Shock Schedule Research Articles

Effects of pharmacological and environmental manipulations on choice between fentanyl and shock avoidance/escape in male and female rats under mutually exclusive and non-exclusive choice conditions.

Substance use disorders are defined by persistent drug consumption despite adverse consequences. Accordingly, we developed two fentanyl-vs-shock avoidance/escape choice procedures in which male and female rats responded under a fixed-ratio (FR)1:FR1 concurrent schedule of shock avoidance/escape and IV fentanyl under either mutually exclusive or non-exclusive choice conditions. Initial experiments using a discrete-trial procedure determined behavioral allocation between mutually exclusive shock avoidance/escape and different fentanyl doses (0.32-18 μg/kg/infusion; Experiment 1). Shock intensity (0.1-0.7 mA) and shock avoidance/escape response requirement (FR1-16) were also manipulated (Experiment 2). Next, we used a free-operant procedure in which shock avoidance/escape and fentanyl were continuously available under non-exclusive conditions, and response-shock (R-S) interval (30-1000 s) was manipulated (Experiment 3). Finally, we tested the hypothesis that extended-access fentanyl self-administration would produce fentanyl dependence, establish fentanyl withdrawal as an endogenous negative reinforcer, and increase fentanyl choice in both procedures (Experiments 4 and 5). The shock avoidance/escape contingency decreased fentanyl self-administration, and rats consistently chose shock avoidance/escape over fentanyl in both choice conditions. Decreasing shock intensity or increasing shock avoidance/escape response requirement failed to increase fentanyl choice, suggesting that fentanyl and shock avoidance/escape are independent economic commodities. Increasing the R-S interval increased fentanyl choice but failed to increase shock delivery. Extended fentanyl access engendered high fentanyl intake and opioid withdrawal signs but failed to increase fentanyl choice under either choice condition. These results suggest that neither positive fentanyl reinforcement nor negative reinforcement by fentanyl withdrawal is sufficient to reduce shock avoidance/escape-maintained responding and increase foot shock as an adverse consequence.

The evolution of day-of-the-week and the implications in crude oil market

The movement of prices in the crude oil market are important to the international economy and financial asset returns. Day-of- the-week effect is a great challenge to the market's effectiveness. We examine the evolution of day-of-the-week and investigate its implications based on the West Texas Intermediate crude oil return from 14 May 2007 to 14 May 2021. We have obtained convincing findings that there is abnormal positive return on Wednesdays because the inventory shock schedule. Abnormal negative return on Mondays disappears sometimes, because bad sentiment is not the only decisive factor, as it is also determined by reactions to good sentiment. The results provide implication for the day-of-the-week effect and new evidence that crude oil market's efficiency changes over time. Policy makers, investors and producers can benefit from this.

Shock-induced hyperalgesia: IV. Generality.

Brief-moderate shock (3, 0.75 s, 1.0 mA) has opposite effects on different measures of pain, inducing antinociception on the tail-flick test while lowering vocalization thresholds to shock and heat (hyperalgesia) and enhancing fear conditioned by a gridshock unconditioned stimulus (US). This study examined the generality of shock-induced hyperalgesia under a range of conditions and explored parallels to sensitized startle. Reduced vocalization thresholds to shock and antinociception emerged at a similar shock intensity. Severe shocks (3, 25 s, 1.0 mA or 3, 2 s, 3.0 mA) lowered vocalization threshold to shock but increased vocalization and motor thresholds to heat and undermined fear conditioned by a gridshock or a startling tone US. All shock schedules facilitated startle, but only brief-moderate shock inflated fear conditioning. The findings suggest that brief-moderate shock enhances the affective impact of aversive stimuli, whereas severe shocks attenuate pain.

Effects of different classes of partial benzodiazepine agonists on punished and unpunished responding in pigeons.

