Escape Responding Research Articles

Anterior hypothalamic parvalbumin neurons are glutamatergic and promote escape behavior

The anterior hypothalamic area (AHA) is a critical structure for defensive responding. Here, we identified a cluster of parvalbumin-expressing neurons in the AHA (AHAPV) that are glutamatergic with fast-spiking properties and send axonal projections to the dorsal premammillary nucleus (PMD). Using invivo functional imaging, optogenetics, and behavioral assays, we determined the role of these AHAPV neurons in regulating behaviors essential for survival. We observed that AHAPV neuronal activity significantly increases when mice are exposed to a predator, and in a real-time place preference assay, we found that AHAPV neuron photoactivation is aversive. Moreover, activation of both AHAPV neurons and the AHAPV → PMD pathway triggers escape responding during a predator-looming test. Furthermore, escape responding is impaired after AHAPV neuron ablation, and anxiety-like behavior as measured by the open field and elevated plus maze assays does not seem to be affected by AHAPV neuron ablation. Finally, whole-brain metabolic mapping using positron emission tomography combined with AHAPV neuron photoactivation revealed discrete activation of downstream areas involved in arousal, affective, and defensive behaviors including the amygdala and the substantia nigra. Our results indicate that AHAPV neurons are a functional glutamatergic circuit element mediating defensive behaviors, thus expanding the identity of genetically defined neurons orchestrating fight-or-flight responses. Together, our work will serve as a foundation for understanding neuropsychiatric disorders triggered by escape such as post-traumatic stress disorder (PTSD).

Brief light as a practical aversive stimulus for the albino rat

Bright light was an effective aversive stimulus for Wistar rats in punishment, escape, and avoidance paradigms. Contingent punishment of lever pressing maintained by concurrent schedules of food delivery shifted presses to an alternate lever, and depressed overall response rates. Periodic non-contingent presentation of the light prompted escape responding (head entry into a hole). Unsignaled avoidance contingencies were not effective, but pre-pulse signaling of light supported avoidance behavior. These results demonstrate a possible alternative to foot-shock, one with greater ecological validity, and one that might avoid some of the physiological effects that accompany electric shock.

Effects of age on thermal sensitivity in the rat.

Age-dependent changes in thermal sensitivity were evaluated with reflex- and operant-based assessment strategies in animals ranging in age from 8 to 32 months. The impact of inflammatory injury on thermal sensitivity was also determined in animals of different ages. The results showed that operant measures of escape behavior are needed to demonstrate significant changes in thermal sensitivity across the life span of female Long-Evans rats. Increased escape from both heat (44.5 degrees C) and cold (1.5 degrees C-15 degrees C) was observed for older animals, with a greater relative increase in sensitivity to cold. Physical performance deficits were demonstrated with aging but were not associated with changes in escape responding. Reflex responding to cold stimulation was impaired in older animals but was also influenced by physical disabilities. Reflex responding to heat was not affected by increasing age. Inflammation induced by formalin injections in the dorsal hindpaw increased thermal sensitivity significantly more in older animals than in their younger counterparts.

Pain as a stressor: Effects of prior nociceptive stimulation on escape responding of rats to thermal stimulation

In our previous studies, psychological stress was shown to enhance operant escape responding of male and female rats. The stressors that produced hyperalgesia were physical restraint and social defeat. Nociceptive input also elicits stress reactions, generating the prediction that pain would facilitate pain under certain circumstances. For example, the usual method of evaluating stress in laboratory animals is to test for effects after termination of the stressor. Accordingly, operant escape performance of male and female rats was evaluated during two successive trials involving nociceptive thermal stimulation. The intent was to determine whether nociceptive sensitivity differed on first trials and during pain-induced stress on second trials. Compared to a first trial of 44.5 °C stimulation, escape responding increased during a second trial of 44.5 °C stimulation (preceded by an escape trial of 10 °C). Similarly, escape from cold (10 °C) was enhanced when preceded by escapable 44.5 °C stimulation. Thus, prior nociceptive stimulation enhanced escape from aversive thermal stimulation. Facilitation of pain by a preceding pain experience is consistent with stress-induced hyperalgesia and contrasts with other models of pain inhibition by concurrent nociceptive stimulation.

