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An investigation of nalorphine and perphenazine as negative reinforcers in an escape paradigm.

Rhesus monkeys were trained to self-administer morphine intravenously at dose levels sufficient to develop physical dependence. The monkeys were then trained to press a lever to escape a continuous infusion of the morphine antagonist, nalorphine. When saline was substituted for the nalorphine, escape responding extinguished. After morphine self-administration was eliminated, responding to escape from nalorphine was maintained in the postdependent monkeys, showing no difference from escape responding during morphine dependence. Finally, perphenazine was substituted for the nalorphine and the monkeys reliably escaped continuous infusions of this phenothiazine. The escape procedure appears useful for analyzing the aversive properties of drugs.

Animals↗

Effects of apomorphine, clonidine or 5-methoxy-NN-dimethyltryptamine on approach and escape components of lateral hypothalamic and mesencephalic central gray stimulation in two inbred strains of mice.

The effects of intraperitoneal injections of increasing doses of apomorphine, clonidine or 5-methoxy-NN-dimethyltryptamine (5-m-DMT) on approach and escape reactions induced by lateral hypothalamic (LH) or mesencephalic central gray (CG) stimulation were compared in BALB/c and DBA/2 mice. Apomorphine increased both the approach latency for LH stimulation and the escape latency for CG stimulation; the BALB/c strain was more reactive than DBA/2 animals. Clonidine reduced the approach latency for LH stimulation only in the BALB/c strain. 5-m-DMT increased escape latency both for LH and CG stimulation only in the DBA/2 strain. These results suggest that the neurochemical regulation of escape reactions respectively generated by LH or CG activation is partially different: dopamine seems to be involved only in CG aversion, whereas serotonin (5-HT) modulates both LH and CG escape reactions. Moreover, our results demonstrate a noradrenergic influence on the appetitive component of LH stimulation. Finally, they confirm that approach and escape reactions, particularly when induced from lateral hypothalamus, depend on distinct neuronal populations.

Animals↗

A delayed onset of haloperidol effects on learned escape and avoidance behavior.

The effects of 0.3 mg/kg haloperidol (H) on the acquisition and maintenance of footshock escape behavior of rats in a one meter runway was investigated. In the acquisition phase, a group (N = 6) given H before testing (HB) showed severely retarded acquisition and performance of the escape response, as compared with a group (N = 6) given H after testing (HA). When the HB and HA treatments were reversed for the groups behavioral performance was initially unaffected. At first, the HA group switched to the HB condition continued to exhibit rapid escape behavior and the HB group switched to the HA treatment continued to have slow escape behavior. Over the course of 8 days of testing, however, the performances of the two groups gradually reversed. After completion of this testing the HB and HA treatments again were switched and the animals were tested for both avoidance and escape behavior. Again, the performance of the animals initially did not change after the treatment switch, but with repeated testing and treatments, the avoidance and escape behavior of the HB group slowed substantially and that of the HA group accelerated markedly. These findings support previous observations that over learned behaviors are much less sensitive to disruption by haloperidol treatment than behaviors which are undergoing learning. The important contribution of the present study was in demonstrating that this insensitivity is a transitional, transient phenomenon and that with chronic treatment and testing, over learned behaviors can be strongly affected by haloperidol.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

An analysis of factors influencing complex water maze learning in rats: effects of task complexity, path order and escape assistance on performance following prenatal exposure to phenytoin.

Three hypotheses on factors determining performance in a complex water maze were tested in rats prenatally exposed to phenytoin. The hypotheses were: 1) that increasing maze complexity would better differentiate experimental effects; in particular, that an expanded version of a maze originally described by Biel would better differentiate groups than Biel's original design; 2) that path order is an important factor determining performance; specifically, that path sequence AB would better differentiate experiments from controls than the opposite order (sequence BA); and 3) that repeated trial failures interfere with learning, a problem putatively prevented by employing assisted (i.e., guided) escape. The specific prediction was that rats tested with assisted escape would learn faster and produce better group differentiation than rats tested with unassisted escape. Pregnant female Sprague-Dawley CD rats were gavaged on days 7-18 of gestation with propylene glycol alone (Control) or containing 100 or 200 mg/kg of phenytoin. Straight channel swimming trials followed by maze trials were begun on separate male/female offspring pairs from each litter on postnatal days 50, 70, or 90. The results confirmed hypothesis 1, i.e., the more complex maze better differentiated phenytoin-related group differences. This was true regardless of whether the phenytoin rats exhibiting circling were included in the analyses or not. The results disconfirmed hypothesis 2, i.e., that path order AB would better differentiate the groups than path order BA. Rather, the data supported the alternate hypothesis, that path order was not a significant determinant of prenatal drug-related maze deficits. This was unchanged regardless of whether phenytoin offspring exhibiting circling were or were not included in the analyses. The implication is that path B alone was sufficient to detect phenytoin's effects on maze performance. Finally, the overall results disconfirmed hypothesis 3, i.e., assisted escape failed to differentiate groups any better than unassisted escape regardless of whether circlers were or were not included in the analyses. However, when more detailed analyses were performed only on rats that failed to find the goal on the first or second trials of path B, an assistance effect was noted. The effect (fewer errors) only occurred in the controls and only on the first two trials of path B. It was concluded that assisted escape was, at best, a minor contribution to improved maze performance.

