Ventromedial septal lesions in rats reduce the effects of inescapable shock on escape performance and analgesia.

In 2 experiments with 104 male Sprague-Dawley rats, lesions of the ventromedial septum (VMS) reduced or eliminated several effects of exposure to inescapable shock, but lesions of the dorsolateral septum did not. Exp I demonstrated that VMS lesions reduced the loss in body weight produced by inescapable shock and eliminated the subsequent (24 hrs later) interference with escape performance (learned helplessness). Exp II demonstrated that VMS lesions reduced the analgesia that occurs immediately following inescapable shock and the analgesia reinstated by exposure to escapable shock 24 hrs later. Findings indicate that VMS lesions reduce several responses to inescapable shock and suggest the possibility that all of these effects may reflect a unitary deficit. It is hypothesized that VMS lesions reduce these effects of exposure to inescapable shock either by reducing the ability of the rats to learn that their responses and shocks were uncorrelated or by reducing the emotional impact of this lack of correlation. (52 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Chlordiazepoxide microinjected into the region of the dorsal raphe nucleus eliminates the interference with escape responding produced by inescapable shock whether administered before inescapable shock or escape testing.

Systemic administration of benzodiazepines before exposure to inescapable shock (IS) blocks the enhanced fear conditioning and escape learning deficits that follow exposure to IS, whereas administration before the subsequent behavioral testing eliminates the enhanced fear but not the interference with escape (N?=?44 male rats). The failure of benzodiazepines to reduce the IS-produced escape learning deficit when given before testing is inconsistent with a recent proposal that interference with escape is mediated by an IS-induced sensitization of dorsal raphe nucleus (DRN) activity. The present experiments demonstrate that chlordiazepoxide will block both the enhancement of fear and interference with escape responding when given before either IS or testing if microinjected in the region of the DRN. This suggests that systemic benzodiazepines fail to block escape deficits when given before testing because action at a site distant from the DRN counters the effect of the drug at the DRN. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

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 outcome suggests that the shuttlebox escape deficit is not caused by high levels of fear in IS subjects. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

8-OH-DPAT microinjected in the region of the dorsal raphe nucleus blocks and reverses the enhancement of fear conditioning and interference with escape produced by exposure to inescapable shock

Prior work suggests that inhibition of the dorsal raphe nucleus (DRN) either during exposure to inescapable electric shock (IS) or during later behavioral testing might block the usual behavioral consequences of IS. The 5-HT1A agonist 8-OH-DPAT was microinjected into the region of the DRN either before exposure to IS or before testing for fear conditioning and escape learning conducted 24 hr later. IS potentiated fear conditioning and interfered with escape performance. These effects were completely prevented by intra-DRN administration of 8-OH-DPAT at either point. Low but not high systemic doses of 8-OH-DPAT had a similar effect, supporting the idea that the effective site of action is presynaptic. The relation between these data and other effects of 8-OH-DPAT is 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 ability 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. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Failure to learn to escape by rats previously exposed to inescapable shock is partly produced by associative interference.

2 experiments demonstrated that the effects of prior exposure to inescapable shock on the subsequent acquisition of an escape response in rats is determined by the nature of the contingency that exists between responding and shock termination during the escape learning task, and not by the amount of effort required to make the response or the amount of shock that the S is forced to receive during each trial. Exp I, using 48 male Simonsen rats, showed that inescapably shocked Ss did not learn to escape shock in a shuttle box if 2 crossings of the shuttle box were required (fixed ratio, FR, -2) to terminate shock, but did learn this FR-2 response if a brief interruption of shock occurs after the 1st crossing of the FR-2. Exp II with 72 Ss showed that inescapably shocked Ss learned a single-crossing escape response as rapidly as did controls, but were severely retarded if a brief delay in shock termination was arranged to follow the response. Results are discussed in terms of the learned helplessness hypothesis, which assumes that prior exposure to inescapable shock results in associative interference. (15 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

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 β-carboline derivatives such as FR-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 show 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. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Failure to learn to escape in rats previously exposed to inescapable shock depends on nature of escape response.