Opioid modulation of reflex versus operant responses following stress in the rat

In pre-clinical models intended to evaluate nociceptive processing, acute stress suppresses reflex responses to thermal stimulation, an effect previously described as stress-induced “analgesia.” Suggestions that endogenous opioids mediate this effect are based on demonstrations that stress-induced hyporeflexia is enhanced by high dose morphine (>5 mg/kg) and is reversed by naloxone. However, reflexes and pain sensations can be modulated differentially. Therefore, in the present study direct comparisons were made of opioid agonist and antagonist actions, independently and in combination with acute restraint stress in Long Evans rats, on reflex lick-guard (L/G) and operant escape responses to nociceptive thermal stimulation (44.5 °C). A high dose of morphine (>8 mg/kg) was required to reduce reflex responding, but a moderate dose of morphine (1 mg/kg) significantly reduced escape responding. The same moderate dose (and also 5 mg/kg) of morphine significantly enhanced reflex responding. Naloxone (3 mg/kg) significantly enhanced escape responding but did not affect L/G responding. Restraint stress significantly suppressed L/G reflexes (hyporeflexia) but enhanced escape responses (hyperalgesia). Stress-induced hyperalgesia was significantly reduced by morphine and enhanced by naloxone. In contrast, stress-induced hyporeflexia was blocked by both naloxone and 1 mg/kg of morphine. Thus, stress-induced hyperalgesia was opposed by endogenous opioid release and by administration of morphine. Stress-induced hyporeflexia was dependent upon endogenous opioid release but was counteracted by a moderate dose of morphine. These data demonstrate a differential modulation of reflex and operant outcome measures by stress and by separate or combined opioid antagonism or administration of morphine.

Acute effects of lorazepam on laboratory measures of aggressive and escape responses of adult male parolees

Acute benzodiazepine administrations typically decrease aggressive responding, but increases in aggression have been reported in some studies. The benzodiazepine lorazepam has been studied less frequently than other benzodiazepines in aggression research, although it is often used to suppress violent aggression in patients. The present study was designed to investigate the effects of acute administrations of lorazepam on aggressive responding in adult humans on a laboratory aggression task. Eight adult males participated in experimental sessions on the Point Subtraction Aggression Paradigm (PSAP), which provided subjects with aggressive, escape and monetary-reinforced response options. Acute oral doses (1, 2 and 4 mg) of lorazepam decreased both aggressive responding and monetary-reinforced responding in seven of eight subjects. In one subject, lorazepam produced dose-dependent increases in aggressive responding. The effects of lorazepam on escape responding were the same as the effects on aggressive responding. The results are consistent with prior research using the PSAP and clinical data showing that benzodiazepines generally decrease aggression, and contrast with other studies that have shown that benzodiazepines can increase aggression. Since lorazepam affected both aggressive and escape responding, it is suggested that while lorazepam often produces sedation, it also modifies human aggressive responding, in part, by suppressing reactions to aversive stimuli.

Freewheel Running Prevents Learned Helplessness/Behavioral Depression: Role of Dorsal Raphe Serotonergic Neurons

Serotonin (5-HT) neurons in the dorsal raphe nucleus (DRN) are implicated in mediating learned helplessness (LH) behaviors, such as poor escape responding and expression of exaggerated conditioned fear, induced by acute exposure to uncontrollable stress. DRN 5-HT neurons are hyperactive during uncontrollable stress, resulting in desensitization of 5-HT type 1A (5-HT1A) inhibitory autoreceptors in the DRN. 5-HT1A autoreceptor downregulation is thought to induce transient sensitization of DRN 5-HT neurons, resulting in excessive 5-HT activity in brain areas that control the expression of learned helplessness behaviors. Habitual physical activity has antidepressant/anxiolytic properties and results in dramatic alterations in physiological stress responses, but the neurochemical mediators of these effects are unknown. The current study determined the effects of 6 weeks of voluntary freewheel running on LH behaviors, uncontrollable stress-induced activity of DRN 5-HT neurons, and basal expression of DRN 5-HT1A autoreceptor mRNA. Freewheel running prevented the shuttle box escape deficit and the exaggerated conditioned fear that is induced by uncontrollable tail shock in sedentary rats. Furthermore, double c-Fos/5-HT immunohistochemistry revealed that physical activity attenuated tail shock-induced activity of 5-HT neurons in the rostral-mid DRN. Six weeks of freewheel running also resulted in a basal increase in 5-HT1A inhibitory autoreceptor mRNA in the rostral-mid DRN. Results suggest that freewheel running prevents behavioral depression/LH and attenuates DRN 5-HT neural activity during uncontrollable stress. An increase in 5-HT1A inhibitory autoreceptor expression may contribute to the attenuation of DRN 5-HT activity and the prevention of LH in physically active rats.

