Opioid Receptors Regulate the Extinction of Pavlovian Fear Conditioning.

Rats received a single pairing of an auditory conditioned stimulus (CS) with a footshock unconditioned stimulus (US). The fear (freezing) that had accrued to the CS was then extinguished. Injection of naloxone prior to this extinction significantly impaired the development of extinction. This impairment was mediated by opioid receptors in the brain and was not observed when naloxone was injected after extinction training. Finally, an injection of naloxone on test failed to reinstate extinguished responding that had already accrued to the CS. These experiments show that opioid receptors regulate the development, but not the expression, of fear extinction and are discussed with reference to the roles of opioid receptors in US processing, memory, and appetitive motivation. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effects of Exercise on Pavlovian Fear Conditioning.

Exercise promotes multiple changes in hippocampal morphology and should, as a result, alter behavioral function. The present experiment investigated the effect of exercise on learning using contextual and auditory Pavlovian fear conditioning. Rats remained inactive or voluntarily exercised (VX) for 30 days, after which they received auditory-cued fear conditioning. Twenty-four hours later, rats were tested for learning of the contextual and auditory conditional responses. No differences in freezing behavior to the discrete auditory cue were observed during the training or testing sessions. However, VX rats did freeze significantly more compared to controls when tested in the training context 24 hr after exposure to shock. The enhancement of contextual fear conditioning provides further evidence that exercise alters hippocampal function and learning. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Hippocampus and Pavlovian Fear Conditioning in Rats: Muscimol Infusions Into the Ventral, but Not Dorsal, Hippocampus Impair the Acquisition of Conditional Freezing to an Auditory Conditional Stimulus.

The authors compared the effects of pharmacological inactivation of the dorsal hippocampus (DH) or ventral hippocampus (VH) on Pavlovian fear conditioning in rats. Freezing behavior served as the measure of fear. Pretraining infusions of muscimol, a GABAA receptor agonist, into the VH disrupted auditory, but not contextual, fear conditioning; DH infusions did not affect fear conditioning. Pretesting inactivation of the VH or DH did not affect the expression of conditional freezing. Pretraining electrolytic lesions of the VH reproduced the effects of muscimol infusions, whereas posttraining VH lesions disrupted both auditory and contextual freezing. Hence, neurons in the VH are importantly involved in the acquisition of auditory fear conditioning and the expression of auditory and contextual fear under some conditions. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Opioid regulation of Pavlovian overshadowing in fear conditioning.

In Pavlovian overshadowing, a stimulus that predicts a biologically important event reduces conditioning to another, equally predictive stimulus. We tested the effects of an opioid antagonist and dopamine agonist on the ability of a salient white noise to overshadow a less salient light. Rats were conditioned to fear a light or a noise–light compound using a mild footshock. Compound-conditioned rats trained under the saline vehicle revealed significant overshadowing of the light by the noise. This overshadowing effect was significantly attenuated in rats trained under the opioid antagonist naltrexone, consistent with an opioid-mediated negative feedback model of conditioning. In line with predictions made by negative feedback-type models, we failed to obtain overshadowing with few trials, suggesting that the processes underlying conditioning during initial trials do not contribute to the opioid-dependent Pavlovian overshadowing obtained in our preparation. Lastly, we compared the involvement of dopamine-mediated and opioid-mediated processes in overshadowing by conditioning rats under the partial dopamine D1 receptor agonist SKF 38393 or the opioid antagonist naltrexone. Both naltrexone and SKF 38393 were found to attenuate overshadowing; however, the behavioral profiles produced by each pharmacological manipulation were distinct. Collectively, these studies demonstrate an important role for both opioid- and dopamine-mediated processes in multiple-trial overshadowing. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Opioid receptors in the midbrain periaqueductal gray regulate prediction errors during Pavlovian fear conditioning.