Animals↗

Distribution of Fos immunoreactivity in the rat brain after freezing or escape elicited by inhibition of glutamic acid decarboxylase or antagonism of GABA-A receptors in the inferior colliculus.

It has been shown that electrical stimulation of the central nucleus of the inferior colliculus (IC) at freezing or escape thresholds activates different neural circuits in the brain. Since electrical stimulation activates cell bodies and fibers of passage it is necessary to use chemical stimulation that activates only post-synaptic receptors. To examine this issue in more detail, we took advantage of the fact that GABAergic neurons exert tonic control over the neural substrates of aversion in the IC. Reduction of GABA transmission in this structure was performed with the use of semicarbazide - an inhibitor of the GABA synthesizing enzyme glutamic acid decarboxylase (GAD) - and the GABA-A receptor antagonist bicuculline. Depending on the dose employed local infusions of semicarbazide (6.0 microg/0.2 microl) or bicuculline (40 ng/0.2 microl) into this region caused freezing and escape, respectively. The results obtained showed that freezing behavior induced by semicarbazide was associated with an increase in Fos expression in the dorsomedial column of the PAG (dmPAG) only, while bicuculline-induced escape was related to widespread increase in Fos labeling, notably in the periaqueductal gray, hypothalamus nuclei, amygdaloid nuclei, the laterodorsal nucleus of thalamus (LD), the cuneiform nucleus (CnF) and the locus coeruleus (LC). Thus, the present data support the notion that freezing and escape behaviors induced by GABA blockade in the IC are neurally segregated: acquisition of aversive information of acoustic nature from the IC probably uses the dmPAG column as a relay station to higher brain centers whereas bicuculline-induced escape activates structures involved in both sensory processing and motor output of defensive behavior. These results support the existence of distinct neural circuits mediating the sensory and motor responses of the defense reaction. The extent of the brain activation during freezing appears to be limited to the anatomical connections of the dmPAG, whereas an overall activation of the limbic system predominates during escape behavior induced by IC stimulation.

Animals↗

Fos-like immunoreactivity in the brain associated with freezing or escape induced by inhibition of either glutamic acid decarboxylase or GABAA receptors in the dorsal periaqueductal gray.

GABAergic neurons exert tonic control over the neural substrates of aversion in the dorsal periaqueductal gray (dPAG). It has been shown that electrical stimulation of this region at freezing or escape thresholds activates different neural circuits in the brain. Since electrical stimulation activates cell bodies and fibers of passage, it is necessary to use chemical stimulation that activates only post-synaptic receptors. To investigate this issue further, reduction of GABA transmission was performed with local injections of either the GABA-A receptor antagonist bicuculline or the glutamic acid decarboxylase (GAD) inhibitor semicarbazide into the dorsolateral periaqueductal gray (dlPAG). Local infusions of semicarbazide (5.0 microg/0.2 microl) or bicuculline (40 ng/0.2 microl) into this region caused freezing and escape, respectively. The results obtained showed that freezing behavior induced by semicarbazide was associated with an increase in Fos expression in the laterodorsal nucleus of the thalamus (LD) and ventrolateral periaqueductal gray (vlPAG), while bicuculline-induced escape was related to widespread increase in Fos labeling, notably in the columns of the periaqueductal gray, hypothalamus nuclei, the central amygdaloid nucleus (Ce), the LD, the cuneiform nucleus (CnF) and the locus coeruleus (LC). Thus, the present data support the notion that freezing and escape behaviors induced by GABA blockade in the dlPAG are neurally segregated: freezing activates only structures that are mainly involved in sensory processing, and bicuculline-induced escape activates structures involved in both sensory processing and motor output of defensive behavior. Therefore, the freezing elicited by activation of dlPAG appears to be related to the acquisition of aversive information, whereas most brain structures involved in the defense reaction are recruited during escape.

