The role of the rat hippocampal system in several effects of context in extinction.

The effect of fornix lesions on some effects of manipulating the context on performance in extinction were studied. In renewal, subjects' responding to an extinguished CS recovered when the CS was presented in the context in which it had been conditioned after extinction in a different context. In reinstatement, it recovered when the CS was tested after independent presentation of the unconditioned stimulus (UCS; an effect mediated by contextual conditioning.) In spontaneous recovery, it recovered after the passage of time, that is, when the CS was tested in a new temporal context. In the conditioned suppression method, fornix lesions had no effect on conditioning, extinction, renewal, or spontaneous recovery; however, they abolished the reinstatement effect. The results suggest that the hippocampal system may be important in the formation of context–UCS associations, but not in other types of learning about the context. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The role of context in re-acquisition of extinguished alcoholic beer-seeking.

We studied the role of context in reacquisition of extinguished reward-seeking. Rats were trained to respond for alcoholic beer, then extinguished and retrained. Reacquisition was faster than acquisition regardless of whether retraining occurred in the original training context, the extinction context, a novel context, or a context with a mixed history of reinforcement. Reacquisition was also rapid after extended extinction training. Nonetheless, context did significantly influence reacquisition via affecting latency to first response: rats took significantly longer to initiate responding when tested in the extinction context. These results suggest that reacquisition of drug and reward seeking is determined by an inhibitory influence caused by the extinction context and a facilitatory influence caused by reintroduction of the reinforcer (Bouton, 1993). (PsycINFO Database Record (c) 2011 APA, all rights reserved)     

Reinstatement of fear to an extinguished conditioned stimulus: Two roles for context.

The authors studied the role of context in reinstatement. Freezing was reinstated when the conditioned stimulus (CS) was extinguished in 1 context and rats moved to another context for reexposure to the shock unconditioned stimulus (US) and test. It was also reinstated (rather than renewed) when rats were shocked in the extinction context and moved to another context for test. This reinstatement was CS specific and reduced by nonreinforced exposures to the extinction context. Rats shocked in the context in which a stimulus had been preexposed froze when tested in another context. These findings suggest 2 roles for context in reinstatement: conditioning of the test context (M. E. Bouton, 1993) and mediated conditioning by the extinction context (P. C. Holland, 1990). (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Renewal of drug seeking by contextual cues after prolonged extinction in rats.

Contextual stimuli associated with drug exposure can modulate various effects of drugs, but little is known about their role in relapse to drug seeking. Using a renewal procedure, the authors report that drug-associated contextual stimuli play a critical role in relapse to drug-seeking previously maintained by a heroin-cocaine mixture (speedball). Rats were trained to self-administer speedball, after which drug-reinforced behavior was extinguished over 20 days in the self-administration context or in a different context. On the test day, rats exposed to the drug-associated context, after extinction in a different context, reliably renewed drug seeking. The authors suggest that the renewal procedure can be used to study mechanisms underlying relapse to drug seeking elicited by drug-associated contextual stimuli. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The effects of acquisition training schedule on extinction and reinstatement of cocaine self-administration in male rats.

Partial reinforcement is known to increase resistance to extinction (Rn) relative to training with continuous reinforcement. This phenomenon, referred to as the partial reinforcement extinction effect, is one of the most robust in learning and conditioning studies. Experiment 1 investigated manipulations known to affect the partial reinforcement extinction effect and determined their possible relevance for drug use patterns. Male rats received intravenous cocaine self-administration training under partial reinforcement (FR-10) training or continuous reinforcement (FR-1) conditions with either a low (0.25 mg/kg infusion) or a high cocaine dose (1.00 mg/kg infusion). Animals were placed on an extinction (recurrent nonreward) schedule for 10 days (1-hr sessions) prior to being tested for cue-induced reinstatement (single 2-hr session). Experiment 2 involved acquisition of cocaine self-administration under FR-1 conditions of short training (15 days) or extended training (30 days) with a low dose (0.25 mg/kg infusion) or a medium dose (0.50 mg/kg infusion) of cocaine reward prior to extinction or reinstatement. Experiment 1 showed that rats trained with FR-10-high dose outcomes exhibited greater Rn than the remaining groups. Additionally, FR-10-high dose and FR-10-low dose rats were more likely to return to active drug seeking during the reinstatement test. In Experiment 2, rats trained under FR-1-medium dose conditions were more persistent during extinction following short acquisition training than comparable rats experiencing extended acquisition training. The reinstatement test was conducted following extinction, in which it was observed that overtraining under FR-1-medium dose reward schedules resulted in a decrease in the tendency to return to active drug seeking. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Renewal and spontaneous recovery, but not latent inhibition, are mediated by gamma-aminobutyric acid in appetitive conditioning.

