Defeat-induced hypoalgesia in the rat: effects of conditioned odors, naltrexone, and extinction

In Experiment 1, male rats were either defeated as a colony intruder by alpha conspecifics or had no defeat experience, and 24 hr later they were given a paw injection of formalin prior to observational tests with or without alpha-colony odors. The combination of defeat and tests with these odors produced conditioned hypoalgesia (i.e., a suppression in paw licking) and freezing. In Experiment 2, defeated rats were given either an injection of naltrexone or saline prior to defeat and 24 hr later prior to testing. An injection of naltrexone prior to defeat increased freezing during defeat and later testing. In contrast, naltrexone during testing did not affect freezing but significantly reduced hypoalgesia. In Experiment 3, a 12-hr exposure session with alpha-colony odors extinguished hypoalgesia in previously defeated rats. These findings are discussed in terms of associative, opioid/nonopioid, and adaptive evolutionary processes.     

Temporal specificity of fear conditioning: effects of different conditioned stimulus-unconditioned stimulus intervals on the fear-potentiated startle effect

Separate groups of rats were given 30 pairings of a light (conditioned stimulus, CS) and 500-ms shock (unconditioned stimulus, US) at CS-US intervals of 0, 25, 50, 100, 200, 800, 3,200, 12,800, or 51,200 ms. Other groups had lights and shocks inconsistently paired. The startle reflex was elicited 2-4 days later with a noise burst alone or 25-51,200 ms after light onset. After CS-US pairings over a wide range of intervals (25-51,200 ms), startle was potentiated in testing, sometimes as rapidly as 50 ms after light onset. Magnitude of potentiation and resistance to extinction were generally greater with longer CS-US intervals. In several groups, potentiation was maximal at a test interval that matched the CS-US interval used in training. This temporal specificity sharpened with increasing numbers of training trials but even occurred with a single training trial in which a 51,200-ms CS-US interval was used. The data indicate that even during simple fear conditioning, animals rapidly learn a temporal CS-US relationship. This has important implications for understanding the neural mechanisms of fear conditioning.     

Interoceptive fear conditioning and panic disorder: the role of conditioned stimulus-unconditioned stimulus predictability

Interoceptive fear conditioning is at the core of contemporary behavioral accounts of panic disorder. Yet, to date only one study has attempted to evaluate interoceptive fear conditioning in humans (see Acheson, Forsyth, Prenoveau, & Bouton, 2007). That study used brief (physiologically inert) and longer-duration (panicogenic) inhalations of 20% CO(2)-enriched air as an interoceptive conditioned (CS) and unconditioned (US) stimulus and evaluated fear learning in three conditions: CS only, CS-US paired, and CS-US unpaired. Results showed fear conditioning in the paired condition, and fearful responding and resistance to extinction in an unpaired condition. The authors speculated that such effects may be due to difficulty discriminating between the CS and the US. The aims of the present study are to (a) replicate and expand this line of work using an improved methodology, and (b) clarify the role of CS-US discrimination difficulties in either potentiating or depotentiating fear learning. Healthy participants (N=104) were randomly assigned to one of four conditions: (a) CS only, (b) contingent CS-US pairings, (c) unpaired CS and US presentations, or (d) an unpaired "discrimination" contingency, which included an exteroceptive discrimination cue concurrently with CS onset. Electrodermal and self-report ratings served as indices of conditioned responding. Consistent with expectation, the paired contingency and unpaired contingencies yielded elevated fearful responding to the CS alone. Moreover, adding a discrimination cue to the unpaired contingency effectively attenuated fearful responding. Overall, findings are consistent with modern learning theory accounts of panic and highlight the role of interoceptive conditioning and unpredictability in the etiology of panic disorder.     