Analysis of Variance↗

Aversive hypothalamic stimulation releases acetylcholine in the nucleus accumbens, and stimulation-escape decreases it.

Hypothalamic electrodes can generate positive reinforcement, as shown by self-stimulation, and negative reinforcement shown by stimulation-escape. It was hypothesized that acetylcholine (ACh) is released in the nucleus accumbens during the aversive state that underlies stimulation-escape. If this is correct, escape behavior should lower extracellular ACh. Rats were prepared with microdialysis probes in the accumbens (posterior shell region) and electrodes in the perifornical lateral hypothalamus. Animals learned to press a lever for 0.5 s trains of stimulation (typically 3600 responses/h). Then they were given automatic stimulation to determine which animals would also learn to press a lever to turn stimulation off for 5 s at a time (typically 75 responses/h). Accumbens microdialysis showed that automatic stimulation caused extracellular ACh to double, but only in the rats that were motivated to learn stimulation-escape. When allowed to escape stimulation, these animals lowered extracellular ACh significantly. It is concluded that ACh release in the accumbens is related to the neural state that animals work to escape.

Acetylcholine↗

Dopamine release in the nucleus accumbens by hypothalamic stimulation-escape behavior.

It is known that lateral hypothalamic stimulation or self-stimulation can release dopamine in the nucleus accumbens (NAc). The present experiment illustrates that an aversively motivated behavior can also do this. Rats were prepared with microdialysis probes in the NAc and electrodes in the lateral hypothalamus (LH) or medial hypothalamus (MH). Automatic stimulation of the LH increased extracellular dopamine in the NAc 30% as reported earlier. The animals would perform both self-stimulation to turn the current on and stimulation-escape to turn it off, suggesting a combination of reward and aversion. Escape responding increased extracellular dopamine (DA) 100%, even though there was less total stimulation. Automatic stimulation of the MH did the opposite of the LH by decreasing accumbens dopamine (-20%), and the animals would only perform stimulation-escape, indicative of pure aversion. But again, extracellular DA in the NAc increased 100% during escape responding. Thus DA can be released during negative reinforcement when an animal's behavior is reinforced by escape from lateral or medial hypothalamic stimulation. This suggests that DA release was correlated with stimulation-escape behavior, rather than the aversiveness of automatic stimulation.

Animals↗

Serotonin in the dorsal periaqueductal gray modulates inhibitory avoidance and one-way escape behaviors in the elevated T-maze.

The dorsal periaqueductal gray has been implicated in the modulation of escape behavior, a defensive behavior that has been related to panic disorder. Intra-dorsal periaqueductal gray injection of serotonin or drugs that mimic its effects inhibits escape induced by electrical or chemical stimulation of this brainstem area. In this study, we investigate whether intra-dorsal periaqueductal gray injection of 5-HT receptor agonists attenuates escape generated by an ethologically based model of anxiety, the elevated T-maze. This test also allows the measurement of inhibitory avoidance, which has been related to generalized anxiety disorder. The effects of the 5-HT receptor agonists were compared in animals with or without a previous exposure to the open arms of the elevated T-maze. In these two test conditions, intra-dorsal periaqueductal gray injection of the endogenous agonist serotonin or the 5-HT(2B/2C) receptor agonist m-chlorophenylpiperazine (mCPP) enhanced inhibitory avoidance, suggesting an anxiogenic effect. The 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) impaired this response, suggesting an anxiolytic effect, and the preferential 5-HT2A receptor agonist 2,5-dimethoxy-4-iodoamphetamine (DOI) was ineffective. All these agonists inhibited escape behavior. Apart from mCPP, the effect on escape was detected only in animals pre-exposed to the open arm. None of the drugs tested affected locomotion in the open-field test. Taken altogether, our findings suggest that 5-HT1A and 5-HT2c receptors in the dorsal periaqueductal gray exert opposed control on inhibitory avoidance, implicating these receptors in anxiety conditioning. As previously observed in tests employing the aversive stimulation of the dorsal periaqueductal gray, 5-HT1A and 5-HT2A receptors in this brain area are involved in escape inhibition. Therefore, in different animal models, the activation of these two subtypes of receptors in the dorsal periaqueductal gray consistently attenuates the expression of a panic-related behavior.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

HLA class I escape drives the evolution of SARS-CoV-2 in human populations.

