Shock Signal Research Articles

Immediate shock, passive avoidance, and potentiated startle: Implications for the unconditioned response to shock

Three experiments were performed to study the immediate-shock freezing deficit, a deficit in freezing in rats that results when electric shock is delivered immediately upon exposure to a novel context. This deficit was accompanied by failures to detect evidence of passive avoidance (Experiment 1) or potentiation of the auditory startle response (Experiment 2). The deficit in freezing was attenuated by preexposure to the shocked context (Experiment 3). The results support the view that fear-related behaviors are activated by signals for shock rather than by shock itself. They also suggest that the immediate-shock freezing deficit is due to a failure to process the to-be-conditioned contextual cues (Fanselow, 1986a, 1990).

Thiol reducing reagents inhibit the heat shock response. Involvement of a redox mechanism in the heat shock signal transduction pathway.

We evaluated the effects of thiol-reducing agents on the heat shock response in human and rodent cells in culture. Using HeLa cells as an example, we demonstrated that dithiothreitol (DTT,2mM) inhibited the heat (42 degrees C) induced increase in the synthesis of heat shock proteins (HSPs), abundance of mRNA of hsp 70, hsp 70 gene promoter activity, and the heat shock factor (HSF) DNA binding activity. This effect of DTT was specific and attributable to its reducing activity; oxidized DTT was ineffective, and other thiol reducing compounds had the same effect as DTT. Time course and dose-response studies showed that DTT significantly inhibited the heat shock induction of heat shock element binding activity with no preincubation and that 0.6 and 1-2 mM DTT gave half-maximal and maximal inhibition, respectively. The effect of DTT was reversible; removal of the DTT-containing medium prior to heat shock rendered the cells fully responsive. Analysis of the effects of DTT on the regulation and function of HSF suggests that DTT blocked an early and important step in the activation process without having a direct effect on the HSF protein. Thus, DTT inhibited the heat-induced trimerization, phosphorylation, and nuclear translocation of HSF and was also effective against a number of other reagents that are known to activate HSF. On the other hand, DTT did not block the response induced by heat shock at 45 degrees C, and in vitro addition of DTT failed to modulate the DNA binding activity of activated HSF present in cell extracts, suggesting that the HSF protein itself is unlikely to be a direct target of action of DTT. These results, together with the observation that activation of HSF DNA binding activity was attenuated under an anoxic condition and that hydrogen peroxide mimicked the effects of heat shock, suggest the involvement of a redox mechanism as an early and important step in the heat shock signal transduction pathway.

Cholecystokinin, but not bombesin, has interoceptive sensory consequences like 1-h food deprivation

A comparison of the interoceptive sensory consequences of cholecystokinin, bombesin, and 1-h food deprivation was conducted in rats. In two experiments, rats were first trained to use stimuli arising from different degrees of food deprivation (1 and 24 h or 1 and 4 h) as discriminative signals for shock, and were then tested for generalized control of discriminative responding (i.e., conditioned freezing) by cues arising from injection of 4 μg/kg (Experiment 1 only) and 8 μg/kg cholecystokinin (Experiment 1A only), 12 μg/kg bombesin (BBS), and isotonic saline, respectively. The effects of these peptides on food intake were also assessed. In both experiments, BBS and cholecystokinin (CCK) each suppressed feeding relative to saline; however, generalization of discriminative responding was obtained only following CCK. Generalization depended on prior learning about food deprivation cues—CCK had little effect on freezing in rats that showed weak discrimination performance (i.e., rats trained with 1- and 4-h deprivation cues). The results indicated that CCK but not BBS produces interoceptive cues like those occurring under 1-h food deprivation.

Potency of food deprivation intensity cues as discriminative stimuli.

Rats were trained to use stimuli arising from 0 and 24 hr without food as discriminative signals for shock. In Experiment 1, one group was shocked under 0-hr food deprivation and not shocked under 24-hr food deprivation. Another group received the reverse contingency. The groups received only 3 training trials under each deprivation level. Learning was revealed in a test phase when greater extinction of freezing was observed under the nonshocked than under the shocked deprivation level for both groups. A similar pattern of results was obtained in Experiment 2 when auditory cues were also relevant throughout training. Furthermore, prior training with food deprivation cues seemed to reduce learning about auditory cues subsequently trained in compound with deprivation stimuli. The results indicate that food deprivation intensity cues can be potent discriminative stimuli. The idea that deprivation cues function as conditioned modulatory stimuli cues is also discussed.

