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 i ncrease in noradrenaline release in several brain regions, and especially i n the hypothalamus, amygdala and locus coeruleus, in the rat brain. These f indings suggest that an increased noradrenaline release could be closely re lated to the provocation of negative emotions such as anxiety and/or fear. In order to confirm this hypothesis, we carried out several studies. Diazep am, 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, an d 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 incre ase in noradrenaline release in these regions and the stress-induced emotio nal 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 b rain regions and these increases were also significantly attenuated by pret reatment with diazepam in a flumazenil reversible manner. Yohimbine, an alp ha(2)-adrenoceptor antagonist which caused a marked increase in noradrenali ne release in the several brain regions, had an anxiolytic action in the tw o behavioral tests involving anxiety, i.e., the conditioned defensive buryi ng test and the modified forced swim test. beta-Carbolines, which possess a nxiogenic 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, am ygdala and locus coeruleus is, in part, involved in the provocation of anxi ety and/or fear in animals exposed to stress, and that the attenuation of t his increase by benzodiazepine anxiolytics acting via the benzodiazepine re ceptor/GABA(A) receptor/chloride ionophore supramolecular complex may be th e basic mechanism of action of these anxiolytic drugs. (C) 2000 Elsevier Sc ience B.V. All rights reserved.