Effects of D-cycloserine on extinction of conditioned freezing.

The present study tested the prediction that D-cycloserine (DCS), a partial N-methyl-D-aspartate agonist, would facilitate extinction of conditioned freezing in male Sprague-Dawley rats. Rats received 5 light-shock pairings (conditioning). The following day, rats received 6 light-alone presentations (extinction training). Twenty-four hours later, rats received 1 light-alone presentation (test). Subcutaneous DCS injection before or after extinction training significantly enhanced extinction, and the dose-response curve for this effect was linear. Increasing the delay of DCS administration after extinction training led to a linear decrease in the facilitatory effect. The effect of systemic administration was replicated by intra-basolateral amygdala infusion. These results suggest that DCS facilitates extinction of conditioned freezing by acting on consolidation processes partly mediated by the basolateral amygdala. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Delayed extinction attenuates conditioned fear renewal and spontaneous recovery in humans.

This study investigated whether the retention interval after an aversive learning experience influences the return of fear after extinction training. After fear conditioning, participants underwent extinction training either 5 min or 1 day later and in either the same room (same context) or a different room (context shift). The next day, conditioned fear was tested in the original room. When extinction took place immediately, fear renewal was robust and prolonged for context-shift participants, and spontaneous recovery was observed in the same-context participants. Delayed extinction, by contrast, yielded a brief form of fear renewal that reextinguished within the testing session for context-shift participants, and there was no spontaneous recovery in the same-context participants. The authors conclude that the passage of time allows for memory consolidation processes to promote the formation of distinct yet flexible emotional memory traces that confer an ability to recall extinction, even in an alternate context, and minimize the return of fear. Furthermore, immediate extinction can yield spontaneous recovery and prolong fear renewal. These findings have potential implications for ameliorating fear relapse in anxiety disorders. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

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 effect of yohimbine on the extinction of conditioned fear: A role for context.

Six experiments with rat subjects examined the effect of yohimbine, an alpha-2 adrenergic autoreceptor antagonist, on the extinction of conditioned fear to a tone. Experiments 1 and 2 demonstrated that systemic administration of yohimbine (1.0 mg/kg) facilitated a long-term decrease in freezing after extinction, and this depended on pairing drug administration with extinction training. However, Experiments 3 and 4 demonstrated that yohimbine did not eradicate the original fear learning: Freezing was renewed when the tone was tested outside of the extinction context. Experiments 5 and 6 found that the contextually specific attenuation of fear produced by yohimbine transferred to another extinguished conditional stimulus (CS) and not to a nonextinguished CS. The results suggest that yohimbine, when administered in the presence of a neutral context, creates a form of inhibition in that context that allows that specific context to reduce fear of an extinguished CS. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Conditioned stimulus familiarity determines effects of MK-801 on fear extinction.

Six experiments studied the role of conditioned stimulus (CS) familiarity in determining the effects of the N-methyl-d-aspartate (NMDA) receptor antagonist MK-801 on fear extinction. Systemic administration of MK-801 (0.1 mg/kg) impaired initial extinction but not reextinction learning. MK-801 impaired reextinction learning when the CS was relatively novel during reextinction training but not initial extinction learning when the CS was relatively familiar during initial extinction training. A context change failed to reinstate the sensitivity of initial fear extinction learning about a relatively familiar CS to MK-801. These experiments show that CS familiarity is an important determinant of effects of MK-801 on fear extinction learning: MK-801 impaired extinction learning about novel stimuli but spared extinction learning about familiar stimuli. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Massed extinction trials produce better short-term but worse long-term loss of context conditioned fear responses than spaced trials.

A series of experiments studied the effects of the interval between extinction trials on the loss of context conditioned freezing responses. Rats were shocked in one context (A) but not in another (B) and subjected to extinction trials in context A. In Experiment 1, massed trials produced more rapid loss than spaced trials. A shift from spaced to massed trials maintained this loss, but the shift from massed to spaced trials restored lost responses. Experiments 2-5 examined this effect of massed trials on responding across spaced trials. They provided evidence that (a) a single trial was as effective as multiple daily massed trials, (b) learning occurred on the first of the massed trials but not on later ones, and (c) the first trial reduced the amount learned across subsequent massed trials. Finally, alternating extinction trials in A and B produced more response loss across spaced trials than blocks of trials in A and B. The results were discussed in terms of the role accorded to self-generated priming in the models developed by A. R. Wagner (1978, 1981). (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Naloxone facilitates extinction but does not affect acquisition or expression of ethanol-induced conditioned place preference.

