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Examination of 5-HT in an Animal Model of Post Traumatic Stress Disorder

George Dodd

Post Traumatic Stress Disorder is an anxiety disorder that can develop after exposure to a terrifying event or ordeal in which grave physical harm has occurred or was threatened. The events that may trigger PTSD include violent personal assaults, natural or human-caused disasters, accidents, or military combat.  Individuals diagnosed with PTSD also have higher rates of smoking, sexually transmitted infections, obesity, cancer, liver disease and they are also more likely to be alcoholics and suffer from irritable bowel syndrome.  PTSD prevalence varies from country to country, but it has been estimated that a person with PTSD is likely to suffer from symptoms for 20 years or more, equating to a loss of one work day per week and a roughly 3 billion dollar associated loss in worker productivity in the United States each year.  Studies have also indicated that suicide attempts in people with PTSD are as high as 19%, and that 9.2% of the world population may experience symptoms of PTSD.  The hallmark psychological symptom of PTSD is an increased allostatic load state following exposure to even mildly stressful stimuli, resulting in a heightened stress and anxiety response known as sensitization. The objective of our study is to understand the mechanisms behind increased sensitization to stressful stimuli following a traumatic event.  Serotonin (5-HT), is a monoamine neurotransmitter synthesized in neurons with cell bodies in the brainstem and axonal projections to forebrain areas such as the amygdala that are implicated in arousal and responses to stress. Extensive evidence suggests that 5-HT receptors have a role in learning and memory, as well as in mood.  5-HT influences circadian rhythms and changes in motor tone across different stages of sleep, and modulates physiological processes such as control of blood glucose, cardiovascular function and thermoregulation. Therapeutic agents that target 5-HT have had a major impact on treating psychiatric disorders such as depression and schizophrenia. The 5-HT reuptake inhibitors (SSRIs) are among the most widely prescribed drugs for treating depression and a variety of other disorders including anxiety, social phobia and premenstrual dysphoria (PMD).  Using an animal model of post traumatic stress disorder, the Auerbach lab is studying 5-HT in brain sites implicated in sensitization to stress. Previous studies suggest that traumatic stress causes abnormally high release of 5-HT in the amygdala, which in rats leads to a behavior called learned helplessness (LH). Although LH in rats only lasts ~2 days, we hypothesize that traumatic stress may result in persistently low resting baseline levels of 5-HT but an exaggerated activation of 5-HT neurons in response to even mildly stressful events. To test this hypothesis, we determined cFOS levels in 5-HT neurons after a mild stress (elevated platform). Rats were tested 1 week after exposure to a severe stressor (inescapable shock) and compared to a control group which was not previously exposed to the severe stressor. To quantify activation of 5-HT neurons, rat brains were double stained for c-fos and 5-HT immediately after exposure to the elevated platform.  c-Fos is a 55kDA protein product of an immediate early response gene that is transcribed in response to arousing stimuli and has become a widely used marker for identifying neurons and circuits activated by stress.  Brain regions examined were 4 major clusters of 5-HT neurons: MRN, DRN, NRM & NRP.                                                               

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