Previous research has reported a role for the neurotransmitter gamma-aminobutyric acid (GABA) in the extinction and renewal of conditioned fear. Here, the authors examine whether GABA is involved in the acquisition, extinction, renewal, spontaneous recovery, and latent inhibition of appetitive conditioning. Using Long-Evans rats, systemic injection of the GABA A receptor inverse agonist FG 7142 was shown to eliminate ABA renewal (Experiment 1) and spontaneous recovery (Experiment 4) of appetitive responding by selectively reducing the recovery of extinguished magazine approach. Furthermore, treatment with FG 7142 had no effects on acquisition or single-session extinction (Experiment 3) or on the context-specific expression of latent inhibition (Experiment 2). These data suggest that ABA renewal and spontaneous recovery, but not latent inhibition or responding during acquisition and an initial extinction session, are mediated by GABAergic mechanisms in appetitive Pavlovian conditioning. They provide support for the view that renewal and spontaneous recovery share a common psychological mechanism. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effects of progesterone on the reinstatement of cocaine-seeking behavior in female rats.

Estradiol benzoate (EB) facilitates the acquisition and reinstatement of cocaine-seeking behavior when administered to ovariectomized (OVX) rats. In contrast, progesterone (P) decreases acquisition of cocaine self-administration, but the effects of P on the reinstatement of drug seeking are not known. The purpose of the present study was to compare the effects of EB and P on the reinstatement of cocaine-seeking behavior in female rats. Rats received either OVX or sham surgery (SH) and were trained to lever press for intravenous cocaine infusions (0.4 mg/kg) under a fixed ratio 1, 20-s time-out schedule during daily 2-hr sessions. After 14 days of stable responding, saline replaced cocaine, and a 21-day extinction period began. After extinction, rats were separated into 5 treatment groups (OVX+EB, OVX+EB+P, OVX+vehicle [VEH], SH+P, or SH+VEH), and VEH, EB, or EB+P was administered 30 min prior to each session for 5 days. After 3 days of hormone treatment, rats received a saline or cocaine (10 mg/kg) injection, and reinstatement of lever responding was assessed. Reinstatement responding in the OVX+EB group was greater relative to the OVX+EB+P, SH+P, and OVX+VEH groups, which had low levels of cocaine-primed responding. The SH+VEH and OVX+EB groups displayed similar high levels of cocaine-elicited reinstatement. The suppression of cocaine-induced reinstatement following P treatment suggests a role for P in the prevention of relapse to cocaine self-administration in female cocaine users. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Experimental renewal in human participants.

Two experiments with human participants are presented that differentiate renewal from other behavioral effects that can produce a response after extinction. Participants played a video game and learned to suppress their behavior when sensor stimuli predicted an attack. Contexts (A, B, & C) were provided by fictitious galaxies where the game play took place. In Experiment 1, participants who received conditioning in A, extinction in B, and testing in A showed some context specificity of conditioning during extinction and a recovery of suppression on test. Experiment 2 demonstrated recovery of extinguished responding when participants were conditioned in A, extinguished in B, and tested in C, a third, neutral context. The experiment also demonstrated that the context of extinction did not control performance by becoming inhibitory. Results are discussed in terms of mechanisms that can produce a response recovery after extinction. The experiments demonstrated a renewal effect: a response recovery that was not attributable to the contexts acting as simple conditioned stimuli and is the first work with human participants to conclusively do so. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The effects of neurotoxic hippocampal lesions on two effects of context after fear extinction.