Although all of the benzodiazepines in use for the treatment of anxiety are presumably full agonists, it is conceivable that partial benzodiazepine agonists may also be clinically effective on the basis of their effects in preclinical models of anxiety. To compare the anxiolytic-like effects of different pharmacological/chemical classes of partial benzodiazepine agonists in the pigeon conflict procedure. Anticonflict effects in pigeons whose responding was maintained under a multiple FR30 food:FR30 food+shock schedule were characterized by 1) the magnitude of punished responding or 2) the percentage of pigeons (n=5-7/dose) showing significant increases in punished responding. The partial allosteric modulators bretazenil and imidazenil produced anticonflict effects comparable with or superior to those observed following administration of the relatively full agonist midazolam. In contrast, neither the beta-carbolines CGS 9896, ZK 95962 and ZK 91296, nor the imidazopyridines, alpidem and zolpidem, produced anticonflict effects comparable to either bretazenil and imidazenil or the relatively full benzodiazepine agonist, midazolam, at the doses examined in this study. Although the beta-carboline ZK 95962 produced some anticonflict effects, none of the other compounds had anxiolytic-like effects like those observed with midazolam, bretazenil or imidazenil. However, because bretazenil and imidazenil produced robust anticonflict activity, the results indicate that partial allosteric modulators could have anxiolytic effects similar to those produced by higher efficacy compounds. Altogether, the results indicate that partial benzodiazepine agonists differ in their ability to produce robust anticonflict effects in the pigeon.

Effects of benzodiazepine agonists on punished responding in pigeons and their relationship with clinical doses in humans.

Anxiolytic drugs generally produce anticonflict effects in both pigeons and rats, although relatively few anxiolytics have been examined in the pigeon and the procedure has not been as completely validated as the rat model. In this study, we examined the antipunishment effects of a variety of benzodiazepine agonists in pigeons and compared the relationship between their potencies to engender anxiolytic-like effects and their clinical doses in humans. In pigeons whose responding was maintained under a multiple FR30food:FR30food+shock schedule, the benzodiazepine agonists diazepam, flunitrazepam, alprazolam, chlordiazepoxide, lorazepam, flurazepam, bromazepam, medazepam, and clorazepate produced dose-related increases in punished responding, and, with the exception of medazepam, decreased unpunished responding at higher doses. Potencies calculated from the percentage of pigeons showing significant increases in punished responding ranged from 0.081 to 11 mg/kg, and these potencies were invariably lower than those for decreases in unpunished responding by factors ranging from 2.2 to more than 14. The comparison of relative potencies of benzodiazepine receptor agonists in pigeons and humans revealed a high positive correlation (0.90, P<0.005), thus demonstrating the predictive validity of this preclinical animal model for anxiolytic benzodiazepines. The results agree with previous findings of robust anticonflict effects of benzodiazepine receptor agonists and extend further the pharmacological characterization to compounds that have not been examined previously in pigeons.

Antipunishment activity of diazepam in rats trained to discriminate diazepam from vehicle.

The anxiolytic and discriminative stimulus effects of drugs in the same rats during a single session were examined in this study. Rats were trained to discriminate diazepam (5 mg/kg) from vehicle in a 2-lever drug discrimination procedure and were then trained to press a 3rd lever under a multiple fixed-interval (60 sec), fixed-ratio 5 + shock schedule of food reward. Diazepam produced substitution for itself in all rats; however, it produced antipunishment effects in some of the rats, suggesting that its discriminative stimulus and antipunishment effects are separable. In contrast, the N-methyl-D-aspartate antagonists, NPC 17742 and phencyclidine, failed to substitute fully for diazepam and did not increase punished responding in any of the rats. These results are consistent with those of studies showing that drugs from this class produce weaker antipunishment effects than diazepam does. The potential utility of this new method is that it allows direct comparisons of the antipunishment and discriminative stimulus effects of putative anxiolytic drugs during a single session with the same animals.

Phencyclidine- and diazepam-like discriminative stimulus effects of inhalants in mice.

