Rick Richardson

Effects of D-Cycloserine on Extinction: Translation From Preclinical to Clinical Work

Administration of benzodiazepines or serotonin reuptake inhibitors in combination with behavior therapy for the treatment of many anxiety disorders has generally lead to only modest gains. In this article we suggest that pharmacotherapy aimed not at treating the symptoms of anxiety but instead aimed at improving the learning that takes place in exposure therapy might actually improve the effectiveness of exposure therapy. This idea was based on animal work showing that the partial N-methyl-D-aspartate (NMDA) agonist D-cycloserine (DCS) facilitated extinction of fear when given either before or shortly after exposure to fearful cues, reduced return of fear that is normally seen when extinction training is followed by stress, and led to generalized extinction, where DCS given in combination with exposure to one fearful cue led to extinction to another cue previously paired with the same aversive event. These finding suggested that DCS might facilitate exposure-based psychotherapy, which was verified in a small clinical study showing that DCS facilitated exposure therapy for fear of heights in a well-controlled virtual reality environment.

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.

A Randomized Controlled Trial of D-Cycloserine Enhancement of Exposure Therapy for Social Anxiety Disorder

BACKGROUND Pilot research has suggested that D-cycloserine (DCS) enhances treatment outcomes for anxiety disorders when employed as an adjunct to exposure therapy (ET). The aim of this study was to determine whether 50 mg of DCS enhances ET for social anxiety disorder (SAD) according to a comprehensive set of symptom and life impairment measures. METHODS In a randomized double-blind placebo-controlled trial, we administered 50 mg of DCS or placebo in combination with ET to 56 participants who met primary diagnosis for SAD. RESULTS Participants administered DCS reported greater improvement on measures of symptom severity, dysfunctional cognitions, and life-impairment from SAD in comparison with placebo-treated participants. Effect sizes were mostly in the medium range. Results also indicated that the amount of adaptive learning about ones ability to give speeches in front of an audience interacted with DCS to enhance treatment outcome. CONCLUSIONS This study shows that the administration of DCS before ET enhances treatment outcomes for SAD. Results also provide the first preliminary evidence to suggest that DCS moderates the relationship between a reduction in negative appraisals about ones speech performance and improvement in overall SAD symptoms.

d-cycloserine facilitates extinction of learned fear: Effects on reacquisition and generalized extinction

BACKGROUND d-cycloserine (DCS) facilitates extinction of learned fear. The aim of this study was to examine whether DCS 1) affects reacquisition of fear (Experiment 1) and 2) produces generalized extinction of fear (Experiment 2). METHODS Following fear conditioning, where a light or a tone conditioned stimulus (CS) was paired with a white-noise burst unconditioned stimulus (US), rats received nonreinforced exposure to one CS (i.e., extinction training). Fear was assessed by measuring CS-elicited freezing, a species-specific defense response. RESULTS Rats given DCS exhibited facilitated extinction of fear but were able to reacquire fear of that CS in a similar manner as saline-treated control animals (Experiment 1). Furthermore, DCS-treated rats exhibited generalized extinction (i.e., they were less fearful of a non-extinguished CS) in comparison to controls (Experiment 2). CONCLUSIONS DCS facilitates extinction of learned fear to the extinguished CS, but also appears to reduce fear of a nonextinguished CS. These findings suggest that this drug may have substantial clinical value in the treatment of anxiety disorders.

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.

Erasing Fear Memories with Extinction Training

Decades of behavioral studies have confirmed that extinction does not erase classically conditioned fear memories. For this reason, research efforts have focused on the mechanisms underlying the development of extinction-induced inhibition within fear circuits. However, recent studies in rodents have uncovered mechanisms that stabilize and destabilize fear memories, opening the possibility that extinction might be used to erase fear memories. This symposium focuses on several of these new developments, which involve the timing of extinction training. Extinction-induced erasure of fear occurs in very young rats, but is lost with the development of perineuronal nets in the amygdala that render fear memories impervious to extinction. Moreover, extinction administered during the reconsolidation phase, when fear memory is destabilized, updates the fear association as safe, thereby preventing the return of fear, in both rats and humans. The use of modified extinction protocols to eliminate fear memories complements existing pharmacological strategies for strengthening extinction.