Stimulus control of immunization against chronic learned helplessness

Two experiments investigated the effectiveness of multiple (five) sessions ofsignaled escapable­ shock pretraining in preventing (immunizing against) the shock-escape impairment produced by an equal number of sessions of signaled inescapable shock. In Experiment 1, rats were exposed to 50 pairings per session of a white-noise stimulus with escapable shock during the immuniza­ tion phase. Subsequently, they were exposed to 50 pairings per session of a different (houselight) stimulus with inescapable shock. Shock-escape performance in a shuttlebox test with constant illumination revealed no evidence of immunization relative to the performance ofrats given five prior sessions of light-signaled inescapable shock only. Experiment 2 was identical in a11 respects to Experiment 1, except that both the escapable- and the inescapable-shock phases for animals in the immunization treatment group involved the same stimulus (houselight) as a shock signal. Under these circumstances, the prior escapable-shock training significantly reduced the shuttle­ box escape deficit engendered by chronic exposure to signaled inescapable shock; performance in the shuttlebox was not reliably different from that ofrats exposed to signaled escapable shock alone. These findings suggest that, under chronic conditions, the development of stimulus con­ trol using Pavlovian conditioning procedures may serve to modulate the normally prophylactic influence on later shock-escape acquisition of serial exposure to escapable and inescapable shocks.

Antibody-Mediated Activation of Drosophila Heat Shock Factor in Vitro

Eukaryotic cells respond to elevated temperatures by rapidly activating the expression of heat shock genes. Central to this activation is heat shock-inducible binding of the transcriptional activator, termed heat shock factor (HSF), to common regulatory elements, which are located upstream of all heat shock genes. The DNA binding activity of the inactive form of Drosophila HSF was induced in vitro by treatment with polyclonal antibodies to the purified, in vivo-activated factor. This finding, together with observations that high temperature and low pH activate HSF binding in vitro, suggests that the inactive form of HSF can directly recognize and transduce the heat shock signal without undergoing a covalent modification of protein structure.

Discontinuation of diazepam and sensitivity to a shock signal: Fear conditioning prior to drug treatment

The present experiment examined the disruptive capacity of a shock CS when Pavlovian training was completed prior to repeated daily treatment with diazepam (DZ). Two groups of rats were given 20 Pavlovian fear conditioning trials (two per day) to establish a light CS as a shock signal. Both groups were then trained for 15 daily sessions to bar press for food reinforcement. Before each session, one group was injected IP with 5 mg/kg DZ and the other with saline. All injections were discontinued after the last training session. Nine days later, the capacity of the CS to disrupt bar pressing was tested. The CS produced greater disruption of bar pressing for rats that had previously received chronic diazepam treatment. The results suggest that DZ discontinuation increases sensitivity to cues established as fear elicitors prior to initial administration of DZ.

The long-term effects of diazepam and pentylenetetrazol on the potentiated startle response

Stress desensitization is observed as a decrease in the disruptive effects of a stressor on behavior when the organism is repeatedly exposed to the stressor. For instrumental behavior, stress desensitization was also reported for rats preexposed to anxiogenic drugs; stress sensitization was reported for rats preexposed to an anxiolytic compound. The present study investigated whether similar effects are found in a noninstrumental task situation. First, rats received 12 daily injections of pentylenetetrazol (PTZ, 20 mg/kg, IP), diazepam (DZP, 5 mg/kg, IP) or saline. After each injection the effect of the drugs on the acoustic startle reflex was measured. No drugs were given during the remainder of the experiment. Eight days later rats were given 5 days of Pavlovian fear conditioning to establish a light as a shock signal. During the next 3 days, potentiation of the startle response by the light was measured. None of the drug treatments had an effect on startle potentiation, indicating that stress sensitivity is not affected by previous administration of PTZ and DZP in a noninstrumental task. An explanation for the different effects found for instrumental and noninstrumental tasks is suggested.

