Modulatory effects of norepinephrine in the lateral bed nucleus of the stria terminalis on behavioral and neuroendocrine responses to acute stress.

The brain noradrenergic system is activated by stress, and modulates the activity of forebrain regions involved in behavioral and neuroendocrine responses to stress, such as the lateral bed nucleus of the stria terminalis (BSTL). This region of the limbic forebrain receives dense noradrenergic innervation, and has been implicated in both anxiety and regulation of the hypothalamic-pituitary-adrenal axis. We hypothesized that stress-induced release of norepinephrine in the BSTL modulates anxiety-like behavioral responses to stress and activation of the hypothalamic-pituitary-adrenal stress axis. Using microdialysis, we showed that release of norepinephrine was increased in the BSTL of male Sprague-Dawley rats during immobilization stress. In the next experiment, we then microinjected noradrenergic antagonists into the BSTL immediately prior to acute immobilization stress to examine noradrenergic modulation of behavioral stress reactivity. Either the alpha(1)-receptor antagonist benoxathian, or a cocktail of beta(1)- and beta(2)-receptor antagonists (betaxolol+ICI 118,551) blocked the anxiety-like reduction in open-arm exploration on the elevated plus-maze, but not the reduction in social behavior induced in the social interaction test. In a third experiment, benoxathian reduced plasma levels of adrenocorticotropic hormone following stress, but beta-receptor antagonists had no effect. From these results we suggest that stress-induced norepinephrine release acts on both alpha(1)- and beta-receptors in the BSTL to facilitate anxiety-like behavioral responses on the plus-maze but not the social interaction test, and modulates hypothalamic-pituitary-adrenal axis activation via alpha(1)-receptors only. Together with previous results in which adrenergic antagonists in central amygdala attenuated behavioral responses on the social interaction test but not the plus-maze, these observations suggest the two behavioral tests measure different dimensions of stress reactivity, and that norepinephrine facilitates different components of the stress response by region- and receptor-specific mechanisms.