Noradrenaline systems in the hypothalamus, amygdala and locus coeruleus are involved in the provocation of anxiety: basic studies.

A variety of stressful events, including emotional stress, cause a marked increase in noradrenaline release in several brain regions, and especially in the hypothalamus, amygdala and locus coeruleus, in the rat brain. These findings suggest that an increased noradrenaline release could be closely related to the provocation of negative emotions such as anxiety and/or fear. In order to confirm this hypothesis, we carried out several studies. Diazepam, a typical benzodiazepine anxiolytic, significantly attenuated not only the immobilization stress-induced increase in noradrenaline release in the three rat brain regions but also the emotional changes of these animals, and these effects were antagonized by flumazenil, a benzodiazepine antagonist. Naloxone and opioid agents, such as morphine, beta-endorphin and [Met(5)]-enkephalin, significantly enhanced and attenuated the stress-induced increase in noradrenaline release in these regions and the stress-induced emotional change, respectively. Two stressful events which predominantly involve emotional factors, i.e., psychological stress and conditioned fear, caused significant increases in noradrenaline release selectively in these three brain regions and these increases were also significantly attenuated by pretreatment with diazepam in a flumazenil reversible manner. Yohimbine, an alpha(2)-adrenoceptor antagonist which caused a marked increase in noradrenaline release in the several brain regions, had an anxiolytic action in the two behavioral tests involving anxiety, i.e., the conditioned defensive burying test and the modified forced swim test. beta-Carbolines, which possess anxiogenic properties, significantly increased noradrenaline release in the hypothalamus, amygdala and locus coeruleus. Taken together, these findings suggest that the increased release of noradrenaline in the hypothalamus, amygdala and locus coeruleus is, in part, involved in the provocation of anxiety and/or fear in animals exposed to stress, and that the attenuation of this increase by benzodiazepine anxiolytics acting via the benzodiazepine receptor/GABAA receptor/chloride ionophore supramolecular complex may be the basic mechanism of action of these anxiolytic drugs.