Source mechanism study of the 1982 New Brunswick, Canada, earthquake sequence using combined surface-wave methods

Abstract A combined phase-matched-filtering and narrow-bandpass-filtering method and a surface-wave Love-to-Rayleigh spectral-amplitude-ratio method are used to analyze the 1982 New Brunswick earthquake sequence. The analysis was carried out on the long-period fundamental-mode surface-wave signals (10 to 50 sec) for the main shock and its four largest aftershocks recorded at three GDSN stations (SCP, LON, and ALQ) in North America. Estimates of source mechanism parameters (focal depth, dip, rake, and strike) obtained for the 9 January 1982 main shock and the largest aftershock on 11 January 1982 are consistent with Wetmiller et al. 9s (1984) results for these events using local and regional body-wave observations. Source mechanism parameters were also obtained for the 9 January 1982, the 31 March 1982, and the 16 June 1982 aftershocks which do not have independent estimates. Since these three events have low signal-to-noise ratios (S/N) at some frequencies, the source parameter estimates are not as well constrained as those of the main shock and the 11 January aftershock. The inferred principal stress orientations are in all cases consistent with the prevailing ENE maximum compressive stress characteristic of most areas in eastern North America. Among the principal aftershocks, the most reliable source parameter estimates were for the 11 January aftershock because of its consistently high S/N seismograms. This aftershock consisted of thrusting on a fault plane conjugate to the main shock fault plane with dip of 40° to 55° to the northeast; rake of 60° to 80°; strike of 337° to 342°; and a depth of 6 km. This result also supports Wetmiller et al. 9s (1984) findings for this event. The 9 January aftershock has a source mechanism similar to that of the main shock but a shallower depth of 6 km (versus 7 km for the main shock). The 31 March aftershock is associated with the upper portion of the main shock rupture, with a much shallower depth of approximately 3 km. The result for the 16 June aftershock is not as dependable; but it appears to have a deeper depth of 8 km or more, which suggests extension of the rupture zone to greater depth. The results of this study indicate that surface-wave data from only a few three-component far-field stations can be used to infer source parameters (including depth) for events as small as about m b 4.5. To the extent that eastern North America is typical of other continental interiors in terms of crustal structure and attenuation, similar capabilities are anticipated for such areas.

The long-term effects of diazepam, lorazepam, and buspirone on behavioral suppression by a shock signal

1. Two experiments examined the long-term effects of treatment with buspirone (a nonbenzodiazepine anxiolytic), diazepam, or lorazepam (two pharmacokinetically distinct benzodiazepines) on the capacity of a shock cue to disrupt appetitively conditioned behavior. 2. In Experiment 1, rats were injected with diazepam (5 mg/kg), buspirone (1.5 mg/kg or .75 mg/kg), or saline shortly before each of 12 bar press training sessions. Injections were suspended and three days later the rats received five days of Pavlovian fear conditioning (bars removed) in which a tone signaled shock. The capacity of the tone to disrupt bar pressing was then assessed. 3. Bar pressing of rats previously injected with diazepam was more suppressed by the shock cue than that of rats previously injected with buspirone or saline. The long-term effects of buspirone and saline did not differ. 4. In Experiment 2, lorazepam had effects different from diazepam during bar press training. Nonetheless, rats previously injected with lorazepam were also more disrupted by a shock cue than were controls. 5. The results suggest that one long-term consequence of treatment with benzodiazepines may be hypersensitivity to behavioral disruption by stimuli that presumably elicit fear or anxiety.

Procedure and reliability of conditioned respiratory suppression

Changes in respiration amplitude, respiration rate, and heart rate in response to a conditioned signal for shock were measured concurrently in kittens and adult cats. The data were analyzed with respect to qualitative and quantitative variability across trials and subjects; correlation among measures; skewness; and kurtosis. Suppression of respiration amplitude was the most reliable response across trials and subjects, with increases in respiration rate second and heart rate by far the least reliable. Correlations between each pair of measures were moderate. Respiration-amplitude responses were negatively skewed, but this deviation from normality was moderate and consistent across subjects. The measurement of conditioned respiratory suppression is a viable addition or alternative to the conditioned emotional response procedure in studies of classically conditioned fear.

Comparison of the interoceptive sensory consequences of CCK, LiCl, and satiety in rats.