It has been shown that abused solvents, such as 1,1,1-trichloroethane (TCE) and toluene, share certain pharmacological properties with central nervous system depressants, such as alcohol and anesthetic vapors. Several vapors were tested for diazepam (DZ)- and phencyclidine (PCP)-like discriminative stimulus effects to further explore their pharmacological specificity. In DZ-trained mice, methoxyflurane fully substituted, and TCE produced partial substitution. Fluorothyl and toluene produced no appreciable DZ-lever responding at any concentration tested. On the other hand, toluene produced concentration-related partial substitution for PCP, whereas methoxyflurane, TCE, and fluorothyl did not substitute. The substitution of some these vapors for DZ or PCP suggests that, like ethanol, the discriminative stimulus effects of abused solvents partially overlap those of N-methyl-D-aspartate antagonists as well as those of gamma amino butyric acid agonists.

The relationship between shock severity and the form of the antinociception observed in pentobarbital-anesthetized rats

Three experiments are reported that explore the opioid/nonopioid nature of environmentally induced antinociception in pentobarbital-anesthetized rats. In Experiment 1, the minimum shock intensity and duration that elicits antinociception was established and two alternative descriptions of the tradeoff between shock intensity and duration were evaluated: the coulometric relationship (duration × intensity) and an extension of Stevens’s power law (duration × intensity3.5). The results support the power law. In Experiments 2 and 3, the relationship between shock severity and the form of the antinociception elicited was examined. It was found that the least severe shock schedules produced a naltrexone-insensitive “nonopioid” antinociception. Increasing shock severity elicited an “opioid” antinociception that was attenuated by naltrexone. When shock severity was increased further, the antinociception again became naltrexone insensitive. Implications of the results are discussed.

Impact of shock on pain reactivity: III. The magnitude of hypoalgesia observed depends on test location.

Pain reactivity is often assessed in rodents by measuring the latency of tail withdrawal from radiant heat (the tail-flick test). Using this test, the authors show that the magnitude of antinociception observed in spinal rats depends on test location; antinociception is observed at, and distal to, where shock is applied, but not at more proximal sites (Experiments 1 & 2). Experiment 3 evaluates the generality of this observation by testing 3 other shock schedules that are known to elicit distinct forms of antinociception. In all but 1 case, the magnitude of antinociception varied as a function of test location. Experiment 4 shows that morphine also has a greater impact at distal test locations. Experiment 5 assessed the impact of tailshock on reactivity to radiant heat applied to the foot. Of the 5 distinct forms of shock-induced antinociception studied, only 2 produce a robust antinociception at this test location.

MOLECULAR CONTINGENCIES IN SCHEDULES OF INTERMITTENT PUNISHMENT

In two experiments, key pecking of pigeons was maintained by a variable-interval 180-s schedule of food presentation. Conjointly, a second schedule delivered response-dependent electric shock. In the first experiment, shocks were presented according to either a variable-interval or a nondifferential interval-percentile schedule. The variable-interval shock schedule differentially delivered shocks following long interresponse times. Although the nondifferential shock schedules delivered shocks less differentially with respect to interresponse times, the two shock schedules equally reduced the relative frequency of long interresponse times. The second experiment differentially shocked long or short interresponse times in different conditions, with resulting decreases in the relative frequency of the targeted interresponse times. These experiments highlight the importance of selecting the appropriate level of analysis for the interaction of behavior and environment. Orderly relations present at one level of analysis (e.g., interresponse times) may not be revealed at other levels of analysis (e.g., overall response rate).

Exploring the edges of Pavlovian contingency space: An assessment of contingency theory and its various metrics

Water-deprived rats served in a conditioned lick suppression paradigm to assess the effects of varying p(US|CS) with p(US|no-CS) = 0, and varying p(US|no-CS) with p(US|CS) = 1, which correspond to the left edge and top edge, respectively, of Rescorla's contingency space. In Experiment 1, the frequency of occurrence of an auditory CS was held constant and 100, 75, 50, 25, or 0% of these CSs were reinforced with footshock. Consistent with prior studies,statistically equivalent asymptotic responding to the CS was seen at partial reinforcement levels of 25% or greater. This equivalent responding was not due to a ceiling effect. In Experiments 2 and 3, varying frequencies of unsignaled shocks were intermingled with a continuously reinforced CS (i.e., partial signaling of the US). Lean schedules of reinforcement of intervals lacking the CS (as low as 3.1% when the non-CS time was divided into intervals equal to CS duration) attenuated asymptotic conditioned responding, and higher schedules of unsignaled shock from 25 to 100% yielded higher and approximately equal attenuations of responding. Simulations of Δ p, the Rescorla-Wagner model, Gibbon and Balsam's scalar expectancy theory, the φ correlation coefficient and other measures of contingency were performed. φ provided the best least-mean-square fit to the data. Possible psychological bases for the apparent superiority of φ are discussed and related to frequency theory. Additionally, the merits and inherent problems of contingency theories in general are reviewed.