The role of escape from the cytotoxic T cell (CTL) response in Severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) evolution remains controversial. Here, we study the origin and spread of SARS-CoV-2 variants whose mutations reduce presentation by the human leukocyte antigen (HLA) class I alleles common in human populations. We find that 35% of mutations that are characteristic of the variants of concern, and 39% of all subsequent viral mutations, facilitate escape of viral epitopes from presentation. Mutations allowing escape from more common HLA alleles reach higher frequencies, particularly in those countries where these HLA alleles are more frequent, indicating that escape is selected by the local genetic composition of the human host population. We also show that viral mutations that accumulated in general-population transmission chains matched population HLA class I allele frequencies as well as, or better than, mutations acquired during persistent infections, suggesting that selection in favor of escape mutations is not limited to immunocompromised individuals. Together, these data reveal CTL escape as a facet of selection, a driver of evolution, and an epidemiological concern for SARS-CoV-2.

Humans↗

Jet-propelled escape in the squid Loligo opalescens: concerted control by giant and non-giant motor axon pathways.

Recordings of stellar nerve activity were made during escape responses in living squid. Short-latency activation of the giant axons is triggered by light-flash stimulation that elicits a stereotyped startle-escape response and powerful jet. Many other types of stimuli produce a highly variable, delayed-escape response with strong jetting primarily controlled by a small axon motor pathway. In such cases, activation of the giant axons is not necessary for a vigorous escape jet. When they are utilized, the giant axons are not activated until well after the non-giant system initiates the escape response, and excitation is critically timed to boost the rise in intramantle pressure. Squid thus show at least two escape modes in which the giant axons can contribute in different ways to the control of a highly flexible behavior.

Animals↗

Effects of acute exposure to stressors on subsequent avoidance-escape behavior.

This paper attempts to show that severely stressful conditions can lead to a deficit in avoidance-escape responding by reducing noradrenergic activity in the brain. It is argued that this stress-induced neurochemical change explains more adequately an avoidance-excape deficit seen previously in dogs after severe inescapable shock than does the "learned helplessness" explanation originally offered for this effect. A series of six experiments are described that test the stress-neurochemical change explanation, which is called the "motor activation deficit" hypothesis. The first experiment showed that a brief exposure to cold swim, which reduced central noradrenergic activity but did not induce "learned helplessness," produced an avoidance-escape deficit similar to that observed after inescapable shock in the original "learned helplessness" studies. Subsequent experiments demonstrated that the deficit induced by cold swim was also similar to the original deficit in that it too dissipated with the passage of time and was reduced by pretraining animals in the correct response. Further experiments then showed that the deficit induced by cold swim was (a) aggravated by raising the height of the barrier between compartments in the shuttle box, and (b) did not occur if the avoidance-escape task used required little motor activity, both of the findings being predicted by the "motor activation deficit" hypothesis. Finally, an avoidance-escape deficit was produced by inescapable shock, and it was found that this stressor likewise did not impair avoidance-escape responding if the task required little skeletal activity, a result not predicted by the "learned helplessness" hypothesis. The paper concludes by discussing how the results presented in this paper, as well as in succeeding papers, support the "motor activation deficit" explanation for certain avoidance-escape deficits, defining the cases to which the explanation applies and discussing the neurotransmitters involved.

Animals↗

Monamines as mediators of avoidance-escape behavior.

A series of three experiments were carried out to test the hypothesis ("motor activation deficit" hypothesis) that the avoidance-escape deficits observed following certain highly stressful conditions result from changes in activity of noradrenergic (or other monominergic) neural systems. These studies indicate that: (1) Depletion of monamines by a single injection of tetrabenazine produces an active avoidance-escape deficit when the avoidance-escape response involves a relatively high degree of motor activity but not when a minimum of motor activity is required. This parallels results found when animals are acutely exposed to a stressor prior to avoidance-escape testing. (2) Daily injections of tetrabenazine for a period of two weeks, like daily exposure to inescapable shock for the same period of time, markedly attenuates the magnitude of the avoidance-escape deficit produced by either a single injection of tetrabenazine or single session of inescapable shock. (3) Decreasing the stress-induced depletion of monamines by the use of an MAO inhibitor serves to protect the animals from the effects of inescapable shock, markedly reducing the avoidance-escape deficit produced by such shock. It is concluded that these results are consistent with the motor activation deficit hypothesis.

Animals↗

The debilitating effect of exposure to noncontingent escape: a test of the learned helplessness model.