The L-type calcium channel blocker nimodipine mitigates “learned helplessness” in rats

We assessed the effect of nimodipine, an L-type calcium channel blocker, on the escape deficit induced by prior exposure to inescapable shock in rats in four experiments. In Experiment 1, we injected rats at each of three time points (i.e., before shock exposure, after shock exposure, and before shuttle escape testing) with one of four doses of nimodipine (0, 0.5, 2.5, 5.0 mg/kg). The 5.0-mg/kg dose was most effective, acting to reduce shuttle escape latencies of inescapably shocked rats to a level comparable with nonshocked controls. No benefit occurred in Experiment 2, however, when nimodipine was administered at only one of the three time points used in the first experiment. Moreover, escape performance did not improve when rats received injections of nimodipine on the 2 days prior the experiment, and then one additional injection at one of the three time points identified above in Experiment 3. Finally, administration of nimodipine at two of the three time points did improve escape responding, but only when injected immediately prior both to shock exposure and the shuttle escape test.

Low dose systemic morphine attenuates operant escape but facilitates innate reflex responses to thermal stimulation

Abstract: Effects of systemic morphine on operant escape responses of rats to thermal stimulation were compared directly with effects on innate licking and guarding responses. For these independent tests, thermal stimulation was delivered via the floor of testing chambers with or without platforms that provided an escape option. The principal findings were (1) administration of 0.5 to 1.5 mg/kg morphine attenuated escape from nociceptive heat and (2) in distinct contrast, licking and guarding responses to heat were enhanced by these doses. When escape responding was calculated as time on the heated plate without licking or guarding, sensitivity to morphine was greater for 44°C than for 47°C or 50°C. Also, escape responses to cold (0°C or 10°C) were unaffected by 1.5 mg/kg morphine. The preferential reduction of heat nociception by morphine was demonstrated also by an operant preference task that gave the animals the option of standing on a cold (10°C) or a hot (45°C) surface. Administration of 0.5 mg/kg morphine increased occupancy of the hot surface. Platform time during operant tests was low and variable for warm stimulation (36°C) and was significantly increased by each level of heat, showing that platform occupancy represented escape from nociception rather than avoidance responses. A lack of significant effects of 1.5 mg/kg morphine on operant performance during cold or warm stimulation controls for effects of systemic morphine other than antinociception. © 2002 by the American Pain Society

Impaired escape performance and enhanced conditioned fear in rats following exposure to an uncontrollable stressor are mediated by glutamate and nitric oxide in the dorsal raphe nucleus

Exposure to uncontrollable aversive events produces a variety of behavioral consequences that do not occur if the aversive event is controllable. Accumulating evidence suggests that exaggerated excitation of serotonin (5-HT) neurons in the dorsal raphe nucleus (DRN) is sufficient to cause these same behaviors, such as poor shuttlebox escape performance and enhanced conditioned fear that occur 24 h after exposure to inescapable tailshock (IS). The aim of the present studies was to explore the possibility that N-methyl- d-aspartate (NMDA) receptor activation and nitric oxide (NO) formation within the DRN might be involved in mediating the behavioral consequences of IS. To this end, either the NMDA receptor antagonist 2-amino-5-phosphonovaleric acid (APV) or the nitric oxide synthase inhibitor Nw-nitro- l-arginine methyl ester ( l-NAME), was microinjected into the DRN before IS or before testing 24 h later. Blocking NMDA receptors with APV in the DRN during IS prevented the usual impact of IS on escape responding and conditioned fear. However, injection of APV at the time of testing only reduced these effects. The DRN was shown to be the critical site mediating blockade of these behavioral changes since injection of APV lateral to the DRN did not alter the behavioral consequences of IS. Conversely, l-NAME was most effective in reversing the effects of IS when administered at the time of testing. These results suggest that there is glutamatergic input to the DRN at the time of IS that produces long-lasting changes in DRN sensitivity. This plasticity in the DRN is discussed as a possible mechanism by which IS leads to changes in escape performance and conditioned fear responding.

Effects of combined hemotoxic and anterolateral spinal lesions on nociceptive sensitivity

