M. Tanaka et al., Noradrenaline systems in the hypothalamus, amygdala and locus coeruleus are involved in the provocation of anxiety: basic studies, EUR J PHARM, 405(1-3), 2000, pp. 397-406
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.