that penetrates the blood-brain barrier have shown that it blocks the development, consolidation, and expression of conditioned fear (Deak et al. 1999). Recent studies in rhesus monkeys showed that oral administration of antalarmin significantly inhibited stress-induced increases in plasma norepinephrine, cortisol, and anxiety-related behaviors (Habib et al. 2000). If applicable to humans, those data suggest that a CRH antagonist could be helpful after an acute traumatic event or in preventing harmful central nervous system changes that occur during chronic stress (Gold et al. 2005).

In summary, most PTSD studies demonstrate alterations consistent with increased feedback inhibition of the HPA axis and increased CRH activity. The degree to which those abnormalities represent predisposing neurobiologic risk factors for PTSD rather than consequences of trauma or of living with PTSD is not clear (Yehuda et al. 2002).

Fear Conditioning

Several investigators have noted that the behavioral and physiologic responses of veterans with PTSD are similar to the effects of fear conditioning in animals (Kardiner and Spiegel 1947; Kolb 1987). Fear conditioning can be adaptive. A person who can anticipate a threat by responding to conditioned contextual cues can rapidly engage in appropriate defensive behaviors. Clinically, specific environmental stimuli may be linked to a traumatic event, a spontaneous panic attack, or an embarrassing social situation in such a way that exposure to a similar cue produces a recurrence of symptoms of anxiety and fear. For example, a Vietnam veteran may associate the smell of stir-fried pork with unpleasant memories of Vietnam or the sound of thunder with being in combat. Fear conditioning occurs outside conscious awareness (LeDoux 1996). For the Vietnam veteran, a formerly neutral stimulus has become frightening because it has been transformed into a fear-conditioned stimulus. Clinically, that means that a traumatized person, when exposed to a fear-conditioned cue, may become frightened, anxious, or irritable for reasons that he or she does not understand. Fear-conditioned responses, once they are established, can persist for long periods. Theoretically, once a conditioned fear stimulus is no longer associated with an aversive outcome, the conditioned fear response should extinguish. However, evidence in animals suggests that extinction is an active process that may involve new learning and that the old fear-conditioned association may persist indefinitely and under the right circumstances become reactivated (Bouton and Nelson 1994).

In addition to the formation of vivid memories, patients with PTSD may fail to recover because fear is not extinguished after trauma. Most trauma survivors appear to respond with the re-experiencing, avoidance, and arousal symptoms of PTSD in the immediate aftermath of trauma. However, most of those fear reactions extinguish over time, and people do not develop chronic PTSD. Prospective studies indicate that those who recover from PTSD show a decrease in PTSD symptoms beginning soon after the trauma, but those who do not recover show a different pattern: their PTSD symptoms decrease in the first month after trauma but then remain fairly steady (Rothbaum et al. 1992); they do not worsen, but their original fear reactions are not extinguished to the extent found in non-PTSD people.

People with PTSD do not seem to benefit from safety signals, such as the presence of a spouse, that potentially could help them to cope with painful fear memories (Herman 1992). An example might be a female rape victim who, before the rape, had a close, intimate relationship with her husband (a safety signal) but now feels unsafe with him and with other men. Similarly, despite the passage of many years and being in an environment very different from Vietnam, a war veteran’s fear can persist despite the presence of many potential safety signals, such as being



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