The effects of spinal lesions on reactions of rats to nociceptive electrocutaneous stimulation (ES) were evaluated by measuring the speed of operant escape responses, the magnitude of hindlimb flexion reflexes and the amplitude of reflex vocalizations. ES intensities ranging from 0.1 to 0.8mA were delivered to either hindpaw of rats that were trained to terminate stimulation (perform an escape response) with one forelimb. Unilateral thoracic lesions within the lateral column were produced by surgically transecting axons, with or without insertion of blood-soaked Gelfoam into the lesion cavity. The latter procedure was intended to standardize and maximize hemotoxic damage to the gray matter at the lesion site. The speed of conscious escape responses to all intensities was reduced contralaterally and to comparable extents following each type of lesion. Involvement of mid-lateral axons was an important determinant of contralateral deficits in escape responding. Escape speed for ipsilateral stimulation was not affected by the lesion without intentional insertion of blood but was reliably increased by addition of blood to the lesion site. Flexion reflexes were substantially decreased contralaterally and slightly decreased ipsilaterally, in accordance with previous investigations of anterolateral lesion effects in monkeys. Early (reflex) vocalizations were essentially eliminated for stimulation contralateral to the lesions, but vocalizations following ipsilateral stimulation were little affected. Postoperative variations in behavioral responsivity over time were not accounted for by pre- and post-estrous stages of the estrous cycle. The principal finding of this study is that hemotoxic accompaniments of a spinal lesion produce hyperalgesia for nociceptive stimulation applied ipsilaterally to segments well caudal to the lesion. This finding indicates that hemotoxic injury of the gray matter near an anterolateral spinal lesion enhances the excitation of certain rostral structures that receive nociceptive information.

Activation of serotonin-immunoreactive cells in the dorsal raphe nucleus in rats exposed to an uncontrollable stressor

The dorsal raphe nucleus (DRN) and its serotonergic terminal regions have been suggested to be part of the neural substrate by which exposure to uncontrollable stressors produces poor escape responding and enhanced conditioned fear expression. Such stressor exposure is thought to selectively activate DRN serotonergic neurons in such a way as to render them transiently sensitized to further input. As a result of this sensitized state, behavioral testing procedures are thought to cause excess serotonergic activity in brain regions that control these behaviors. The present studies were conducted to investigate activity in the DRN following exposure to escapable and yoked, inescapable tailshock. Neural activity was characterized using immunohistochemistry to detect the immediate early gene product Fos in serotonin-immunoreactive cells in the DRN. Inescapable tailshock led to greater serotonergic neural activity than did escapable tailshock, supporting the hypothesis that uncontrollable stressors preferentially activate serotonergic neurons in the DRN.

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.

A new computer-assisted two-way avoidance conditioning equipment for rats: Behavioral and pharmacological validation

A new PC-controlled two-way avoidance conditioning equipment for rats is described. The position of the rat within the two-compartment shuttle-box is monitored by means of 4 + 4 horizontal photocell beams. Experimental conditions and procedures, such as CS-UCS interval, photocell operations, shock strength, and so on, can conveniently be preset by the experimenter. The successful operation of the shuttle-box is evidenced by rapid and efficient acquisition of the avoidance behavior, and approximately 100% median avoidance performance was obtained within 5 successive days of training (20–25 trials per day). In a separate experiment, different groups of rats received avoidance training (0–5 sessions) at 8 weeks of age, and a retention avoidance performance was weak ( r = 0.33, NS), and performance during the acquisition process appears to be a poor predictor of final performance. As expected, a number of dopamine (DA) receptor blocking agents (DA D 1 and/or D 2 selective) produced a selective suppression of the avoidance behavior, that is, the suppression of avoidance responding was matched by a corresponding increase in escape responding (with no escape failures).

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 beta-carboline derivatives such as FG-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 slow 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.

Evaluation of a stable CCK agonist (A68552) in conditioned avoidance responding in mice, rats, and primates: Comparison with typical and atypical antipsychotics

In a variety of in vivo and in vitro tests, cholecystokinin (CCK) has been shown to produce effects that would suggest a functional antagonism of dopamine. On that basis, it has been hypothesized that CCK could have antipsychotic effects. We compared the CCK agonist, A68552, to the antipsychotics haloperidol (HAL), clozapine (CLOZ) and sulpiride (SULP) in various forms of conditioned avoidance using rats, mice, and cynomolgus monkeys. In rats, HAL disrupted both acquisition of a conditioned shelf-jump avoidance response and performance of the response by previously trained animals. CLOZ and SULP were ineffective in suppressing performance by previously trained rats but blocked acquisition of the response. CLOZ disrupted avoidance responding on the first 3 of 4 consecutive days of acquisition. SULP significantly suppressed avoidance responding on the last 3 days and significantly increased escape failures on day 2. A68552 administered during acquisition failed to significantly suppress avoidance responding. In mice, both HAL and CLOZ blocked performance of two-way shuttle conditioned avoidance at doses (0.1 and 3.0 mg/kg, IP, respectively) that had no effect on escape responding. A68552 at doses up to 1.07 mg/kg IP had no effect on performance. Mice treated with A68552 during acquisition showed a mild but statistically significant suppression of avoidance and an equivalent suppression of escape responding. Cynomolgus monkeys trained in a conditioned avoidance procedure were sensitive to the disruptive effects of HAL at a dose of 0.03 mg/kg IM while A68552 was without significant effect at doses up to those producing emesis (0.214 mg/kg, IM). A68552 does not resemble either HAL or the “atypical” antipsychotics, CLOZ or SULP, in conditioned avoidance tests.