New Findings on Extinction of Conditioned Fear Early in Development: Theoretical and Clinical Implications

Research with adult animals suggests that extinction depends, at least partly, on new inhibitory learning that is specific to the context in which it is learned. However, several recent studies show that extinction processes are dissociated across development. The present article reviews research on the behavioral and neurobiological mechanisms underlying extinction in developing rats. To summarize, postweanling aged rats (i.e., 24-day-olds) display adult-like extinction in that they show renewal, reinstatement, spontaneous recovery, and compound summation of extinguished stimuli. However, preweanling aged rats (i.e., 17-day-olds) do not show any of those behavioral phenomena. Pharmacological studies also show that reducing N-methyl-D-aspartate, gamma-aminobutryic acid, and opioid neurotransmission impairs extinction in 24-day-old rats, but extinction in P17 rats is only affected by the blocking of opioid neurotransmission. Lastly, extinction in 24-day-old rats involves the amygdala and the ventromedial prefrontal cortex (vmPFC), which are critical brain areas in the neural circuitry of extinction in adult rats. Interestingly, extinction in 17-day-old rats involves the amygdala but not the vmPFC. The existing models of extinction cannot account for these developmental differences. These findings showing that distinct processes mediate extinction at different stages of development may have significant clinical implications, which are discussed in this review.

Effects of multiple exposures to D-cycloserine on extinction of conditioned fear in rats.

Previous research has shown that an acute, post-training injection of D-cycloserine (DCS) facilitates extinction of conditioned fear in rats; however, the effects of multiple exposures to DCS in this situation are not known. In Experiment 1, rats were conditioned (light-shock pairings) and 24 h later given six extinction (light-alone) trials followed by an injection of DCS (15 mg/kg) or saline. The next day, all rats were tested for light-elicited freezing. In Experiment 2, the effect of DCS on extinction was tested in the same manner, except that rats were pre-exposed to DCS (0, 1, or 5 injections) just prior to conditioning. In Experiment 3, rats received five pre-exposures of DCS but conditioning occurred either 2 or 28 days after the last pre-exposure. The results showed that DCS facilitated extinction of conditioned freezing to the light CS when no drug pre-exposure had occurred, but pre-exposure to DCS just prior to conditioning disrupted the facilitation of extinction effect. When 28 days were interposed between pre-exposure and conditioning, the facilitatory effects of DCS on extinction were restored. These findings suggest that DCS has significant clinical value but that behavioral desensitization may occur with multiple exposures; however, desensitization is not permanent and is reduced by the passage of time.

Impaired Extinction Retention in Adolescent Rats: Effects of D-Cycloserine

The developmental trajectory of the prefrontal cortex (PFC) in both rats and humans is nonlinear, with a notable decline in synaptic density during adolescence, potentially creating a ‘natural lesion’ preparation at this age. Given that the PFC is critically involved in retention of extinction of learned fear in adult humans and rodents, the present study examined whether adolescent rats exhibit impaired extinction retention. The results of experiment 1 showed that adolescent rats were impaired in extinction retention, compared with both younger and older rats. The partial NMDA receptor agonist D-cycloserine (DCS) improved extinction retention in adolescent rats (experiment 2), but only if administered immediately after extinction training (experiment 3). In addition, providing extended extinction training improved extinction retention in adolescent rats in a manner similar to that of DCS (experiment 4). The results of this study show that adolescent rats exhibit impaired extinction retention, and that this can be reduced through either DCS or extended extinction training. These novel findings have potential implications for clinical treatments of fear and anxiety disorders in adolescent patients.

Fear Extinction across Development: The Involvement of the Medial Prefrontal Cortex as Assessed by Temporary Inactivation and Immunohistochemistry

Extinction in adult animals, including humans, appears to involve the medial prefrontal cortex (mPFC). However, the role of mPFC in extinction across development has not yet been studied. Given several recent demonstrations of developmental differences in extinction of conditioned fear at a behavioral level, different neural circuitries may mediate fear extinction across development. In all experiments, noise conditioned stimulus (CS) and shock unconditioned stimulus (US) were used. In experiment 1A, temporary unilateral inactivation of the mPFC during extinction training impaired long-term extinction the following day in postnatal day 24 (P24) rats but not in P17 rats. In experiment 1B, bilateral inactivation of the mPFC again failed to disrupt long-term extinction in P17 rats. In experiment 2, extinction training increased phosphorylated mitogen-activated protein kinase (pMAPK) in the mPFC for P24 rats but not for P17 rats, whereas rats of both ages displayed elevated pMAPK in the amygdala. Across both ages, “not trained,” “reactivated,” and “no extinction” control groups expressed very low numbers of pMAPK-immunoreactive (IR) neurons across both neural structures. This result indicates that the mere conditioning experience, the exposure to the CS, or the expression of CS-elicited fear in and of itself is not sufficient to explain the observed increase in pMAPK-IR neurons in the mPFC and/or the amygdala after extinction. Together, these findings show that extinction in P17 rats does not involve the mPFC, which has important theoretical and clinical implications for the treatment of anxiety disorders in humans.