Three conditioned suppression experiments with rats examined the role of the hippocampus in 2 effects of context after extinction. Reinstatement is the context-specific recovery of fear to an extinguished conditioned stimulus (CS) that occurs following independent presentations of the unconditioned stimulus (UCS), after extinction. Renewal is the recovery of fear when the CS is presented in the context in which it was conditioned, after extinction in a different context. Results indicated that neurotoxic lesions of the hippocampus, performed before conditioning, abolished reinstatement, which depends on context–UCS associations, but not renewal, which does not. This dissociation is not the result of differences in the recentness of context learning that ordinarily governs the 2 effects. The results suggest that the hippocampus is necessary for some, but not all, types of contextual learning. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

A retrieval cue for extinction attenuates response recovery (renewal) caused by a return to the conditioning context.

When conditioning and extinction are conducted in different contexts, a return to the conditioning context causes a renewal of conditioned responding. The results of 4 experiments with rats in an appetitive conditioning preparation suggest that renewal results from a failure to retrieve extinction outside the extinction context. Presentation of a cue from extinction during renewal testing attenuated the renewal effect; attenuation depended on the cue's correlation with extinction. On its own, the cue did not elicit responding, suggesting it was not a conditioned excitor; it also failed tests for conditioned inhibition. The authors propose that it worked by retrieving a memory of extinction. The findings parallel previous results with spontaneous recovery and are thus consistent with the view that renewal and spontaneous recovery result from a common mechanism. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effects of a context shift and multiple context extinction on reactivity to alcohol cues.

Cue exposure treatment (CET) attempts to reduce the influence of conditioned substance cues on addictive behavior via extinction, but has received only modest empirical support in clinical trials. This may be because extinction learning appears to be context dependent and a change in context may result in a return of conditioned responding (i.e., renewal), although this has received only limited empirical examination. The current study used a 4-session laboratory analogue of CET to examine whether a change in context following 3 sessions of alcohol cue exposure with response prevention would result in renewal of conditioned responding. In addition, this study examined whether conducting extinction in multiple contexts would attenuate renewal of conditioned responding. In one-way between-subjects design, 73 heavy drinkers (71% men) were randomized to 3 conditions: (a) single context extinction (extinction to alcohol cues in the same context for 3 sessions followed by a context shift at the fourth session), (b) multiple context extinction (extinction to alcohol cues in different contexts each day for all 4 sessions), and (c) pseudoextinction control condition (exposure to neutral cues in the same context for 3 sessions followed by exposure to alcohol cues at the fourth session). The results revealed the predicted cue reactivity and extinction effects, but the hypotheses that a context shift would generate renewed cue reactivity and that multiple contexts would enhance extinction were not supported. Methodological aspects of the study and the need for parametric data on the context dependency of extinction to alcohol cues are discussed. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The role of corticotropin-releasing factor and corticosterone in stress- and cocaine-induced relapse to cocaine seeking in rats

We have shown previously that footshock stress and priming injections of cocaine reinstate cocaine seeking in rats after prolonged drug-free periods (Erb et al., 1996). Here we examined the role of brain corticotropin-releasing factor (CRF) and the adrenal hormone corticosterone in stress- and cocaine-induced reinstatement of cocaine seeking in rats. The ability of footshock stress and priming injections of cocaine to induce relapse to cocaine seeking was studied after intracerebroventricular infusions of the CRF receptor antagonist D-Phe CRF12-41, after adrenalectomy, and after adrenalectomy with corticosterone replacement. Rats were allowed to self-administer cocaine (1.0 mg/kg/infusion, i.v) for 3 hr daily for 10-14 d and were then placed on an extinction schedule during which saline was substituted for cocaine. Tests for reinstatement were given after intermittent footshock (10 min; 0.5 mA) and after priming injections of saline and cocaine (20 mg/kg, i.p.). Footshock reinstated cocaine seeking in both intact animals and animals with corticosterone replacement but not in adrenalectomized animals. The CRF receptor antagonist D-Phe CRF12-41 blocked footshock-induced reinstatement at all doses tested in both intact animals and animals with corticosterone replacement. Reinstatement by priming injections of cocaine was only minimally attenuated by adrenalectomy and by pretreatment with D-Phe CRF12-41. These data suggest that brain CRF plays a critical role in stress-induced, but only a modulatory role in cocaine-induced, reinstatement of cocaine seeking. Furthermore, the data show that although reinstatement of cocaine seeking by footshock stress requires minimal, basal, levels of corticosterone, stress-induced increases in corticosterone do not play a role in this effect.     

Effects of D-cycloserine on the extinction of appetitive operant learning.