Mice (DBA/2J) received a Pavlovian procedure in which a distinctive floor stimulus was paired 4 times with ethanol (2 g/kg). A different floor stimulus was paired with saline. Naloxone (0.0, 1.5, or 10.0 mg/kg, intraperitoneal) given before each ethanol trial did not interfere with acquisition of conditioned preference, although naloxone alone produced conditioned aversion. When naloxone (0.0, 0.15, 1.5, 3.0, or 10.0 mg/kg) was given for the first time during testing, mice showed conditioned preference during the first 10 min. However, preference subsequently decreased dose-dependently over time. Control studies eliminated alternative interpretations based on pharmacokinetics or presence of an aversive state. The overall pattern of results suggests that naloxone facilitated extinction of conditioned place preference and supports the hypothesis that ethanol-induced conditioned reinforcement is mediated by the endogenous opioid system. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Baclofen facilitates the extinction of methamphetamine-induced conditioned place preference in rats.

The powerful, long-lasting association between the rewarding effects of a drug and contextual cues associated with drug administration can be studied using conditioned place preference (CPP). The GABAB receptor agonist baclofen facilitates the extinction of morphine-induced CPP in mice. The current study extended this work by determining if baclofen could enhance the extinction of methamphetamine (Meth) CPP. CPP was established using a six-day conditioning protocol wherein Meth-pairings were alternated with saline-pairings. Rats were subsequently administered baclofen (2 mg/kg i.p. or vehicle) immediately after each daily forced extinction session, which consisted of a saline injection immediately prior to being placed into the previously Meth- or saline-paired chamber. One extinction training cycle, consisted of six once-daily forced extinction sessions, mimicking the alternating procedure established during conditioning, followed by a test for preference (Ext test). CPP persisted for at least four extinction cycles in vehicle-treated rats. In contrast, CPP was inhibited following a single extinction training cycle. These data indicate that Meth-induced CPP was resistant to extinction, but extinction training was rendered effective when the training was combined with baclofen. These findings converge with the prior demonstration of baclofen facilitating the extinction of morphine-induced CPP indicating that GABAB receptor actions are independent of the primary (unconditioned) stimulus (i.e., the opiate or the stimulant) and likely reflect mechanisms engaged by extinction learning processes per se. Thus, baclofen administered in conjunction with extinction training may be of value for addiction therapy regardless of the class of drug being abused. (PsycINFO Database Record (c) 2011 APA, all rights reserved)     

Characteristics of a conditioned response in human subjects during extinction trials following a single traumatic conditioning trial.

A single experience of respiratory paralysis can be used to establish a conditioned response (CR) to a hitherto neutral stimulus. Respiratory paralysis to those undergoing it is horrific but not painful. The CR does not extinguish but becomes stronger as time passes despite repeated extinction trials. The skeletal aspects of the response are more variable than the autonomic aspects and do not provide any constant stimulus input. The results do not fit an "anxiety-reduction" explanation for the inextinguishability of traumatically conditioned responses but suggest that these responses have characteristics not mediated by reinforcement. (20 ref.) (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)     

Extinction of a conditioned motor response following hypnosis.

The administration of a standard hypnosis induction procedure to 6 randomly assigned experimental Ss resulted in the disappearance of a recently acquired conditioned motor response. When hypnosis was terminated by another standard procedure the CR reappeared. On subsequent trials its appearance followed the usual extinction pattern. An equated control group (6 Ss) gave responses that followed the usual extinction pattern during both a extinction trials. Possible interpretations were considered and suggestions for further study made. (20 ref.) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Systemic or intrahippocampal delivery of histone deacetylase inhibitors facilitates fear extinction.

