Through its broad connections with cortical structures, the hippocampus, hypothalamus, amygdala, and spinal cord, the LC organizes affective, cognitive, and motor responses to acute stressors.3 Activation of LC neurons leads to secretion of norepinephrine (NE), which recruits the multiple pathways involved in modulating behavioral responses to acute stressors. For example, upon receiving electrical stimulation to their locus ceruleus, restrained monkeys will immediately

wake up and exhibit behaviors such as head and body turning, eye scanning, Inhibitors,research,lifescience,medical tongue movement, hair pulling, and escape struggling. These behavioral responses are similar to those elicited when they arc threatened in their natural environment.4 The noradrenergic system also modulates cognitive and behavioral

Inhibitors,research,lifescience,medical adaptations to chronic stressors. Repeated exposure to a stressful stimulus leads to increased NE secretion and facilitates the process of behavioral stress sensitization, whereby the animal develops a heightened behavioral response to further presentations of the same stimulus. Exposure to severe Inhibitors,research,lifescience,medical and repeated stress depletes brain NE concentrations and leads to behavioral changes such as decreased exploration in a plus-maze novelty task, decreased appetite, and deficits in previously well-learned behavioral tasks.5 Such behavioral changes induced by chronic stress have been characterized by the term “learned helplessness.”6 These animal models differ from PTSD in that the development of stress sensitization and learned MEK162 cost helplessness requires repeated exposure to stressful stimuli, while PTSD can develop after Inhibitors,research,lifescience,medical only a single exposure to traumatic stress. Despite Inhibitors,research,lifescience,medical this important

difference, stress sensitization and learned helplessness models are useful in explaining behavioral changes associated with PTSD, such as heightened reactions to traumarelated stimuli and decreased interest in usual-life activities.7 Through its reciprocal connections with the amygdala, the LC/NF, axis also mediates classically conditioned fear responses in animals. In Bay 11-7085 this model, the repeated pairing of a neutral stimulus such as a bright light with a noxious stimulus, such as an electrical shock, eventually results in a conditioned fear response to the previously neutral stimulus when it is presented alone.8 Reactivation of the neuronal connections between the LC and amygdala that are established during acute stress exposure may explain the failure of animals to extinguish stress-related associations. Conditioned fear patterns may underlie features of PTSD such as heightened arousal responses to ordinary noises and increased avoidance behaviors, while failure of extinction may subserve persistent alarm reactions to reminders of past trauma.