Results of previous studies show that dogs exposed to inescapable shocks in a Pavlov harness subsequently fail to learn to escape shock in a shuttle box. The present 6 experiments attempted to replicate this finding with male Sprague-Dawley rats (N = 182). In agreement with many previous investigations, Exp I found that Ss exposed to inescapable shock did not fail to learn to escape in a shuttle box. Exp II, III, and IV varied the number, intensity, and temporal interval between inescapable shocks and did not find failure to learn in the shuttle box. An analysis of responding in the shuttle box revealed that Ss shuttled rapidly from the very 1st trial, whereas dogs acquire shuttling more gradually. Exp V and VI revealed that Ss exposed to inescapable shock failed to learn to escape when the escape response was one that was acquired more gradually. Exp V utilized a double crossing of the shuttle box as the escape response and Exp VI utilized a wheel-turn response. (20 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

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. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The dorsal raphe nucleus is a site of action mediating the behavioral effects of benzodiazepine receptor inverse agonist DMCM.

Systemic administration of benzodiazepine receptor inverse agonists leads to behavioral changes similar to those produced by inescapable shock (IS). The dorsal raphe nucleus (DRN) is a critical structure mediating IS effects. The present experiments determined whether the DRN is a site mediating the behavioral changes produced by benzodiazepine receptor inverse agonists. Microinjection of the inverse agonist Methyl 6,7-Dimethoxy-4-ethyl-β-carboline-3-carboxylate (DMCM) in the region of the DRN produced enhancement of fear conditioning as assessed by the amount of freezing in the presence of shock cues as well as interference with shuttlebox escape learning assessed 24 hr later. Furthermore, lesion of the DRN blocked the effects of systemic DMCM on fear conditioning and escape learning. These data suggest that the DRN is indeed critical in mediating these behavioral consequences of DMCM and further support a role for the DRN in producing the behavioral changes induced by IS. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Controllability and safety signals exert dissimilar proactive effects on nociception and escape performance.

In the present experiments we assess the ability of exteroceptive safety signals to proactively mimic shock controllability. In Experiment 1, animals were given escapable shock, yoked inescapable shock, restraint, or yoked shock with a stimulus coincident with shock offset on Day 1 and then given inescapable shock on Day 2. Safety signals attenuated the hypoalgesia following the first shock session. On Day 2, however, animals that had been preshocked with safety signals were not less hypoalgesic than those previously restrained. Conversely, shock controllability did not attenuate the hypoalgesia following the first session but proactively attenuated hypoalgesia during the second. Unlike animals preexposed to controllable shock, those given safety signals evidenced shuttle escape deficits 24 hr following the Day 2 inescapable shock treatment. Safety signals therefore failed to exert "immunization" effects. By employing identical preshock and shuttle test procedures, in Experiment 2 we demonstrated that safety signals completely block development of the escape deficit which otherwise results from the initial inescapable shock exposure. Thus, safety signals effectively reduce the impact of shock delivered in the same session but are ineffective in reducing the effect of subsequent shock. These results suggest that distinct processes underlie the effects of controllability and safety signals. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Corticosterone is involved in foot shock-induced inactivity in rats

Inescapable shock (IS) exposure induces behavioral inactivity, related to behavioral alterations in subsequent tests (i.e., escape failure, and inactivity during shuttle box task). Metyrapone (150 mg/kg, IP), a corticosterone (CS) synthesis inhibitor, administered 3 h prior to IS reduced inactivity during this aversive experience. Forty-eight hours later, when these rats were submitted to a shuttle box task, a reduction in both escape failure and inactivity was observed. These effects were reversed by CS (20 mg/kg, SC) and dose dependent of the synthetic glucocorticoid dexamethasone, both administered 1 h before IS. When metyrapone was administered 3 h before the shuttle box task to IS-exposed animals, escape failures and inactivity were markedly reduced. This effect was subsequently reversed by CS. The dynamics of changes in serum CS concentrations after both IS and shuttle box task paralleled behavioral changes. Animals injected with metyrapone before IS, which displayed active behavior, showed serum CS levels stable at their basal levels after shock, and their secretion pattern was quite attenuated after the shuttle box task, whereas vehicle-, CS alone-, and metyrapone + CS-injected animals showed higher serum CS concentrations post-IS, which slowly decreased to their corresponding basal levels. CS secretion after the shuttle box task was similar for the three groups: it had the same magnitude as after IS, though the decrease was faster. In all groups, animals displayed passive behavior. These results indicate that glucocorticoids are involved in the onset and expression of passive behaviors induced by uncontrollable stressors. Therefore, it is possible to suggest a functional relationship between CS released by exposure to inescapable stressor and the behavioral strategies adopted by rats under this stressful condition.     