The authors used a within-subject blocking design to study the role of ventrolateral periaqueductal gray (v1PAG) opioid receptors in regulating prediction errors during Pavlovian fear conditioning. In Stage I, the authors trained rats to fear conditioned stimulus (CS) A by pairing it with shock. In Stage II, CSA and CSB were copresented and followed with shock. Two novel stimuli, CSC and CSD, were also copresented and followed with shock in Stage II. CSA blocked fear from accruing to CSB. Blocking was prevented by systemic pretreatment with naloxone. Blocking was also prevented in a dose-dependent and neuroanatomically specific fashion by vlPAG infusions of the μ-opioid receptor antagonist CTAP. These experiments show that v1PAG μ-opioid receptors contribute to Pavlovian fear learning by regulating predictive error. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Two roles of the context in Pavlovian fear conditioning.

At both empirical and theoretical levels, multiple functional roles of contextual information upon memory performance have been proposed without a clear dissociation of these roles. Some theories have assumed that contexts are functionally similar to cues, whereas other views emphasize the retrieval facilitating properties of contextual information. In Experiment 1, we observed that one critical parameter, the spacing of trials, could determine whether the context would function as a conditioned stimulus or as a retrieval cue for memories trained in different phases. Experiments 2 and 3 doubly dissociated these functions by selectively disrupting one role but not the other, and vice versa. Overall, these observations identify one determinant of different functions of contextual information and pose a major challenge to theories of learning that assume exclusively one or the other function of the context. Moreover, these data emphasize the importance of parametric variations on behavioral control, which has critical implications for studies designed to understand the role of the hippocampus in processing of contextual attributes. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Anterograde amnesia for Pavlovian fear conditioning and the role of one trial overshadowing: Effects of preconditioning exposures to morphine in rat.

Four experiments studied anterograde deficits in Pavlovian fear conditioning following prolonged exposure to the μ-opioid receptor agonist morphine. Injections of morphine produced temporally graded anterograde amnesia characterized by deficits in contextual and conditioned-stimulus (CS) conditioning 1 or 7 days and selective impairment in CS conditioning 21 days after last injection. This anterograde deficit in conditioning did not recover across a retention interval, was absent when rats were tested immediately after conditioning, and required the presence of an auditory CS. These results suggest that anterograde deficits in Pavlovian fear conditioning emerged from differences in susceptibility to 1-trial overshadowing of context by CS. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

A Role for CS-US Contingency in Pavlovian Conditioning.

Two experiments evaluated the role of conditioned stimulus-unconditioned stimulus (CS-US) contingency in appetitive Pavlovian conditioning in rats. In both experiments, some groups received a positively contingent CS signaling an increased likelihood of the US relative to the absence of the CS. These groups were compared with control treatments in which the likelihood of the US was the same in the presence and absence of the CS. A trial marker served as a trial context. Experiment 1 found contingency sensitivity. There was a reciprocal relationship between responding to the CS and the trial marker. Experiment 2 showed that this result was not stimulus or response specific. These results are consistent with associative explanations and the idea that rats are sensitive to CS-US contingency. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

NMDA Receptor Modulation of Incidental Learning in Pavlovian Context Conditioning.

Rats exposed to a footshock show conditional fear when reexposed to the shock context. Immediate presentation of shock after placement in the context significantly reduces this fear. Preexposure to the context in the absence of shock, coupled with a minimum preshock interval during training, overcomes this immediate shock deficit. Because rats learn about the context during preexposure and express that learning after being reinforced, the context preexposure effect is an aversive analogue of latent learning. The authors examined the effect of the N-methyl-D-aspartate (NMDA) receptor antagonist D,L-2-amino-5-phosphovalerate (APV) on the facilitatory effect of context preexposure. Rats were preexposed to a chamber after APV administration. The next day they were placed in the same chamber without drug and received shock 35 s later. APV blocked the facilitatory effect of preexposure. Therefore NMDA receptors are important for contextual latent learning. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Opioid receptors regulate retrieval of infant fear memories: Effects of naloxone on infantile amnesia.