Effects of recent exposure to a conditioned stimulus on extinction of Pavlovian fear conditioning

In six experiments we studied the effects of a single re-exposure to a conditioned stimulus (CS; "retrieval trial") prior to extinction training (extinction-reconsolidation boundary) on the development of and recovery from fear extinction. A single retrieval trial prior to extinction training significantly augmented the renewal and reinstatement of extinguished responding. Augmentation of recovery was not observed if the retrieval and extinction training occurred in different contexts. These results contrast with those reported in earlier papers by Monfils and coworkers in rats and by Schiller and coworkers in humans. We suggest that these contrasting results could depend on the contrasting influences of either: (1) occasion-setting contextual associations vs. direct context-CS associations formed as a consequence of the retrieval trial or (2) discrimination vs. generalization between the circumstances of conditioning and extinction.     

Effects of contingency violations on the extinction of a conditioned fear inhibitor and a conditioned fear excitor

Rats were used in a conditioned-suppression paradigm to assess the effects of contingency variations on responding to a conditioned inhibitor (CS-) and a conditioned excitor (CS+). In Experiment 1, various unconditioned stimulus (US) frequencies were equated across the presence and absence of a CS- in the context of either background cues (continuous-trial procedure) or an explicit neutral event (discrete-trial procedure). With both procedures, a CS-alone treatment enhanced inhibition, whereas treatments involving 50% or 100% reinforcement for the CS- eliminated inhibition without conditioning excitation to that CS. The latter outcome also occurred in Experiment 2, with discrete-trial training equating considerably reduced US frequencies for the presence and absence of the CS-. In further evidence that inhibition was eliminated without conditioning excitation to the CS-, Experiment 3 showed that a novel CS did not acquire excitation when 25%, 50%, or 100% reinforcement was equated across the presence and absence of that CS in the context of a discrete-trial event. Using the procedures of Experiment 1, Experiment 4 showed that a CS+ was extinguished by a CS-alone treatment but was substantially maintained by treatments involving 50% or 100% uncorrelated reinforcement. These effects for a CS+ and a CS- implicate CS-US contiguity, rather than contingency, as the factor determining the extinction of a CS.     

Learning and memory in conditioned fear extinction: effects of D-cycloserine

This review addresses the effects of the cognitive enhancer D-cycloserine (DCS) on the memory processes that occur in conditioned fear extinction, which is the experimental model for exposure techniques to reduce clinical anxiety. All reported rat studies show an enhanced fear extinction effect when DCS is administered acutely before or shortly after extinction training. DCS also promotes the generalization of this fear extinction effect. In addition, DCS reduces some forms of relapse (reduced reinstatement, reduced spontaneous recovery), but not others (contextual renewal, rapid reacquisition). It is argued that this pattern of results is best explained by assuming that DCS promotes extinction learning to the background context, resulting in enhanced contextual inhibition. Four human studies have produced mixed results, but some methodological issues complicate the reported failures. It is concluded that DCS is a promising tool as an adjunct to extinction techniques in exposure treatment, but that more pre-clinical and clinical research is needed to fully characterize its behavioral consequences.     

Excitatory strength of expressive faces: effects of happy and fear expressions and context on the extinction of a conditioned fear response

In a recent study, Orr and Lanzetta (1984) showed that the excitatory properties of fear facial expressions previously described (Lanzetta & Orr, 1981; Orr & Lanzetta, 1980) do not depend on associative mechanisms; even in the absence of reinforcement, fear faces intensify the emotional reaction to a previously conditioned stimulus and disrupt extinction of an acquired fear response. In conjunction with the findings on acquisition, the failure to obtain extinction suggests that fear faces have some of the functional properties of "prepared" (fear-relevant) stimuli. In the present study we compared the magnitude of conditioned fear responses to happy and fear faces when a potent danger signal, the shock electrodes, are attached or unattached. If fear faces are functionally analogous to prepared stimuli, then, even in the absence of veridical support for an expectation of shock, they should retain excitatory strength, whereas happy faces should not. The results are consistent with this view of fear expressions. In the absence of reinforcement, and with shock electrodes removed, conditioned fear responses and basal levels of arousal were of greater magnitude for the fear-face condition than for the happy-face condition.     