Several recent studies have shown that chromatin, the DNA-protein complex that packages genomic DNA, has an important function in learning and memory. Dynamic chromatin modification via histone deacetylase (HDAC) inhibitors and histone acetyltransferases may enhance hippocampal synaptic plasticity and hippocampus-dependent memory. Little is known about the effects of HDAC inhibitors on extinction, a learning process through which the ability of a previously conditioned stimulus, such as a conditioning context, to evoke a conditioned response is diminished. The authors demonstrate that administration of the HDAC inhibitors sodium butyrate (NaB) systemically or trichostatin A (TSA) intrahippocampally prior to a brief (3-min) contextual extinction session causes context-evoked fear to decrease to levels observed with a long (24-min) extinction session. These results suggest that HDAC inhibitors may enhance learning during extinction and are consistent with other studies demonstrating a role for the hippocampus in contextual extinction. Molecular and behavioral mechanisms through which this enhanced extinction effect may occur are discussed. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

AMPA receptor GluR2, but not GluR1, subunit deletion impairs emotional response conditioning in mice.

Deletions of gria1 or gria2 genes encoding alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic-acid-receptor subunits differ in their effects on appetitive conditioning. The authors investigated whether similar differences would occur in an aversive conditioning test. The ability of a discrete stimulus paired with footshock to subsequently inhibit food-maintained operant responding (conditioned emotional response) was examined in mice with deletions of gria1 or gria2 genes. Whereas gria1 knockout (KO) mice performed normally compared with wild-type (WT) controls, gria2 KO mice displayed no reduction in response rates when the shock-paired stimulus was presented. Nevertheless, gria2 KOs displayed evidence of freezing in a footshock-paired context, indicating that aversive learning could occur. In addition, gria1 KO mice showed some evidence of increased anxiety, and gria2 KOs showed reduced anxiety, in the elevated plus-maze. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Rapid reacquisition of fear to a completely extinguished context is replaced by transient impairment with additional extinction training.

A series of experiments studied reacquisition of fear reactions to a completely extinguished context. Reacquisition was rapid when reconditioning occurred as soon as the fear reactions were completely extinguished, showing that the original conditioning was intact. However, when reconditioning occurred after massive extinction training, fear reactions were depressed but then recovered across a long retention interval. This recovery was due to reconditioning and was similar to that produced by conditioning a massively preexposed context. These results show that massive extinction converts a potentially dangerous context into one that is merely familiar. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Reinstatement of extinguished fear by β-adrenergic arousal elicited by a conditioned context.

Five experiments examined the reinstatement of fear (freezing) produced by recent reexposure to a dangerous context. Rats were trained to fear a conditioned stimulus (CS) and a distinctive context with shock. The CS was then extinguished. A 2-min interval between reexposure to the dangerous context and presentation of the extinguished CS in a different context reinstated freezing when the CS was tested the next day. Propranolol (a β-adrenergic antagonist) blocked reinstatement of extinguished fear without decreasing freezing to a nonextinguished CS. Administration of epinephrine (an adrenergic agonist) reinstated extinguished fear without reexposure to the dangerous context. The results suggest a role for β-adrenergic activity elicited by exposure to a conditioned context in the reinstatement of extinguished fear. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Time and stimulus specificity in extinction of the conditioned nictitating membrane response in the rabbit (Oryctolagus cuniculus).

The present experiments demonstrated that, in the rabbit nictitating membrane preparation, a conditioned response (CR) can be selectively eliminated in one portion of a conditioned stimulus (CS) while it is still paired with the unconditioned stimulus (US). Rabbits were initially trained with two stimuli (tone, light). Each was paired with the US by using a mixture of two CS-US interstimulus intervals (ISIs): 200 ms and 1,200 ms in Experiment 1; 150 ms and 500 ms in Experiment 2. The CRs showed double peaks, one for each ISI. Subsequently, one CS (A) was trained with only the longer ISI, whereas the other CS (B) continued to be trained with both ISIs. Consequently, the CR peak based on the shorter ISI disappeared for CSA but not for CSB. The later CR peaks during both CSA and CSB were maintained. These results support time-based models of conditioning. Implications for proposed mechanisms of extinction are discussed. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Increased spontaneous recovery with increases in conditioned stimulus alone exposures.

