabolic demands of neuronal over-activation during escape testing in inescapably shocked rats and the loss of normal behavioral function due to compensatory adenosine regulation in the brain.

Inhibition of adenosine deaminase by erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA) mimics the effect of inescapable shock on escape learning in rats.

Three experiments examined the role of adenosine neuroregulation in the production of shuttle-escape deficits caused by prior exposure to inescapable electric shock in rats (learned helplessness). Intracerebroventricular administration of erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA), a selective adenosine deaminase inhibitor, mimicked the effect of earlier inescapable shock at a dose of 2.5 microM in previously restrained rats. Performance deficits produced by EHNA or by earlier exposure to inescapable shock were reversed by intraperitoneal injection of 10 mg/kg caffeine, an adenosine receptor antagonist. Finally, preexposure to an ineffective number of shocks interacted in synergy with an ineffective pretest dose (1.0 microM) of EHNA to maximize shuttle-escape latencies. These data implicate endogenous adenosine neuroregulation as a proximate mechanism in learned helplessness and conservation-withdrawal.

The interaction of diet and stress in rats: high-energy food and sucrose treatment.

Exposure to inescapable shock typically reduces eating and body weight in rats. The present study examined the modulation of stress effects by prestress diet and poststress sugar availability. Maintenance on a high-fat, high-energy food attenuated stress-induced weight loss and anorexia and increased high-energy food selection when a low-energy wet mash was the only alternative. Access to sugar after stress also reduced short-term weight loss; among rats maintained on high-energy food, body weight was spared absolutely. The dependence of stress effects on pre- and poststress diet alternatives may speak to individual differences in the stress-eating relationship in humans. More generally, these results support a conceptualization of stress in terms of metabolic challenge and the integrated reorganization of energy regulatory processes.

Poststress glucose mitigates behavioral impairment in rats in the "learned helplessness" model of psychopathology.

Three experiments examined the effects of poststress glucose treatment in the learned helplessness model of psychopathology in rats. In experiment 1, rats were given access to water or 40% aqueous glucose immediately following exposure to inescapable tailshocks or simple restraint in a 2 x 2 factorial design. Inescapably shocked rats failed to drink the glucose solution during the poststress interval and failed to show any improvement 24 hours after stress induction in shuttle-escape performance. Consequently, all rats received preexposure to a sweetened glucose cocktail in an attempt to increase poststress ingestion following inescapable shock treatment in experiment 2. Under these conditions, poststress intake of the glucose cocktail eliminated behavioral impairment in inescapably shocked rats relative to water-treated shocked rats and water- and glucose-treated restrained controls. Experiment 3 demonstrated that glucose prophylaxis occurs in the absence of sucrose when rats are preexposed to a 40% glucose solution prior to stress induction.

Individual differences in vulnerability to inescapable shock in rats.

The present study determined whether individual differences in neophobia during an open-field pretest predict vulnerability to inescapable electric shock, as measured by 2 tests of learned helplessness in rats. Shuttle-escape latencies and saccharin finickiness increased across groups that had received increasing numbers of inescapable shocks 24 hr earlier. Dispersion in the test measure as well as the percentage of variance explained by pretest neophobia were greater when no or few shocks were delivered in the interpolated stress phase. Pretest neophobia was positively related to stress vulnerability in both tests under these conditions. Further increments in stressor severity overwhelmed even the most stress-resistant rats, thereby decreasing dispersion in the test measure and eliminating the predictive value of pretest neophobia. This pattern of outcomes was more robust for the shuttle-escape measure of helplessness.

Stress and adenosine: I. Effect of methylxanthine and amphetamine stimulants on learned helplessness in rats.

In 3 experiments, the authors examined the effect of methylxanthine and amphetamine stimulants on deficits in shuttle-escape responding produced by earlier exposure to inescapable electric shock in rats. Caffeine completely reversed escape deficits in inescapably shocked rats when injected just before shuttle-escape testing but failed to prevent a test deficit when injected before shock pretreatment. Dose-response curves indicated that, whereas caffeine and theophylline were equally effective at reversing escape deficits, amphetamine not only failed to improve performance in preshocked rats but retarded escape in restrained (no-shock) controls. This amphetamine-induced deficit was reversed by cotreatment with caffeine. These data are discussed in terms of the role of adenosine receptor activation in helplessness and conservation-withdrawal.

Stress and adenosine: II. Adenosine analogs mimic the effect of inescapable shock on shuttle-escape performance in rats.

In 3 experiments, the authors examined the role of adenosine regulation in escape deficits produced by earlier exposure to inescapable shock in rats (learned helplessness). Adenosine analogs injected before escape testing mimicked the effect of earlier inescapable shock, with the magnitude of the deficit varying with dose and drug specificity for A2 adenosine receptors. Agonist-induced and stress-induced escape deficits were eliminated by pretest treatment with the centrally acting adenosine receptor antagonist theophylline but not the peripheral antagonist 8-[p-sulfophenyl]-theophylline. Finally, preexposure to an ineffective number of inescapable shocks interacted in synergy with an ineffective pretest injection of adenosine agonist to maximize deficits in escape performance. These data implicate energy regulation and a central compensatory action by adenosine in the aspects of helplessness related to conservation-withdrawal.

Dissociation of interference with the speed and accuracy of escape produced by inescapable shock.