The authors examined the role of the endogenous opioid system in infantile amnesia for contextual fear conditioning. Rats that were 18 days of age received an aversive footshock in a novel context. Rats displayed conditioned fear when tested 1 min after training but not 24 hr after training. Systemic injection of the opioid receptor antagonist naloxone prior to test, but not immediately after training, alleviated infantile amnesia. Naloxone also alleviated infantile amnesia when injected prior to test 7 days after training. These effects of naloxone were due to actions on central rather than peripheral opioid receptors and were not due to any tendency of the drug to produce fear or freezing. These results show that central opioid receptors regulate retrieval of fear memories in infant rats. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Disruption of Pavlovian contextual conditioning by excitotoxic lesions of the nucleus accumbens core.

Nucleus accumbens (NAcc) core lesions were performed either before or after Pavlovian aversive conditioning. NAcc core lesions had no effect on discrete-cue or contextual conditioned freezing during acquisition. During retention testing, neither pre- nor posttraining lesions had any effect on conditioned freezing to the discrete cue. However, pretraining lesions resulted in a profound impairment of contextual conditioned freezing in a retention test, and posttraining lesions resulted in a smaller impairment. NAcc core lesions had no effect on sensory or motor processes, as measured by shock reactivity and spontaneous locomotor activity. These results suggest that during acquisition, processes independent of the NAcc core mediate contextual conditioned freezing, but that the NAcc is implicated in the retention of this aversive memory. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Fear, Conditioning, and Aging: Theoretical Comment on LaBar et al. (2004).

Age-related impairments in associative learning have been found in studies using classical conditioning of motor responses. However, it is as yet unclear whether conditioning of fear responses is similarly affected by aging. K. S. La Bar et al. (2004; see record 2004-19432-004) aimed to address this issue by studying age effects on fear conditioning applying a discrimination paradigm. Considering these results, this commentary discusses methodological issues in investigating fear conditioning as well as similarities and differences between associative learning of motor and autonomic responses with respect to neuronal substrates, susceptibility to aging, and the role of awareness of stimulus contingencies in mediating aging effects. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Temporal-difference prediction errors and Pavlovian fear conditioning: Role of NMDA and opioid receptors.

Three experiments studied temporal-difference (TD) prediction errors during Pavlovian fear conditioning. In Stage I, rats received conditioned stimulus A (CSA) paired with shock. In Stage II, they received pairings of CSA and CSB with shock that blocked learning to CSB. In Stage III, a serial overlapping compound, CSB 3 CSA, was followed by shock. The change in intratrial durations supported fear learning to CSB but reduced fear of CSA, revealing the operation of TD prediction errors. N-methyl- D-aspartate (NMDA) receptor antagonism prior to Stage III prevented learning, whereas opioid receptor antagonism selectively affected predictive learning. These findings support a role for TD prediction errors in fear conditioning. They suggest that NMDA receptors contribute to fear learning by acting on the product of predictive error, whereas opioid receptors contribute to predictive error. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Differential Effects of 8-OH-DPAT on Two Forms of Appetitive Pavlovian Conditioning in the Rat.

Rats were trained on an appetitive Pavlovian conditioning task in which the conditioned stimulus (CS) was either localized (a light in the food tray) or nonlocalized (an increase in the general level of illumination). The conditioned response (CR) of approaching the site of food delivery in the presence of the CS was monitored. Presession treatment with the 5-HT1A agonist 8-OH-DPAT (subcutaneous injections at a dose of 0.15 mg/kg) retarded acquisition of the CR, but only when the localized CS was used. The results confirm the general proposal that serotonergic processes are involved in learning. The selective effect of the drug is not to be explained in terms of its motor effects and is consistent with the specific suggestion that systemic administration of 8-OH-DPAT is especially effective in disrupting learning tasks mediated by hippocampal mechanisms. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Association learning of likes and dislikes: A review of 25 years of research on human evaluative conditioning.

Evaluative conditioning refers to changes in the liking of a stimulus that are due to the fact that the stimulus has been paired with other, positive or negative stimuli. Although evaluative conditioning appears to be subjected to certain boundary conditions, significant evaluative conditioning effects have been obtained using a large variety of stimuli and procedures. Some data suggest that evaluative conditioning can occur under conditions that do not support other forms of Pavlovian conditioning, and several models have been proposed to account for these differences. In the present article, the authors summarize the available literature, draw conclusions where possible, and provide suggestions for future research. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Role of the anterior cingulate cortex in the control over behavior by Pavlovian conditioned stimuli in rats.