A series of experiments used the compound test procedure (Rescorla, 2002) to measure the size of spontaneous recovery of freezing responses by rats to a latently inhibited and/or extinguished conditioned stimulus (CS). The size of recovery was greater: to a pre-exposed and conditioned CS than to a CS just conditioned or just pre-exposed; to an extensively pre-exposed or extinguished CS than to a moderately pre-exposed or extinguished CS; and to a pre-exposed and extinguished CS than to a CS just pre-exposed or just extinguished. These results show that the size of recovery is proportional to the size of the depression produced by CS-alone exposures regardless of whether they occurred before, after, or both before and after conditioning. The results are discussed in terms of some contemporary models of recovery and of the inferences permitted by the use of the compound assessment technique. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Spontaneous recovery but not reinstatement of the extinguished conditioned eyeblink response in the rat.

Reinstatement—the return of an extinguished conditioned response (CR) after reexposure to the unconditioned stimulus (US)—and spontaneous recovery—the return of an extinguished CR with the passage of time—are 2 of 4 well-established phenomena that demonstrate that extinction does not erase the conditioned stimulus (CS)–US association. However, reinstatement of extinguished eyeblink CRs has never been demonstrated, and spontaneous recovery of extinguished eyeblink CRs has not been systematically demonstrated in rodent eyeblink conditioning. In Experiment 1, US reexposure was administered 24 hr prior to a reinstatement test. In Experiment 2, US reexposure was administered 5 min prior to a reinstatement test. In Experiment 3, a long, discrete cue (a houselight), present in all phases of training and testing, served as a context within which each trial occurred to maximize context processing, which in other preparations has been shown to be required for reinstatement. In Experiment 4, an additional group was included that received footshock exposure, rather than US reexposure, between extinction and test, and contextual freezing was measured prior to test. Spontaneous recovery was robust in Experiments 3 and 4. In Experiment 4, context freezing was strong in a group given footshock exposure but not in a group given eye shock US reexposure. There was no reinstatement observed in any experiment. With stimulus conditions that produce eyeblink conditioning and research designs that produce reinstatement in other forms of classical conditioning, we observed spontaneous recovery but not reinstatement of extinguished eyeblink CRs. This suggests that reinstatement, but not spontaneous recovery, is a preparation- or substrate-dependent phenomenon. (PsycINFO Database Record (c) 2011 APA, all rights reserved)     

Early-life exposure to fibroblast growth factor-2 facilitates context-dependent long-term memory in developing rats.

Fibroblast growth factor-2 (FGF2) is a potent neurotrophic factor that is involved in brain development and the formation of long-term memory. It has recently been shown that acute FGF2, administered at the time of learning, enhances long-term memory for contextual fear conditioning as well as extinction of conditioned fear in developing rats. As other research has shown that administering FGF2 on the first day of life leads to long-term morphological changes in the hippocampus, in the present study we investigated whether early life exposure to FGF2 affects contextual fear conditioning, and renewal following extinction, later in life. Experiment 1 demonstrated that a single injection of FGF2 on Postnatal Day (PND) 1 did not lead to any detectable changes in contextual fear conditioning in PND 16 or PND 23 rats. Experiments 2 and 3 demonstrated that 5 days of injections of FGF2 (from PND 1–5) facilitated contextual fear conditioning in PND 16 and PND 23 rats. Experiment 4 demonstrated that the observed facilitation of memory was not due to FGF2 increasing rats' sensitivity to foot shock. Experiment 5 showed that early life exposure to FGF2 did not affect learning about a discrete conditioned stimulus, but did allow PND 16 rats to use contextual information in more complex ways, leading to context-dependent extinction of conditioned fear. These results further implicate FGF2 as a critical signal involved in the development of learning and memory. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The manipulation of dominance in monkeys with conditioned fear.

"2 group dominance tests were conducted on 10 rhesus monkeys. On the basis of these tests 5 pairs of animals adjacent, or nearly adjacent, in the hierarchy were given an additional 5 dominance determinations. The animal in each pair which received the greater number of raisins in each of the 7 tests between the 2 animals was designated as dominant. This animal in each pair was subjected to avoidance conditioning with this submissive partner as the conditioned stimulus… . The dominance status was found to be significantly reversed following the completion of conditioning. It was suggested that this observation provides behavioral evidence for the presence of fear in avoidance conditioning which is independent of the conditioning situation." (PsycINFO Database Record (c) 2010 APA, all rights reserved)