Four experiments with rat subjects examined whether D-cycloserine (DCS), a partial NMDA agonist, facilitates the extinction of operant lever-pressing reinforced by food. Previous research has demonstrated that DCS facilitates extinction learning with methods that involve Pavlovian extinction. In the current experiments, operant conditioning occurred in Context A, extinction in Context B, and then testing occurred in both the extinction and conditioning contexts. Experiments 1A and 1B tested the effects of three doses of DCS (5, 15, and 30 mg/kg) on the extinction of lever pressing trained as a free operant. Experiment 2 examined their effects when extinction of the free operant was conducted in the presence of nonresponse-contingent deliveries of the reinforcer (that theoretically reduced the role of generalization decrement in suppressing responding). Experiment 3 examined their effects on extinction of a discriminated operant, that is, one that had been reinforced in the presence of a discriminative stimulus, but not in its absence. A strong ABA renewal effect was observed in all four experiments during testing. However, despite the use of DCS doses and a drug administration procedure that facilitates the extinction of Pavlovian learning, there was no evidence in any experiment that DCS facilitated operant extinction learning assessed in either the extinction or the conditioning context. DCS may primarily facilitate learning processes that underlie Pavlovian, rather than purely operant, extinction. (PsycINFO Database Record (c) 2011 APA, all rights reserved)     

"The effects of neurotoxic hippocampal lesions on two effects of context after fear extinction": Errata.

Reports an error in the original article by R. J. Frohardt et al (Behavioral Neuroscience, 2000 [Apr], Vol 114[2], 227-240). On page 229, there is an error in the Method section. The second full sentence on that page should read: Neurotoxic lesions of hippocampus were produced by injections of a mixture of 5.0 μg ibotenic acid and 5.0 μg NMDA per 0.5 ml of normal saline. (The following abstract of this article originally appeared in record 2000-15286-001): Three conditioned suppression experiments with rats examined the role of the hippocampus in 2 effects of context after extinction. Reinstatement is the context-specific recovery of fear to an extinguished conditioned stimulus (CS) that occurs following independent presentations of the unconditioned stimulus (UCS), after extinction. Renewal is the recovery of fear when the CS is presented in the context in which it was conditioned, after extinction in a different context. Results indicated that neurotoxic lesions of the hippocampus, performed before conditioning, abolished reinstatement, which depends on context-UCS associations, but not renewal, which does not. This dissociation is not the result of differences in the recentness of context learning that ordinarily governs the two effects… (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effects of extinction context and retrieval cues on renewal of alcohol-cue reactivity among alcohol-dependent outpatients.

Pavlovian conditioning models have led to cue-exposure treatments for drug abuse. However, conditioned responding to drug stimuli can return (be renewed) following treatment. Animal research and a previous study of social drinkers indicated that extinction is highly context dependent but that renewal could be reduced by the inclusion of a cue from the extinction context. This study extends this research to a clinical sample. Alcohol-dependent outpatients (N = 143) completed an extinction trial to reduce craving and salivation responses to alcohol cues. They were then randomized to renewal tests in either the same context as extinction, a different context, the different context containing an extinction cue, or the different context with cue plus a manipulation to increase the salience of the cue. Contrary to predictions, the different context did not produce the expected renewal effect. Although the generalization of extinction effects beyond the cue-exposure context is a positive clinical finding, it is inconsistent with basic research findings on the context dependence of extinction. Possible explanations for this inconsistency are discussed. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Expression of renewal is dependent on the extinction-test interval rather than the acquisition-extinction interval.

A recent finding suggested that when extinction occurs shortly after acquisition, renewal of an extinguished fear response (fear-potentiated startle) to a light conditioned stimulus (CS) is diminished (Myers, Ressler, & Davis, 2006). The present study attempted to extend this finding using a white-noise CS and freezing as the behavioral measure of fear. In Experiments 1A and 1B, we observed renewal whether extinction occurred 10 min or 24 hr after acquisition. In contrast, renewal was not observed if test occurred 10 min after extinction (Experiment 2). Experiment 3 demonstrated that expression of extinction at the 10-min extinction-test interval was attenuated by a pretest subcutaneous injection of the γ-aminobutyric acid (GABA) inverse agonist FG7142. These findings suggest that renewal is influenced more by the extinction-test interval than the acquisition-extinction interval. Further, the failure to see renewal 10 min after extinction suggests that there is a separate context memory that undergoes a different consolidation function than the CS-no US memory formed during extinction. Finally, the expression of extinction appears to be GABA dependent regardless of the extinction-test interval or the test context. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Central CRF receptor antagonist α-helical CRF9-41 blocks reinstatement of extinguished fear: The role of the bed nucleus of the stria terminalis.