Effects of serotonin agonists on operant behavior in the squirrel monkey: Quipazine, MK-212, trifluoromethylphenylpiperazine, and chlorophenylpiperazine

The behavior of squirrel monkeys was studied under fixed-interval (FI) schedules with responding maintained either by food presentation or by termination of stimuli correlated with impending electric shock delivery (stimulus-shock termination). The 5-HT agonists m-trifluoromethylphenylpiperazine (TFMPP), m-chlorophenylpiperazine (mCPP), and 6-chloro-2(1-piperazinyl)pyrazine (MK-212) decreased responding under both the food and shock schedules (0.3−5.6 mg/kg). These decreases in responding were blocked by the nonselective 5-HT antagonists methysergide and mianserin (0.3, 1.0 mg/kg), but not by the selective 5-HT 2 antagonists ketanserin (0.3−1.7 mg/kg) or pirenperone (0.001−0.1 mg/kg). Quipazine (0.3−5.6 mg/kg) decreased responding under the food schedule, and this effect was blocked by both the nonselective and selective 5-HT 2 antagonists. This pattern of antagonism suggests that the decreases in responding produced by quipazine involve significant actions at 5-HT 2 sites, whereas those produced by TFMPP, mCPP, and MK-212 do not. In contrast to the decreases in responding seen with the food schedules, quipazine produced moderate increases in responding under the shock schedules. Moreover, these increases in responding were not blocked by methysergide or mianserin, but instead were enhanced. The results with antagonists suggest that certain behavioral effects of quipazine are probably due to actions at 5-HT 2 sites, whereas similar effects of TFMPP, mCPP, and MK-212 are more related to actions at other 5-HT receptor subtypes.

Role of supraspinal systems in environmentally induced antinociception: Effect of spinalization and decerebration on brief shock-induced and long shock-induced antinociception.

Prior research suggests that afferent nociceptive information can directly activate the opioid and nonopioid brainstem antinociceptive systems. Grau (1987a) has hypothesized that direct activation occurs when an organism is exposed to severe aversive stimuli and that forebrain systems mediate the activation of the antinociception systems when mild aversive stimuli are used. The present experiments tested this hypothesis by examining the impact of spinalization and decerebration on the antinociception observed after mild (3 0.75-s 1.0-mA shocks) and vs. severe (3 25-s 1.0-mA shocks) tailshocks. It was found that spinal transection eliminated the antinociception observed after both shock schedules, whereas decerebration blocked mild shock-induced, but not severe shock-induced, antinociception. Surprisingly, decerebration potentiated severe shock-induced antinociception. The opioid antagonist naltrexone had no effect on the antinociception observed after severe shock in sham or decerebrate rats.

Reconciling differences in drug effects on behavior punished or maintained by response‐produced shock

