Facilitation of Fear Extinction in Rats via Activation of NMDA Receptors: Relevance to Exposure Therapy for the Treatment of PTSD or Phobia

Traumatic events (childhood abuse, rape, combat, severe auto accidents) lead to vivid fear memories. These fear memories often come to mind (flashbacks), leading to distraction, loss of sleep, loss of concentration and distress. Exposure therapy (extinction) can be effective in reducing these fear memories but takes time and sometimes is only partially successful or of limited duration. Hence, treatments are needed that could improve the efficacy of exposure therapy in post-traumatic stress disorders (PTSD) or phobias. Animal studies indicate that conditioned fear (pairing a stimulus - conditioned stimulus) with shock) provides a model system to analyze traumatic fear conditioning. These studies show that extinction (repeated presentation of a conditioned stimulus in the absence of shock) models processes involved in exposure therapy in humans. Extinction does not erase fear memories but instead is an active learning process leading to associations that compete with or suppress fear memories. Extinction is a fragile process that depends on the place where extinction and fear assessment take place that can be disrupted by stress or the passage of time. Animal studies show that extinction requires activation of a particular brain protein (the N-methyl-D-aspartate (NMDA) type glutamate receptor) in the amygdala, a brain area critically involved in fear and anxiety. Compounds that block this receptor block the development of extinction. NMDA receptor function can be enhanced by a compound called D-cycloserine. In rats systemic administration or local infusion into the amygdala of D-cycloserine dose-dependently facilitates the rate of extinction of conditioned fear. This requires concomitant exposure to the conditioned stimulus and involves NMDA receptors. This compound has been used in humans for other purposes and is well tolerated with no serious side effects. Clinical trials are underway to evaluate whether D-cycloserine will provide an effective pharmacological adjunct to exposure therapy in phobic patients or patients with PTSD.