A. Concas et al., MODULATION OF GAMMA-AMINOBUTYRIC-ACID (GABA) RECEPTORS AND THE FEEDING RESPONSE BY NEUROSTEROIDS IN HYDRA-VULGARIS, Neuroscience, 85(3), 1998, pp. 979-988
gamma-Aminobutyric acid (GABA) receptors are present in membrane prepa
rations from Hydra vulgaris, one of the most primitive organisms with
a nervous system. These receptors are sensitive to muscimol and benzod
iazepines and appear to be important in the regulation of the feeding
response. The effects of neurosteroids. general anaesthetics, and GABA
antagonists on GABA(A) receptors in membranes prepared from Hydra and
on the feeding response have now been investigated. The neurosteroids
tetrahydroprogesterone and tetrahydrodeoxycorticosterone increased [H
-3]GABA binding to hydra membranes with nanomolar potency (EC50, 141 /- 11 and 623 +/- 36 nM, respectively) and high efficacy (maximal incr
ease 79+/-6.5 and 62+/-4%, respectively), whereas the 3 beta-hydroxy e
pimer of tetrahydroprogesterone was ineffective. The benzodiazepine re
ceptor ligands diazepam (100 mu M), clonazepam (100 mu M) and abecarni
l (30 mu M) enhanced [H-3]GABA binding to Hydra membranes by 22; 20 an
d 24%, respectively; effects abolished by the specific benzodiazepine
antagonist flumazenil (100 mu M). On the contrary, the peripheral benz
odiazepine receptor ligand 4'chlorodiazepam failed to affect [H-3]GABA
binding to Hydra membranes. The general anaesthetics propofol and alp
haxalone similarly increased (+38% and +30%, respectively) [H-3]GABA b
inding. Moreover, [H-3]GABA binding to Hydra membranes was completely
inhibited by the GABA(A) receptor antagonist SR 95531, whereas bicucul
line was without effect. The modulation of GABA(A) receptors in vitro
by these various drugs correlated with their effects on the glutathion
e-induced feeding response in the living animals. Tetrahydroprogestero
ne and tetrahydrodeoxycorticosterone (I to 10 mu M) prolonged, in a do
se-dependent manner, the duration of mouth opening induced by 10 mu M
glutathione, with maximal effects of +33 and +29%, respectively, appar
ent at 10 mu M neurosteroid. Alphaxalone (10 mu M) similarly increased
(+33%) the effect of glutathione. The effects of steroids on the feed
ing response were inhibited by SR 95531 in a dose-dependent manner; t-
butylbyclophosphorothyonate (1 mu M), a specific Cl- channel blocker,
which pei se, like picrotoxin but not bicuculline, shortened the durat
ion of the response, also counteracted the steroids effects at 1 mu M.
These results suggest that the modulation of GABA(A) receptors by ste
roids is an ancient characteristic of the animal kingdom and that the
pharmacological properties of these receptors have been highly conserv
ed through evolution. (C) 1998 IBRO. Published by Elsevier Science Ltd
.