In three experiments we assessed the degree to which ad lib feeding, injection of cholecystokinin (CCK), and injection of lithium chloride (LiCl) produce states with similar sensory consequences. In each experiment, two groups of rats were trained to use cues arising from food deprivation and satiation as discriminative signals for shock. One group was shocked when deprived but not when nondeprived. The other group received the reversed discrimination. Testing began when incidence of freezing was greater under the shocked deprivation than under the nonshocked deprivation condition. In Experiment 1, the rats were tested under 24-hr food deprivation after injections of CCK, LiCl, and saline (in counterbalanced order). We reasoned that if either CCK or LiCl induce satiety-like states, they should promote patterns of responding different from those produced by saline but similar to those produced by ad lib feeding. The effects of CCK on freezing did not differ from those of saline, whereas both CCK and LiCl had effects that were different from ad lib feeding. This pattern of results was also obtained when deprivation level during training and testing was reduced to 8 hr (Experiment 1A) and also when rats received small amounts of food in conjunction with CCK (Experiment 2). The intubation of a high-calorie stomach load (Experiment 1A) produced a response profile like that observed after free feeding. Freezing after LiCl treatment differed from that observed after free feeding and from that found after injection of CCK. The results indicate that rats can differentiate between the sensory consequences of the states produced by CCK, by LiCl, and by ad lib feeding.

Long-term effects of yohimbine on behavioral sensitivity to a stressor.

Two experiments examined the long-term effects of repeated administration of yohimbine, a suspected anxiogenic drug, on behavioral sensitivity to a conditioned cue for shock. In Experiment 1, rats were trained to bar press following injection of yohimbine (either 1 or 2 mg/kg) or saline. At the end of this training, injections were suspended and the rats were given Pavlovian fear conditioning to establish a light as a shock signal. Rats were then returned to the bar press situation (about 2 weeks after their last injection) and the capacity of the light to disrupt responding was tested. Rats previously treated with yohimbine were less disrupted by the light than were controls. In contrast, Experiment 2 found that previously experiencing the yohimbine-induced state only in the home cage increased subsequent disruption of bar pressing by the light. Yohimbine pretreatment had no effect on acquisition of freezing behavior to the light, nor on bar pressing during testing in the absence of the light, in either experiment. The results show that yohimbine can have long-term effects on behavior in the presence of a stressor, and that the nature of these effects are dependent upon environmental and/or behavioral context in which the yohimbine-induced state was experienced. These findings appear compatible with an internal stimulus view of stress and stress inoculation.

The long-term effects of diazepam and pentylenetetrazol on behavioral sensitivity to a stressor

Rats were trained to bar press for sucrose reinforcement following daily injections of 20 mg/kg pentylenetetrazol (PTZ), 5 mg/kg diazepam (DZ), or saline. At the end of 12 days of this training, all injections were suspended for the remainder of the experiment. Five days later, the rats were given 10 days of Pavlovian fear conditioning (two trials per day) to establish a light as a shock signal. Next, the rats were returned to the bar press situation to test the capacity of the light to suppress responding. Rats previously treated with DZ showed stronger conditioned fear of the light than did rats originally trained following injections of either PTZ or saline. In contrast, bar pressing by PTZ-treated rats was less suppressed by light than was control performance. The results indicate that modification of the behavioral effects of environmental stressors can be a long-term consequence of drug treatments. DZ treatments had the long-term effect of increasing behavioral disruption by a stressor, while treatment with PTZ reduced the stressor's negative behavioral impact. These findings appear compatible with the idea that behavioral sensitivity to stressors is dependent, in part, on learning about the stimulus properties of internal states.

Shock signals and the development of stress-induced analgesia.

Shock signals and the development of stress-induced analgesia.

Shock signals and the development of stress-induced analgesia.

We report five experiments in which we investigated the effects of "feedback signals" on the pattern of hypoalgesia produced by inescapable shocks. A 5-s lights-out stimulus coincident with shock termination had no effect on the naltrexone-insensitive (nonopioid) hypoalgesia, which occurred after 10 inescapable shocks, but completely blocked the naltrexone-sensitive (opioid) hypoalgesia, which followed 100 inescapable shocks. The stimulus prevented the development of the opioid hypoalgesia rather than merely masking its measurement. This effect did not depend on the use of lights-out as the stimulus but did depend on the temporal relation between the stimulus and shock. Stimuli immediately preceding or simultaneous with shock had no effect. Surprisingly, stimuli randomly related to shock also blocked the opioid hypoalgesia. Simultaneous measurement of both hypoalgesia and fear conditioned to contextual cues revealed that the level of fear did not predict the blockade of hypoalgesia. Different backward groups received different temporal gaps between shock termination and the signal. An interval between 2.5 s and 7.5 s eliminated the effect of the signal on fear, but 12.5-17.5 s were required to eliminate the effect of the signal on hypoalgesia. The opioid hypoalgesia blocking power of the random stimulus was entirely attributable to those stimuli occurring within 15 s of the termination of the preceding shock. The implications of these results for the explanation of stimulus feedback effects and for stress-induced analgesia are discussed.