To investigate the contribution of the anterior cingulate cortex (ACC) to stimulus-reward learning, rats with lesions of peri- and postgenual ACC were tested on a variety of Pavlovian conditioning tasks. Lesioned rats learned to approach a food alcove during a stimulus predicting food, and responded normally for conditioned reinforcement. They also exhibited normal conditioned freezing and Pavlovian-instrumental transfer, yet were impaired at autoshaping. To resolve this apparent discrepancy, a further task was developed in which approach to the food alcove was under the control of 2 stimuli, only 1 of which was followed by reward. Lesioned rats were impaired, approaching during both stimuli. It is suggested that the ACC is not critical for stimulus-reward learning per se, but is required to discriminate multiple stimuli on the basis of their association with reward. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Fear conditioning in inbred mouse strains: An analysis of the time course of memory.

Three mouse strains were examined for short- and long-term memory for Pavlovian fear conditioning measured 1 hr and 24 hr after conditioning. Both DBA/2J and CBA/J mice exhibit reduced long-term memory for contextual fear conditioning compared with C57BL/6J mice. In cued fear conditioning, however, DBA/2J mice show reduced short- and long-term memory compared with C57BL/6J mice, whereas CBA/J mice exhibit reductions only in short-term memory. These results underscore the importance of examining the time course of memory retention, and they suggest that inbred mouse strains may provide a diversity of phenotypes. The results also suggest that the processes of short- and long-term memory storage as well as contextual and cued fear conditioning are dissociable and are mediated by genetically distinct neurobiological mechanisms. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Enhancement of responding to A after A+/AX+ training: Challenges for a comparator theory of learning.

Two appetitive Pavlovian conditioning experiments with rats investigated the associative changes that A undergoes in an A+/AX+ blocking procedure. Conditioned responding to A was enhanced relative to stimulus B, which had been conditioned in isolation (B+). This result was interpreted in terms of the formation of a within-compound association between A and X. The results of Experiment 2 supported this conclusion by demonstrating that X had associative strength of its own and, furthermore, that extinguishing X resulted in a similar level of responding to A and B. These results are considered in terms of retrospective revaluation theories of learning. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Single Neurons in the Dentate Gyrus and CA1 of the Hippocampus Exhibit Inverse Patterns of Encoding During Trace Fear Conditioning.

Trace fear conditioning is a hippocampus-dependent learning task that requires the association of an auditory conditioned stimulus (CS) and a shock unconditioned stimulus (US) that are separated by a 20-s trace interval. Single-neuron activity was recorded simultaneously from the dentate gyrus (DG) and CA1 of rats during unpaired pseudoconditioning and subsequent trace fear conditioning. Single neurons in DG showed a progressive increase in learning-related activity to the CS and US across trace fear conditioning. Single neurons in CA1 showed an early increase in responding to the CS, which developed into a decrease in firing later in trace conditioning. Correlation analyses showed that DG and CA1 units exhibit inverse patterns of responding to the CS during trace fear conditioning. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

D-Cycloserine and the Facilitation of Extinction of Conditioned Fear: Consequences for Reinstatement.

Several recent studies have reported that D-cycloserine (DCS), a partial N-methyl-D-aspartate agonist, facilitates extinction of learned fear in rats. Other studies have shown that representation of the unconditioned stimulus (US) can reinstate learned fear after extinction. This study examined whether this reinstatement effect occurs in Sprague-Dawley rats given DCS at the time of extinction. Results showed that saline-treated rats exhibited the reinstatement effect but DCS-treated rats did not (Experiments 1 and 2). This lack of reinstatement in DCS-treated rats was not due to residual effects of DCS on either US or context processing (Experiment 3). Overall, these results (a) raise questions about the mechanisms underlying DCS facilitation of extinction and (b) suggest that DCS might have substantial practical benefit. (PsycINFO Database Record (c) 2010 APA, all rights reserved)