Effects of triazolam on human aggressive, escape and point-maintained responding

Placebo and triazolam (0.125, 0.25 and 0.5 mg/70 kg of body weight) were administered to male subjects under double-blind conditions prior to experimental sessions which provided three operant response options. These options were: 1) responding maintained by the presentation of points exchangeable for money, 2) responding which ostensibly resulted in the subtraction of points from a fictitious person was termed aggressive since this responding resulted in the delivery of an aversive stimulus to another person, and 3) responding which ostensibly protected the subject's point counter from subtractions initiated by the other person and was termed escape. Aggressive and escape responding were initiated by subtracting points from the subject. Point subtractions were attributed to the other person. Aggressive and escape responding were maintained by initiation of provocation-free intervals (PFI), during which no further point subtractions were presented. Triazolam produced dose-dependent decreases in point-maintained and escape responding. The effects of triazolam on aggressive responding varied across subjects.

Human Aggressive and Escape Responding: Effects of Provocation Frequency

The effect of point loss frequency on aggressive and escape responding was investigated in two experiments. Subjects could respond on levers marked “A,” “B,” or “C” available as nonreversible options. Subjects were instructed that “A” responses earned points exchangeable for money, “B” responses subtracted points from a second subject, and “Cm responses protected their counter from point loss for a period of time. These options were defined as nonaggressive (A), aggressive (B), and escape (C) responses, respectively. A variable time schedule of point loss engendered aggressive and escape responding. The preexperimental instructions attributed point losses to the subject’s fictitious partner. Levers B and C responding escaped point loss by initiating an interval free of provocation (PFI). In Experiment 1 systematically decreasing PFI increased the frequency of point loss and increased aggressive responding for three of the four subjects. In Experiment 2 Pfi durations were systematically alternated between 500 seconds and 125 seconds in an Abab or Baba design. Escape responding increased as a function of increased provocation frequency for all subjects. Order of exposure affected frequency of aggressive and escape responses.

Selective anorexigenic effects of corticotropin releasing hormone in the rhesus monkey

Glowa, John R., John D. Bacher, Miles Herkenham and Phil W. Gold: Selective Anorexigenic Effects of Corticotropin Releasing Hormone in the Rhesus Monkey. Prog. Neuro-Psychopharmacol. & Biol, Psychiat. 1991, 15 :379–391. 1. 1. Rhesus monkeys were equipped with a novel intracerebroventricular (i.c.v.) cannula system and trained to respond under operant schedules of food presentation or termination of stimuli associated with the delivery of shock (escape) . 2. 2. CRH decreased food-maintained behavior in a dose-related manner over the range of (0.3–10 μg/kg) but did not affect escape responding, demonstrating a selective effect on food-maintained responding. 3. 3. This selective effect was related to the tendency for responding to stop after delivery of a food pellet when higher doses of CRH were given, consistent with the notion that a conditioned aversion to food was established in the presence of CRH. 4. 4. This may suggest that in hyperaroused clinical states such as depression and anorexia nervosa, focus is shifted away from appetitive tasks as a result of increased levels of CRH.

Effects of acute administration of diazepam andd-amphetamine on aggressive and escape responding of normal male subjects

Normal males participated in sessions providing two operant response options and were administered either diazepam (study I and II) or d-amphetamine (study II). The acute effects of diazepam on human aggressive responding, which ostensibly subtracted points from another person, were determined in study I. Study II was conducted to determine the extent to which social context and response consequence influenced diazepam (study I) and d-amphetamine (previous research) effects on aggressive responding. In study II, the other response option was escape responding which protected the subject's counter from point losses. Aggressive and escape responding were engendered by subtracting points from the subject's counter, and maintained by initiation of intervals free of point loss. Point subtractions were attributed to the other person (study I) or to a machine (study II). Responding to accumulate points exchangeable for money was available in both studies. Acute diazepam administration decreased aggressive responding in most subjects (study I), slightly increased escape responding (study II), and decreased responding to accumulate points. In study II, d-amphetamine increased both escape responding and responding to accumulate points. The effects of d-amphetamine and diazepam were altered by the instructed source of point loss.