Animal Models of Relevance to PTSD

Abstract

Posttraumatic stress disorder or PTSDI is a psychiatric disorder of considerable prevalence and morbidity and can affect persons of any age and ethnic or socioeconomic background.2-10 It is, unfortunately, a far too common outcome of participation in war, affecting 15.2% of Vietnam theater veterans 20 years after the war." Its prevalence may be even higher in inner city communities exposed to compound community trauma. In one small northeastern city, it was found to affect 67% of adolescents frequenting a community medical clinic for routine preventive health care.lz Reducing exposure to trauma would obviously be the most effective and immediate means of controlling the induction of PTSD and should be given the highest social priority. Beyond such efforts, understanding the means by which the extreme stress of trauma is neurobiologically transduced to produce PTSD may help in its prevention and treatment. Clinical studies have yielded, thus far, important empiric findings on ways in which the neurobiology of persons with PTSD differs from that of normal controls and from that of individuals with other psychiatric disorders. The most robust findings include apparent increased baseline activation of the noradrenergic system13 and exaggerated noradrenergic responses to pharmacologic perturbation of that system,I4 decreased 24-hour urine cortisol l e v e l~, l~'~ opiate antagonist-sensitive increases in stress-induced analgesia?' apparent enhanced negative feedback in the hypothalamic-pituitary-adrenal axis increased circulating thyroid hormone levels,22 increased cerebrospinal fluid corticotropin-releasing factor:3 and diminished hippocampal volume as measured by magnetic resonance imaging.w26These findings are invaluable in guiding further scientific studies. For example, it would be useful to know if these neurobiologic characteristics are sequelae of threshold trauma in all individuals or only in those individuals predisposed in some way to the development of PTSD. It would also be useful to know if any of these characteristics could be premorbid and thereby predispose to PTSD symptom formation on exposure to trauma. It is also not clear whether or how these findings relate to specific symptoms of PTSD. Also, are they early manifestations of PTSD or do they develop over time? Indeed, if these neurobiological stigmata of PTSD can be 'Address for correspondence: Ann M. Rasmusson, M.D., Psychiatry Service/l16A, Connecticut VA Healthcare System, West Haven Campus,

Attention, learning, and memory performances and intellectual resources in Vietnam veterans: PTSD and no disorder comparisons.

“…Similarly, greater intellectual sophistication may facilitate the development of personal resources such as educational attainment, occupational achievement, and other socioeconomic factors, which appear to buffer stress impact (Hobfoll, 1989;Ursano, Wheatley, Sledge, Rahe, & Carlson, 1986). Additionally, if exposure to stress is associated with neurobiological alterations, as animal models suggest (see Bremner et al, 1999;Rasmusson & Charney, 1997, for reviews), then higher levels of premilitary intelligence may reflect reduced central system vulnerability to stress. Indirect support for this hypothesis can be found among studies documenting increased psychological symptoms in trauma survivors with a history of brain injury (Chemtob et al, 1998;R.…”

“…Bremner et al, 1999;Rasmusson & Charney, 1997) and findings from the psychopathology literature that indicate that preexposure indices of intellectual resources are associated with PTSD diagnosis (Centers for Disease Control Vietnam Experiences Study, 1988;Green et al, 1990;Harel et al, 1988;Kulka et al, 1990;Macklin et al, 1998;Pitman et al, 1991;Sutker et al, 1990), we predicted that neurocognitive and intellectual performances would be independently associated with PTSD severity after controlling statistically for shared variances between the two variable sets.…”

“…However, it remains unclear if such neurobiological abnormalities are a result of exposure to stress or instead reflect premorbid vulnerabilities. Although animal models have suggested that exposure to prolonged laboratory-induced stress results in neurobiological alterations to the organism (see Bremner et al, 1999;Rasmusson & Charney, 1997, for reviews), research examining the neurobiological correlates of trauma-induced stress disorders in humans is necessarily correlational.…”

Induction and Expression of Fear Sensitization Caused by Acute Traumatic Stress

“…Altered HPA axis responsiveness may contribute to the sensitized responses PTSD patients experience to innocuous events that are perceived as threatening; that is, PTSD symptoms may develop via a sensitization process involving the HPA axis that causes less intense stressors to be perceived as stronger than they are (Rasmusson and Charney, 1997;Yehuda, 1997). The initial traumatic event activates the stress response, but upon receiving reminders of the trauma or mild but similar stressors, the stress response reactivates.…”

Questions and Hypotheses

“…Knowledge about the connections between the neurobiological and the therapeutic effects of MDMA is far from complete, but it has been observed that MDMA acutely decreases activity in the left amygdala (Gamma et al 2000). This action is compatible with its reported reduction in fear or defensiveness, and is in contrast to the stimulation of the amygdala observed in animal models of conditioned fear, a state similar to PTSD ( Rasmusson andCharney 1997, Davis andShi 1999).…”