AbstractComparable patterns of behavior maintained by different events are affected similarly by certain drugs and differently by others. The present paper argues that patterns of behavior maintained by response‐produced shock (“shock‐maintained behavior”), although similar in appearance to lever pressing maintained by more conventional positive reinforcers, are generated through differential punishment of long interresponse times; hence, drug effects on this behavior should more closely resemble drug effects on pressing suppressed by punishment. Because the operants suppressed in these procedures are diametrically opposed (long interresponse times vs. pressing), the baseline patterns of behavior will differ (suppressing long interresponse times produces high rates of pressing, punishing pressing produces low rates). Furthermore, any drug‐induced changes in the frequency of the punished operant will result in what appear to be dissimilar drug effects if the rate of only one operant class serves as the dependent variable. That is, drugs that increase the rate of pressing that has been suppressed by punishment should increase long interresponse times similarly suppressed. This results in an overall increase in pressing rate under typical punishment procedures, but a decrease in overall pressing rates (an increase in the rate of punished long interresponse times) under shock‐maintenance procedures. Hence, similar drug effects on these inversely related operants should generate opposite changes in pressing rate under the two sets of procedures. A review of the literature revealed this to hold true in 12 of 15 cases. Drug effects on comparable patterns of pressing maintained by shock or food presentation split more evenly. The literature indicates that, of 21 such, comparisons between pressing maintained under fixed‐interval schedules of food or shock, ten yielded comparable drug effects under both, and 11 yielded dissimilar effects. These results suggest that what appear to be dissimilar drug effects on pressing maintained or suppressed by shock may in fact be similar effects on the inversely related operants differentiated under these procedure.

Lithium effects on adjunctive alcohol consumption. III: FT-shock as the inducing schedule.

Under conditions in which a mild shock (0.5 mA, 200 msec) was delivered, independently of the subject's behavior, every 90 sec (an FT 90-sec shock schedule), subjects receiving chronic lithium chloride in their drinking water (25 mEq/l), showed a rapid acquisition of an adjunctive alcohol consumption, while subjects in the control groups did not. Following termination of the FT-shock condition (extinction), subjects in all groups showed an increase in alcohol consumption, relative to both baseline and adjunctive levels.

Differential effects of pentobarbital and cocaine on punished and nonpunished responding.

Similar rates of punished and nonpunished responding, maintained with equated rates of reinforcement, were established in pairs of rats. One subject of each pair was exposed to a random-ratio schedule of food presentation. The interreinforcement intervals for this subject comprised the intervals of a random-interval schedule of reinforcement for the other (yoked) rat. The random-ratio schedule maintained rates of responding higher than those maintained by the same rate of reinforcement schedule according to the yoked random-interval contingency. A random-ratio schedule of electric foot shock added to the random-ratio schedule of food presentation suppressed rates of responding such that similar rates of responding were observed in rats of both groups. Pentobarbital (3.0 to 17.0 mg/kg) increased punished responding at doses that had little effect on or decreased nonpunished responding, whereas cocaine (5.6 to 30 mg/kg) increased nonpunished responding at doses that decreased or did not alter punished responding. Qualitatively different effects of pharmacological agents on punished and nonpunished responding can be obtained using procedures that generate similar rates and temporal patterns of punished and nonpunished responding. The effects of pentobarbital and cocaine on responding can be determined by factors other than simply the baseline rate of responding.

Effects of the novel benzodiazepine agonist quazepam on suppressed behavior of monkeys

Behavioral effects of the benzodiazepine agonist quazepam were compared with those of lorazepam in squirrel monkeys responding under a fixed-interval schedule of food presentation with a superimposed fixed-ratio schedule of response-produced shock. Low and intermediate i.v. doses of quazepam (0.1–1.0 mg/kg) and lorazepam (0.03–0.3 mg/kg) increased rates of suppressed responding, yet the maximal increases in rate were less after quazepam than after lorazepam. Higher doses of both drugs tended to increase responding less or decrease it and, with quazepam, frequent sleep was observed for 2–3 days afterwards. The dose-response curves for quazepam and lorazepam were shifted to the right following i.v. pretreatment with the benzodiazepine antagonists Ro 15-1788 (0.18–3.0 mg/kg) or AHR-11797 (1.0–5.6 mg/kg); in this regard, AHR-11797 was less potent than Ro 15-1788. Although the effects of quazepam on suppressed responding are likely due to actions at benzodiazepine receptors, these effects may be influenced by or reflect a more prominent sleep-promoting action of the drug.

GABA-related drugs modulate the behavioral effects of lorazepam.