The present experiments assessed the necessity of central CRF in reinstatement of extinguished fear. Using the fear-potentiated startle procedure, rats were given light-shock pairings (fear conditioning) followed by light-alone extinction training. Rats were then given unsignaled shocks to reinstate fear to the light conditioned stimulus (CS). Intracerebroventricular administration of the CRF antagonist α-Helical CRF9-41 prior to reinstatement training dose-dependently prevented reinstatement. Further, α-Helical CRF9-41 administration prior to reinstatement training or the test for reinstatement of fear to the extinguished CS prevented reinstatement at both treatment times, suggesting that CRF activity is critical for this type of return of fear to an extinguished CS. The abolition of reinstatement by drug administration was not due to state-dependent learning, as rats treated with the drug prior to both reinstatement training or testing also failed α-Helical CRF9-41 in the bed nucleus of the stria terminalis suggested that this area is a site at which central CRF is involved in this form of relapse. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effects of extinction context and retrieval cues on alcohol cue reactivity among nonalcoholic drinkers.

Pavlovian conditioning models have influenced the development of cue exposure treatments for drug abuse. However, poor maintenance of extinction performance (renewal) after treatment is a common problem. A treatment-analogue experiment tested the role of context in renewal, as well as a potential strategy for reducing renewal. Seventy-eight social drinkers completed extinction trials to reduce saliva and urge reactivity to alcohol cues and were randomly assigned to a renewal test in either the same context as extinction, a different context, or the different context containing a cue from the extinction context (E-cue). As predicted, the different context produced greater renewal than the same context and renewal was attenuated when the E-cue was present. These results offer preliminary evidence for the context dependence of extinction to alcohol cues and for the use of an extinction cue to improve the generalizability of exposure therapies. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Contextual control of the extinction of conditioned fear: Tests for the associative value of the context.

When male Wistar rats received pairings of a CS with shock in one context and then extinction of the CS in another, fear of the CS was renewed when the CS was returned to and tested in the original context (Exps I and III; 40 Ss). No such renewal was obtained when the CS was tested in a 2nd context after extinction had occurred in the conditioning context (Exp IV; 24 Ss). In Exp II, shocks presented following extinction reinstated fear of the CS, but only if they were presented in the context in which the CS was tested. In each experiment, the associative properties of the contexts were independently assessed. Contextual excitation was assessed primarily with context-preference tests in which Ss chose to sit in either the target context or an adjoining side compartment. Contextual inhibition was assessed with summation tests. Although reinstatement was correlated with demonstrable contextual excitation present during testing, the renewal effect was not. There was no evidence that contextual inhibition developed during extinction. Results suggest that fear of an extinguished CS can be affected by the excitatory strength of the context but that independently demonstrable contextual excitation or inhibition is not necessary for contexts to control that fear. (41 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Treatments that weaken Pavlovian conditioned fear and thwart its renewal in rats: Implications for treating human phobias.

In experiments using a total of 144 albino rat subjects, the authors assessed the ability of fear-weakening treatments to prevent fear renewal (relapse). Conditioned suppression of operant behavior served as the measure of fear in an A-B-A (acquisition-treatment-test) renewal paradigm. In Experiment 1, 100 nonreinforced exposures to a feared cue during treatment (extinction) did not reduce fear renewal relative to 20 exposures. In Experiment 2, explicitly unpaired (EU) treatments thwarted both renewal and reacquisition. In Experiment 3, conditioned inhibition (CI) and differential conditioning (DC) treatments weakened renewal and resisted both reacquisition and a form of reinstatement. In Experiment 4, EU, DC, and CI treatments all thwarted renewal. Evidence suggested that the ability of the treatments to do so reflected the combined effects of transfer of extinction across treatment and test contexts and habituation to the unconditioned stimulus. (PsycINFO Database Record (c) 2010 APA, all rights reserved)