Overt behavior and ultrasonic vocalization in a fear conditioning paradigm: a dose-response study in the rat

The behavioral analysis of laboratory rats is usually confined to the level of overt behavior, like locomotion, behavioral inhibition, instrumental responses, and others. Apart from such visible outcome, however, behaviorally relevant information can also be obtained when analyzing the animals' ultrasonic vocalization, which is typically emitted in highly motivational situations, like 22-kHz calls in response to acute or conditioned threat. To further investigate such vocalizations and their relationship with overt behavior, we tested male Wistar rats in a paradigm of Pavlovian fear conditioning, where a tone stimulus (CS) was preceding an aversive foot-shock (US) in a distinct environment. Importantly, the shock dose was varied between groups (0-1.1 mA), and its acute and conditioned outcome were determined. The analysis of visible behavior confirms the usefulness of immobility as a measure of fear conditioning, especially when higher shock doses were used. Rearing and grooming, on the other hand, were more useful to detect conditioned effects with lower shock levels. Ultrasonic vocalization occurred less consistently than changes in overt behavior; however, dose-response relationships were also observed during the phase of conditioning, for example, in latency, call rate and lengths, intervals between calls, and sound amplitude. Furthermore, total calling time (and rate) were highly correlated with overt behavior, namely behavioral inhibition as measured through immobility. These correlations were observed during the phase of fear conditioning, and the subsequent tests. Importantly, conditioned effects in overt behavior were observed, both, to the context and to the CS presented in this context, whereas conditioned vocalization to the context was not observed (except for one rat). In support and extent of previous results, the present data show that a detailed analysis of ultrasonic vocalization can substantially broaden and refine the spectrum of analysis in behavioral work with rats, since it can provide information about situational-, state-, and subject-dependent factors which are partly distinct from what is visible to the experimenter.     

Classical fear conditioning in the anxiety disorders: a meta-analysis

Fear conditioning represents the process by which a neutral stimulus comes to evoke fear following its repeated pairing with an aversive stimulus. Although fear conditioning has long been considered a central pathogenic mechanism in anxiety disorders, studies employing lab-based conditioning paradigms provide inconsistent support for this idea. A quantitative review of 20 such studies, representing fear-learning scores for 453 anxiety patients and 455 healthy controls, was conducted to verify the aggregated result of this literature and to assess the moderating influences of study characteristics. Results point to modest increases in both acquisition of fear learning and conditioned responding during extinction among anxiety patients. Importantly, these patient-control differences are not apparent when looking at discrimination studies alone and primarily emerge from studies employing simple, single-cue paradigms where only danger cues are presented and no inhibition of fear to safety cues is required.     

Footshock intensity and generalization in contextual and auditory-cued fear conditioning in the rat

The relationship between US (footshock) intensity and the two conditioned freezing responses (to acoustic CS and to "context") was investigated in fear conditioning. Administered footshock intensity was 0.00, 0.15, 0.30, 0.60, 0.90, and 1.20 mA to six different groups of 70-day-old male Albino Wistar rats. To measure contextual freezing, the animals were again placed inside the conditioning apparatus without acoustic CS and US presentation. To measure acoustic CS freezing, the animals were placed in a totally different apparatus and only the acoustic CS was presented. The 0.15 mA footshock intensity was not sufficient to condition the animals, in fact no freezing was exhibited as in the non-shocked control group. The 0.30 mA footshock intensity was sufficient only to condition the animals to the acoustic CS, whereas the 0.60 mA was sufficient to condition the animals both to acoustic CS and to context. Footshock intensities (0.90 and 1.20 mA) did not elicit any significant increase in conditioned freezing for either acoustic CS or context but at the highest one the generalization phenomenon appeared (freezing in the different context before presentation of acoustic CS). Acoustic CS freezing to all over-threshold intensities was longer than that to context. In conclusion, freezing responses to acoustic CS and context after increasing footshock intensities follow distinct patterns, and intermediate footshock intensities (0.60 and 0.90 mA) appear to be the most useful for eliciting conditioned freezing responses to acoustic CS and to context without inducing a generalized fear status contamination.