Benzodiazepines and naltrexone administered before inescapable shock block behavioral consequences of the inescapable shock such as poor shuttle box escape, reduced activity in reaction to shock, reduced social interaction, and so on. Anxiogenic beta-carboline derivatives such as FG-7142 can produce these effects by themselves. In the present study, neither diazepam nor naltrexone had any effect on the interference with Y-maze choice escape accuracy produced by inescapable shock even though they both eliminated the reduction in Y-maze escape response speed produced by inescapable shock. Analogously, FG-1742 did not lead to a reduction in Y-maze choice escape response accuracy even though it did slow escape responding. These data imply that inescapable shock interferes with escape choice learning and escape response speed by different mechanisms, the former not involving fear-anxiety processes.

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.

Suppression of feeding and body weight by inescapable shock: modulation by quinine adulteration, stress reinstatement, and controllability.

Three experiments examined food intake and body weight in rats after exposure to one session of intermittent, inescapable electric shock. Quinine adulteration and shock both suppressed feeding (Experiment 1); recovery of feeding after shock was impeded when quinine adulteration was combined with a mild daily stress reinstatement (Experiment 2). Body weight also was suppressed by shock (Experiments 1 and 2); control over shock provided some protection against this deficit (Experiment 3). These results suggest roles for "finickiness" and vulnerability to mild stressors in the maintenance of eating disorders associated with stress and depression. The findings also may have implications for interpretation of deficits in appetitively motivated behaviors after stress.

Predictable and unpredictable shock stimulates gastric contractility and causes mucosal injury in rats.

The effects of tailshock on gastric contractility and lesions were investigated in rats exposed to 100 1-mA tailshocks while confined inside plastic tubes. A light preceded each shock in one group and was randomly presented with respect to shock in the other. Following the session, animals were given 3 hr of rest before being sacrificed. Contractility of the corpus of the stomach was measured by means of chronically implanted extraluminal force transducers. Contractility was measured in 10-min blocks and analyzed by computer. Lesions were quantified by inspection; quantitative histology was performed on corpus and antrum sections. Signaled (n = 13) and unsignaled (n = 17) shock stimulated high-amplitude gastric contractions in fasted rats, which continued for 2 hr after the shock session. Cumulative contractile activity (1.5-hr shock plus 2-hr rest) in shocked animals was twice that in restrained and unrestrained control animals (n = 19, p less than .05), and contractile activity had a 30%-40% greater average amplitude than after a meal. Compared with unrestrained controls, shocked rats had visibly more mucosal injury (2.2 +/- 0.5 mm2 vs. 0.1 +/- 0 mm2). Larger cumulative contractile activity was associated with a larger area of erosions (r = .36, p less than .05). Frequency and duration of contractions did not distinguish between shocked and unshocked groups. We conclude that in rats, signaled and unsignaled tailshock stimulates persistent, high-amplitude gastric contractions and is associated with injury of the mucosa of the stomach.

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.

Learned helplessness: an experimental model of the DST in rats.

Elevated ratings of anxiety and agitation in Dexamethasone Suppression Test (DST) nonsuppressors suggest a role for psychological stress in the generation of the hypothalamic-pituitary-adrenal cortical (HPAC) abnormalities characteristic of depression. We employed the learned helplessness model of depression to test the effectiveness of psychological stress in inducing a resistance of plasma corticosterone levels to dexamethasone suppression. Inescapably shocked rats exhibited corticosterone levels that were significantly more resistant to dexamethasone suppression than were the levels of rats receiving an equivalent amount of escapable shock or no shock. These results confirm the hypothesis that HPAC resistance to dexamethasone suppression is enhanced by the distress associated with the inefficacy of behavioral coping responses. The present findings represent the first analog of the DST in the learned helplessness model of depression. This DST model allows investigations into neurobiological mechanisms underlying the HPAC alterations in depression.

Stimulus- and pellet-induced drinking during a successive discrimination.

In three experiments, interim water drinking was examined in rats exposed to a multiple schedule whose two components were extinction and a variable-time 30-s schedule of food delivery. Two different drinking patterns were observed in Experiment 1. Pellet-induced drinking, characterized by high rates of postpellet drinking in the variable-time component, with little or no drinking in extinction, occurred when the acquisition of stable postpellet drinking preceded discrimination training. Stimulus-induced drinking, characterized by a burst of drinking at the onset of extinction, with no drinking during the variable-time schedule, occurred when discrimination training preceded all other experimental conditions. With extended training, stimulus-induced drinking eventually was accompanied by postpellet drinking. In Experiment 2, the rate of stimulus-induced drinking and the number of sessions during which it occurred without postpellet drinking were found to be inversely related to component duration. In Experiment 3, the rate of schedule-induced drinking was found to vary directly with component duration.

Librium prevents the analgesia and shuttlebox escape deficit typically observed following inescapable shock.

Administration of a benzodiazepine, chlordiazepoxide (CDP), prior to exposure to inescapable shock prevented both the long-term analgesia and the shuttle-escape deficit typically observed following inescapable shock. If given only prior to testing, CDP had little effect. The protective effects of CDP were determined not to be a result of state dependency or a general facilitatory effect of the drug on escape performance. It is suggested that the induction of anxiety or fear by inescapable shock is critical in mobilizing endogenous changes such as transmitter depletion which are thought to be responsible for the deficits observed.

Effects of task-irrelevant cues and reinforcement delay on choice-escape learning following inescapable shock: evidence for a deficit in selective attention.

Prior exposure to inescapable shock has been reported to interfere with choice-escape learning, but several investigators have failed to obtain this effect. A series of five experiments examined the conditions under which choice-escape learning in an automated Y-maze is impaired by pretreatment with inescapable shock. Inescapably shocked rats made more errors and responded more slowly than did controls only when shock termination was delayed and task-irrelevant cues were present during choice-escape training. These findings are discussed in terms of information processing and neurochemical consequences of exposure to inescapable shock.