Therapeutic effects of exercise: Wheel running reverses stress-induced interference with shuttle box escape.

Exercise can reduce symptoms of depression and anxiety in humans, but therapeutic effects of exercise in an animal model of stress-related mood disorders have yet to be demonstrated. In the current study, the authors investigated the ability of wheel running to reverse a long-lasting interference with shuttle box escape produced by uncontrollable stress. Rats who remained sedentary following uncontrollable foot shock demonstrated robust conditioned freezing behavior to the stressor environment and deficits in shuttle box escape learning. Voluntary access to running wheels for 6 weeks, but not 2 weeks, following uncontrollable foot shock reduced the expression of conditioned freezing and reversed the escape deficit. Results demonstrate a long-lasting interference with shuttle box escape that can be reversed by exercise in a duration-dependent fashion. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Associative structure of fear memory after basolateral amygdala lesions in rats.

The authors have recently demonstrated that rats with basolateral amygdala (BLA) lesions acquire Pavlovian fear conditioning after overtraining. However, it is not known whether the associative basis of Pavlovian fear memory acquired by rats with BLA lesions is similar to that of intact rats. Associations are typically formed between the conditional (CS) and unconditional (US) stimuli (stimulus-stimulus; S-S), although it is possible for stimuli to enter into association with the responses they produce (stimulus-response; S-R). Indeed, the central nucleus of the amygdala, which is essential for fear conditioning in rats with BLA lesions, may mediate S-R associations in some Pavlovian tasks. The authors therefore used a postconditioning US inflation procedure (i.e., exposure to intense footshock USs) to assess the contribution of S-S associations to fear conditioning after overtraining in rats with BLA lesions. In Experiment 1, intact rats that were overtrained and later inflated displayed elevated freezing levels when tested, indicating that S-S associations contribute to overtrained fear memories. Interestingly, neither neurotoxic BLA lesions nor temporary inactivation of the BLA during overtraining prevented the inflation effect (Experiment 2 and 3, respectively). These results reveal that S-S associations support Pavlovian fear memories after overtraining in both intact rats and rats with BLA lesions, and imply that the central nucleus of the amygdala encodes CS-US associations during fear conditioning. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Potentiation, overshadowing, and prior exposure to inescapable shock.

Four experiments are reported which explore the possibility that prior exposure to inescapable shock alters the way in which animals process information from responding during subsequent escape training. The stimulus consequences of responding were manipulated in each experiment. Rats received escapable shock, yoked, inescapable shock, or no shock prior to fixed ratio-2 (FR-2) shuttle escape training. A novel change in illumination following each shuttle response had opposite effects on inescapably shocked and control subjects. It dramatically improved the performance of inescapably shocked rats but impaired the performance of restrained subjects. The signal had no effect on escape trained animals. Response-produced auditory cues following each lever press on an FR-3 lever-press escape task were also observed to improve learning in inescapably shocked rats but to impair learning in restrained controls. The relation between lever pressing and the exteroceptive cue was manipulated. The exteroceptive cue enhanced learning in inescapably shocked rats when any two of the three required lever presses produced the cue. In contrast, the performance of restrained animals was impaired whenever the third response of the FR-3 produced the cue. Otherwise performance was unimpaired. The implications of these results are discussed with respect to the phenomena of potentiation and overshadowing, as well as to ways in which prior exposure to inescapable shock might alter information processing. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Isolation and characterization of the human prosaposin promoter

Male C57BL/6N mice were chosen to determine Fos production during acquisition of context-dependent fear and after re-exposure to the conditioning context. Fear-conditioning was induced by a single exposure of mice to a context followed by an electric shock. Control groups consisted of mice exposed to context only (Context group) or to an immediate electric shock. When contextual retention was measured 24 h after conditioning (retention test 1), significant contextual generalization was observed. However, when animals were exposed to a different context from days 2-5 after conditioning and then tested for retention on day 6 (retention test 2), generalization was markedly reduced. After the training, the fear-conditioned mice produced higher Fos levels than mice exposed to an immediate shock in the hippocampus, medial amygdaloid nucleus and parietal somatosensory cortex. Both shock groups produced significantly more Fos than the Context group in the central nucleus of the amygdala. After retention test 1, fear-conditioned mice generated more Fos in the hippocampus and central amygdaloid nucleus than the two control groups. However, all groups exhibited similarly low Fos production after retention test 2. The results demonstrated that simultaneous Fos production in the hippocampus, central and medial nuclei of amygdala and somatosensory parietal cortex closely paralleled the ability of mice to acquire conditioned fear. In contrast, Fos production after the retention tests did not correlate with the expression of conditioned fear.     