The behavioral effects of the GABA-related drugs SL 75102 (4-[[(4-chlorophenyl)-(5-fluoro-2-hydroxyphenyl)-methylene]amino]butyric acid) and THIP (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyrindin-3-ol) were studied alone and in combination with lorazepam. Two groups of squirrel monkeys responded under a fixed-interval schedule of food presentation. In one group, responding was suppressed by superimposing a fixed-ratio schedule of response-produced electric shock; responding was not suppressed in the second group. Dose-response curves were determined by administering cumulative doses IV during timeout periods that preceded sequential components of the fixed-interval schedule. Neither SL 75102 (1.0-30.0 mg/kg) nor THIP (0.1-3.0 mg/kg) significantly altered rates of either suppressed or nonsuppressed responding, whereas lorazepam (0.01-0.3 mg/kg) produced dose-related increases in response rate under both schedules. Pretreatment with 1.0 mg/kg SL 75102 significantly enhanced the rate-increasing effects of lorazepam on suppressed responding. Pretreatment with 10.0 mg/kg SL 75102 also enhanced the rate-increasing effects of lorazepam on nonsuppressed responding. In contrast, the rate-increasing effects of lorazepam were not enhanced by pretreatment with 0.3 or 1.0 mg/kg THIP under either schedule. Moreover, pretreatment with 1.0 mg/kg THIP attenuated the rate-increasing effects of lorazepam on nonsuppressed responding. Enhancement of the behavioral effects of lorazepam by SL 75102 may reflect positive allosteric interactions between the two drugs at the benzodiazepine-GABA receptor complex.

Effects of lesions to the dorsal noradrenergic bundle on counterconditioning of punished barpressing

The possible contribution of the dorsal noradrenergic bundle (DB) to the development of a simple form of counterconditioning (an associative mechanism leading to behavioural tolerance for stress) was assessed by comparison of the performance of animals with 6-hydroxydopamine-induced lesions of the DB to that of sham-operated (SH) animals. Animals engaging in barpressing for food reward on a random-interval (RI) 64 sec schedule were presented with a stimulus signalling the concurrent operation of an RI-64 sec schedule of response-contingent shock. In the control condition (punishment), shock and reward never occurred as a result of the same barpress. In the experimental condition (counterconditioning), the frequency of shock and reward were the same as for the punishment condition but the two events always occurred in succession, with food following shock, as a consequence of the same barpress. DB lesions had no effect on the acquisition of rewarded barpressing or on the initial acquisition of the discrimination between the shock-free and shock-containing (signalled) components of the schedule. However, once performance on the discrimination had reached asymptote, DB animals in the punishment control group showed significantly less suppression to the signal than SH animals. The counterconditioning schedule used was effective, leading to significantly reduced response suppression in the SH animals in comparison to the SH group subjected to punishment. The pattern of findings in the DB groups was consistent with a blockade by the lesion of the development of counterconditioning. These results suggest, therefore, that the DB is involved in at least one associative mechanism leading to tolerance for stress.

SELECTIVE PUNISHMENT OF INTERRESPONSE TIMES: THE ROLES OF SHOCK INTENSITY AND SCHEDULING

Two experiments investigated the roles of shock intensity and scheduling in selective punishment of interresponse times. In each experiment the punishment contingencies were imposed on a background of rats' responding maintained by a variable-interval schedule of food presentation. In Experiment 1 all interresponse times greater than 8 seconds produced shock. In Experiment 2 all interresponse times greater than 8 seconds but less than 12 seconds produced shock. In each experiment shock intensity was initially 0.3 milliamperes (mA) and then was varied through an ascending sequence ranging from 0.1 mA to 0.4 mA, in 0.1-mA increments. Experiment 1 produced response-rate increases at low intensities (0.1 and 0.2 mA) but eliminated responding at the remaining intensities. Experiment 2 produced response-rate increases only with 0.1-mA shock, although responding was maintained at all shock parameters investigated. Analysis of the interresponse times per opportunity showed differential suppression of the targeted responses in all cases except the high-intensity shock phases of Experiment 1. The current data support and extend previous studies of selective interresponse-time-dependent shock schedules but suggest that response-rate increases are not a necessary outcome of this type of procedure. The view that variable-interval schedules of shock presentation selectively target long interresponse times was also supported.