Facilitation of Fear Extinction by D-Cycloserine: Theoretical and Clinical Implications

Abstract

Anxiety disorders are among the most common psychological disturbances in the industrialized world. Current behavioral therapy procedures for these disorders are somewhat effective, but their efficacy could be substantially improved. Because these procedures are largely based on the process of extinction, manipulations that enhance extinction may lead to improvements in treatment effectiveness. We review the evidence that D-cycloserine (DCS), a partial NMDA agonist, facilitates extinction of learned fear in rats. Although only a few studies have examined the effects of DCS on extinction of learned fear, this work suggests that this drug may have a number of potential clinical benefits. In addition, attempts at interpreting this research illustrate our limited understanding of the processes involved in extinction.A substantial percentage of the industrialized world's population will suffer from an anxiety disorder at some point, and consequently, the burden-of-disease costs (both financial and personal) associated with these disorders are extremely high (e.g., Andrews et al. 2001). As a result, there is considerable interest in developing effective treatments for anxiety disorders. Many current therapies for anxiety disorders (e.g., systematic desensitization, flooding, and implosion) involve controlled exposures to the feared stimulus. In other words, these therapies are based on the process of extinction. Although these therapies are the most effective current form of treatment for anxiety disorders (Foa 2000), they could be improved in a number of ways. For example, some patients who begin treatment fail to complete it (i.e., they drop out after a few sessions), and some patients who successfully complete treatment later relapse (i.e., their symptoms return). Manipulations that enhance the process of extinction might reasonably be expected to lead to an improved efficacy of these therapies. Specifically, if such manipulations reduce the number of sessions required, then fewer patients may fail to complete treatment. If these manipulations also somehow reduced the incidence of relapse, then their benefits would be even greater.In the past decade, considerable effort has been directed at increasing our understanding of extinction. Much of this research has involved Pavlovian conditioned fear. In such studies, an animal is first exposed to pairings of an initially neutral conditioned stimulus (CS; e.g., light or tone) with a naturally aversive unconditioned stimulus (US; e.g., shock). After this experience, presentations of the CS elicit a number of behaviors usually associated with the state of fear (e.g., tachycardia, elevated blood pressure, potentiated startle response). These learned fear responses can be reduced, however, by repeatedly presenting the CS by itself; in other words the learned fear responses can be extinguished (see Myers and Davis 2002, for operational and conceptual definitions of extinction). Although extinction is a very simple process procedurally, it has proven to be quite complex theore...

Glutamate NMDA Receptors within the Amygdala Participate in the Modulatory Effect of Glucocorticoids on Extinction of Conditioned Fear in Rats

“…All of these results suggest amygdaloid glucocorticoid receptor dysfunction impairs normal fear extinction. Our results are consistent with the growing body of evidences implying that the extinction process can be enhanced by pharmacological intervention (Quartermain et al, 1994;Roscorla, 2000;Walker et al, 2002;Pitman et al, 2002;Ledgerwood et al, 2003Ledgerwood et al, , 2004Richardson et al, 2004;Yang and Lu, 2005). Our studies suggest that glucocorticoid replacement during a controlled therapy session might restore the normal extinction in PTSD patients.…”

NMDA receptor in conditioned flavor-taste preference learning: Blockade by MK-801 and enhancement by D-cycloserine

“…Unlike its enhancement of extinction in other models of learning (Ledgerwood et al, 2005;Richardson et al, 2004), DCS did not potentiate reversal learning in CFTP when the flavors paired with fructose and saccharin were reversed (i.e., the old CS+ was now paired with S and the old CS− was now paired with F). In both DCS− and vehicle-treated rats, intake of the previously established CS+ decreased and intake of the reversed CS+ increased in 2-bottle preference tests.…”

NMDA Partial Agonist Reverses Blocking of Extinction of Aversive Memory by GABAA Agonist in the Amygdala

“…There is evidence that the partial NMDA agonist DCS facilitates extinction of learned fear in rats and was suggested to have substantial clinical value in the treatment of anxiety disorders and to have a number of potential clinical benefits (Birk, 2004;Ledgerwood et al, 2005;Ressler et al, 2004). Specifically, in fear conditioning, it has been shown that systemic or intra-amygdala administration of DCS before extinction training facilitated extinction Richardson et al, 2004;Walker et al, 2002). Here, we found that microinfusing DCS together with muscimol reversed the impairing effects of muscimol on CTA extinction.…”