Two studies were conducted to test the hypothesis that exposure to noncontingent escape leads to performance deficits similar to those observed when subjects are exposed to noncontingent aversive outcomes from which there is no escape, and that causal attributions mediate these deficits. Previous attempts to produce "appetitive helplessness" (deficits resulting from exposure to noncontingent positive events) have been plagued by subjects' tendency to believe that they are responsible for positive events. In Experiment 1, 40 subjects were exposed to contingent or noncontingent noise escape trials. As predicted by the learned helplessness model, subjects who received inescapable noise performed less well on a subsequent anagram task than subjects exposed to escapable noise. Similarly, subjects who escaped from the noise owing to the benevolence of a powerful other rather than because of their own efforts, showed performance deficits paralleling those of the inescapable noise subjects. In Experiment 2, subjects who escaped an aversive tone through no effort of their own showed subsequent performance deficits, but globality of their self-reported attributions did not predict subsequent anagram performance. The results of these studies provide support for the hypothesis that uncontrollability, independent of the valence of a particular outcome, is responsible for helplessness deficits, but do not support the mediational role of attributions, at least in the laboratory.

Achievement↗

The C-start escape response of Polypterus senegalus: bilateral muscle activity and variation during stage 1 and 2.

The fast-start escape response is the primary reflexive escape mechanism in a wide phylogenetic range of fishes. To add detail to previously reported novel muscle activity patterns during the escape response of the bichir, Polypterus, we analyzed escape kinematics and muscle activity patterns in Polypterus senegalus using high-speed video and electromyography (EMG). Five fish were filmed at 250 Hz while synchronously recording white muscle activity at five sites on both sides of the body simultaneously (10 sites in total). Body wave speed and center of mass velocity, acceleration and curvature were calculated from digitized outlines. Six EMG variables per channel were also measured to characterize the motor pattern. P. senegalus shows a wide range of activity patterns, from very strong responses, in which the head often touched the tail, to very weak responses. This variation in strength is significantly correlated with the stimulus and is mechanically driven by changes in stage 1 muscle activity duration. Besides these changes in duration, the stage 1 muscle activity is unusual because it has strong bilateral activity, although the observed contralateral activity is significantly weaker and shorter in duration than ipsilateral activity. Bilateral activity may stiffen the body, but it does so by a constant amount over the variation we observed; therefore, P. senegalus does not modulate fast-start wave speed by changing body stiffness. Escape responses almost always have stage 2 contralateral muscle activity, often only in the anterior third of the body. The magnitude of the stage 2 activity is the primary predictor of final escape velocity.

Animals↗

Noncontingent escape as treatment for self-injurious behavior maintained by negative reinforcement.

We extended research on the role of noncontingent positive reinforcement following a functional analysis of attention-maintained self-injurious behavior to self-injury maintained by negative reinforcement in 2 young males with developmental disabilities. During a pretreatment functional analysis, each participant's self-injury was shown to be differentially sensitive to escape from instructional activities as negative reinforcement. During noncontingent escape, escape from learning activities was provided on a fixed-time schedule that was not influenced by the participant's behavior. One participant was also exposed to differential negative reinforcement of other behavior. During this condition, escape from instructional activities was provided contingent on the omission of self-injury for prespecified intervals. Results showed that the provision of escape, even when noncontingent, resulted in significant reductions in self-injury. These results are particularly interesting in light of the experimental history of noncontingent reinforcement as a control rather than as a therapeutic procedure. Noncontingent escape is discussed as a form of extinction that may be less likely than other forms of extinction to produce severe side effects.

Adolescent↗

Interaction between reflexive fighting and cooperative escape.

Subjects separated by a Plexiglas partition were trained to follow a cooperative escape procedure which produced behavior like the escape responding of individual subjects. Removal of the partition produced fighting and less efficient escape. Efficient escape behavior was restored and fighting disappeared when the partition was replaced. Neither increased space nor a moving toy affected escape behavior. The results indicate that switching animals from an isolated to a social situation produced a change in the effect of shock upon escape which was related to shock-induced fighting.

Animals↗

Escape from an effortful situation.

This experiment investigated the tendency to escape from a situation requiring effortful responding. Five human subjects responded in a situation where the response mechanism required 20-lb force to operate; responses were reinforced according to a variable-interval schedule. A subject escaped from this situation by emitting a vocal response which produced a 60-sec "easy period". During the easy period the reinforcement contingency was switched to a response mechanism requiring 1 lb to operate. It was found that: (1) Escape responding could be conditioned and maintained by producing the easy period; the easy period did not maintain escape responding when the force requirement in the normal situation was equated with it. (2) The rate of escape responding was a function of the magnitude of the force normally required. (3) When easy periods were scheduled after fixed ratios, pausing from the end of the previous easy period to the first escape response was noted. It was concluded that a situation requiring high-force responding is a negative reinforcer. The pattern of fixed-ratio responding suggests that this reinforcer produces typical schedule control in human subjects.

Adolescent↗