Learning about deprivation intensity stimuli.

Rats demonstrated that they can use deprivation-produced stimuli as discriminative signals for shock in three experiments that used observation of freezing behavior as the index of learning. In Experiment 1, one group was shocked under 24-hr, but not under 0-hr food deprivation. Another group received the reversed discrimination. Both groups froze more under their shocked than under their nonshocked deprivation level. Furthermore, freezing was greatest under a given deprivation level for the group shocked under that level. Behavior was shown to be a function of this learning during subsequent testing under other deprivation levels. In Experiment 2, rats discriminated between deprivation intensities approximating those encountered under free-feeding conditions, and behavior under other deprivation levels also depended on this learning. Experiment 3, using 6- and 23-hr food deprivation, showed that discriminative responding occurred in the absence of cues arising from the recent memory of food in the home cage. Generalization of discriminative control to cues produced by intubation of a high calorie load and to injection of insulin (Experiment 3A) provided evidence that animals learned about the interoceptive stimulus consequences of their deprivation states. The results encourage the view that learning about internal stimulus aspects of food deprivation plays a role in appetitive behavior.

Electroconvulsive shock and cyclic AMP signal transduction: effects distal to the receptor.

Chronic electroconvulsive shock (ECS) induced a significant decrease in noradrenaline- and forskolin-stimulated cyclic AMP production in rat cortical slices, whereas a single ECS had a much smaller effect. In a cortical membrane preparation, adenylate cyclase activity in response to stimulation by forskolin, guanosine-5'-(beta,gamma-imido) triphosphate, and Mn2+ ions was significantly increased in membranes derived from rats that had received chronic ECS, but was either unchanged or reduced in membranes from rats that received a single treatment only. The results are interpreted in terms of changes occurring at components of the adenylate cyclase enzyme distal to the receptor.

Inhibition of the heat shock response and synthesis of glucose-regulated proteins in Ca2+-deprived rat hepatoma cells

Rat hepatoma cells become refractory to the induction of heat shock proteins and highly resistant to severe hyperthermia when incubated in Ca2+-free medium. The Ca2+-depleted cells synthesize polypeptides identified as the glucose-regulated proteins, but these proteins do not appear to be directly involved in the inhibition of the heat shock response. The results suggest that a Ca2+-dependent metabolic process is involved in the generation of the heat shock signal and/or mediates a step in the subsequent cascade of events that leads to the induction of heat shock protein synthesis and cell death.

Alleviation of response suppression to conditioned aversive stimuli by lesions of the dorsal noradrenergic bundle

Rats with neurotoxic lesions of the dorsal ascending noradrenergic bundle (DB) were compared with sham-operated (SH) controls on the acquisition, steady state and extinction of response suppression maintained by a classical (conditioned suppression) or an instrumental (discriminated punishment) contingency. DB lesions interfered neither with the acquisition of the reference response of sucrose-rewarded barpressing nor with unconditioned responding to the overhead flashing light subsequently used as a signal of shock. The acquisition of discriminated response suppression was also unaffected by the lesion under both types of contingency. However, once discriminated suppression had stabilized, both the conditioned and the discriminative stimulus used were significantly less effective in maintaining suppression in DB animals than in SH controls provided that low intensity footshock (0.2 mA) was used as the unconditioned stimulus (UCS). Upon increase of UCS intensity (to 0.5 mA) normal suppression was observed in the DB group under both contingencies. Extinction of the classical contingency reinstated the difference between DB and SH performance: DB lesion resulted in significantly faster extinction of fear. In contrast, extinction of the discriminated punishment contingency was unaffected by the lesion, although generalized response suppression dissipated faster in the DB than in the SH animals trained under this condition. Our results offer no support for the reinforcement hypothesis of DB function (normal acquisition of barpressing and of discriminated suppression of barpressing); mixed support (greater initial generalization of suppression in DB animals) and contradiction (more rapid extinction of conditioned suppression in DB animals) for the attentional hypothesis; and weak support (reduced suppression and more rapid extinction of suppression in DB animals, but only within limited experimental parameters) for the anxiety hypothesis of DB function. Hence none of the extant theories of DB function offer a ready explanation of the pattern of results presented here. A simple interpretation which conforms with the sparsity of positive behavioural findings in the literature on DB lesions is that forebrain noradrenaline contributes to the detection and utilization of conditioned stimuli; but that this contribution is critical only for the detection of stimuli with low associative strength.