Effects of amygdala, hippocampus, and periaqueductal gray lesions on short- and long-term contextual fear.

Examines the effects of amygdala, hippocampus, and periaqueductal gray (PAG) lesions on contextual fear conditioning in 48 female rats. Freezing behavior served as the measure of conditioning. Unlesioned control Ss showed reliable conditional freezing in the testing chamber when observed both immediately and 24 hrs after footshocks. In contrast, Ss with amygdala or ventral PAG lesions exhibited a significant attenuation in freezing both immediately and 24 hrs after the shocks. Dorsal PAG lesions had no effect on freezing at either time. Ss with hippocampal lesions displayed robust freezing behavior immediately following the shock, even though they showed a marked deficit in freezing 24 hrs after the shock. These results indicate that there are anatomically dissociable short- and long-term conditional fear states. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

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

Previous research has shown that rats, like dogs, fail to escape following exposure to inescapable shock. 3 experiments were conducted with a total of 121 male Sprague-Dawley rats to further explore parallels between rat and dog helplessness. The failure to escape did not dissipate in time; Ss failed to escape 5 min, 1 hr, 4 hrs, 24 hrs, and 1 wk after receiving inescapable shock. Ss that first learned to jump up to escape were not retarded later at barpressing to escape following inescapable shock. Failure to escape could be broken up by forcibly exposing the S to an escape contingency. Therefore, the effects of inescapable shock in the rat parallel learned helplessness effects in the dog. (23 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Retrograde abolition of conditional fear after excitotoxic lesions in the basolateral amygdala of rats: Absence of a temporal gradient.

The role of the basolateral amygdala (BLA) in the acquisition and expression of Pavlovian fear conditioning was examined in 80 rats. Excitotoxic lesions were made in the BLA using N-methyl-{d}-aspartate 7 days before or 1, 14, or 28 days after Pavlovian fear conditioning. Conditioning consisted of three pairings of a tone with an aversive footshock in a novel chamber, and freezing behavior served as an index of conditional fear. BLA lesions abolished conditional freezing to both the contextual and acoustic conditional stimuli at all training-to-lesion intervals, and the magnitude of the impairment did not vary as a function of the training-to-lesion interval. Reacquisition training elevated levels of freezing in rats with BLA lesions but did not reduce the magnitude of their deficit in relation to that of controls. These results reveal that neurons in the BLA have an enduring role in the expression of conditional fear. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Cross-stressor immunization against the behavioral deficits introduced by uncontrollable shock.

In 4 experiments with 204 male CD-1 mice, exposure to inescapable shock disrupted performance in both shock- (SE) and water-escape (WE) tasks. These deficits were prevented in Ss that were previously trained in the same task. However, an asymmetrical immunization effect was seen in a cross-stressor paradigm. Whereas deficits of WE performance engendered by inescapable shock were prevented by prior SE training, the deficits of SE were not eliminated by prior WE training. Evidently, the immunization effect occurs when initial training and subsequent testing are conducted in the same task or when the initial training and uncontrollable stress session involve the same aversive stimulus. Norepinephrine (NE) determinations revealed that reductions of NE introduced by inescapable shock were unaffected by prior SE training and were enhanced by prior exposure to the stress of water immersion. Thus, although the performance deficit introduced by inescapable shock may be related to variations of NE, the immunization effect probably was unrelated to alterations of NE. Data provisionally suggest that the immunization stems from 2 independent factors: Initially training Ss in an active escape task may (a) disrupt subsequent learning that the inescapable stress actually is uncontrollable and (b) limit the influence of the motor deficits introduced by uncontrollable shock on subsequent escape performance. (28 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)