Noradrenergic mechanisms in stress and anxiety: I. Preclinical studies

There is considerable preclinical evidence for a relationship between noradrenergic brain systems and behaviors associated with stress and anxiety. The majority of noradrenergic neurons are located in the locus coeruleus (pons), with projections throughout the cerebral cortex and multiple subcortical areas, including hippocampus, amygdala, thalamus, and hypothalamus. This neuroanatomical formation of the noradrenergic system makes it well suited to rapidly and globally modulate brain function in response to changes in the environment, as occurs during the presentation of stressors. Stress exposure is associated with an increase in firing of the locus coeruleus and with associated increased release and turnover of norepinephrine in brain regions which receive noradrenergic innervation. Increased firing of the locus coeruleus is also associated with behavioral manifestations of fear, such as arched back and piloerection in the cat. Exposure to chronic stress results in long-term alterations in locus coeruleus firing and norepinephrine release in target brain regions of the locus coeruleus. Norepinephrine is also involved in neural mechanisms such as sensitization and fear conditioning, which are associated with stress. These findings are relevant to an understanding of psychiatric disorders, such as panic disorder and post-traumatic stress disorder (PTSD), the symptoms of which have been hypothesized to be related to alterations in noradrenergic function.