Thomas R. Minor

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.

Taste and emotionality in rats selectively bred for high versus low saccharin intake

Rats were selectively bred for high versus low saccharin ingestion, a putative measure of enhanced stress and emotionality (Dess, 1991). In Experiment 1, third-generation Occidental high-saccharin (HiS) and low-saccharin (LoS) rats were tested for saccharin ingestion and emotionality. The saccharin test confirmed that the lines differed on the selection phenotype. In addition, LoS rats were more emotional, as evidenced by longer emergence latencies and more defecation in a modified open-field test. In Experiment 2, LoS rats had lower quinine preference scores and drank saccharin-adulterated glucose less avidly. These outcomes are reminiscent of the behavior shown by inescapably shocked rats. Unlike helpless rats, however, LoS rats drank less avidly during a dilute sucrose test, an effect more reminiscent of chronic mild stress. The lines did not differ reliably on intake of concentrated glucose or Polycose, even when the latter was mixed with saccharin. In Experiment 3, LoS rats preferred saccharin less strongly than did HiS rats at concentrations of 0.05% to 0.7% and had an aversion to a 1.0% solution. In Experiment 4, LoS rats were affected more by shock, as assessed by stress-induced anorexia. These and other recent findings support the notion of shared mechanisms for taste, emotionality, and stress vulnerability.

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.

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.

Avoidance perseveration during extinction training in Wistar-Kyoto rats: an interaction of innate vulnerability and stressor intensity.

Given that avoidance is a core feature of anxiety disorders, Wistar-Kyoto (WKY) rats may be a good model of anxiety vulnerability for their hypersensitivity to stress and trait behavioral inhibition. Here, we examined the influence of strain and shock intensity on avoidance acquisition and extinction. Accordingly, we trained WKY and Sprague-Dawley (SD) rats in lever-press avoidance using either 1.0-mA or 2.0-mA foot-shock. After extinction, neuronal activation was visualized by c-Fos for overall activity and parvalbumin immunoreactivity for gamma-aminobutyric acid (GABA) neuron in brain areas linked to anxiety (medial prefrontal cortex and amygdala). Consistent with earlier work, WKY rats acquired lever-press avoidance faster and to a greater extent than SD rats. However, the intensity of foot shock did not differentially affect acquisition. Although there were no differences during extinction in SD rats, avoidance responses of WKY rats trained with the higher foot shock perseverated during extinction compared to those WKY rats trained with lower foot shock intensity or SD rats. WKY rats trained with 2.0-mA shock exhibited less GABAergic activation in the basolateral amygdala after extinction. These findings suggest that inhibitory modulation in amygdala is important to ensure successful extinction learning. Deficits in avoidance extinction secondary to lower GABAergic activation in baslolateral amygdala may contribute to anxiety vulnerability in this animal model of inhibited temperament.

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.

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.

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.

Stressor controllability and learned helplessness research in the United States : Sensitization and fatigue processes

Recent work in the learned helplessness paradigm suggests that neuronal sensitization and fatigue processes are critical to producing the behavioral impairment that follows prolonged exposure to an unsignaled inescapable stressor such as a series of electric tail shocks. Here we discuss how an interaction between serotonin (5-HT) and corticosterone (CORT) sensitizes GABA neurons early in the pretreatment session with inescapable shock. We propose that this process eventually depletes GABA, thus removing an important form of inhibition on excitatory glutamate transmission in the amygdala, hippocampus, and frontal cortex. When rats are re-exposed to shock during shuttle-escape testing 24 hrs later, the loss of inhibition (as well as other excitatory effects) results in unregulated excitation of glutamate neurons. This state of neuronal over-excitation rapidly compromises metabolic homeostasis. Metabolic fatigue results in compensatory inhibition by the nucleoside adenosine, which regulates neuronal excitation with respect to energy availability. The exceptionally potent form of inhibition associated with adenosine receptor activation yields important neuroprotective benefits under conditions of metabolic failure, but also precludes the processing of information in fatigued neurons. The substrates of adaptive behavior are removed; performance deficits ensue.