Modulation of GABA(A) receptor gene expression by allopregnanolone and ethanol.
Expression of specific gamma-aminobutyric acid type A (GABA(A)) receptor subunit genes in neurons is affected by endogenous modulators of receptor function such as neuroactive steroids. This effect of steroids appears to be mediated through modulation of GABA(A) receptor signalling mechanisms that control the expression of specific receptor subunit genes. Furthermore, the specific outcomes of such signalling appear to differ among neurons in different regions of the brain. Neuroactive steroids such as the progesterone metabolite allopregnanolone might thus exert differential effects on GABA(A) receptor plasticity in distinct neuronal cell populations, likely accounting for some of the physiological actions of these compounds. Here we summarise experimental data obtained both in vivo and in vitro that show how fluctuations in the concentration of allopregnanolone regulate both the expression and function of GABA(A) receptors and consequently affect behaviour. Such regulation is operative both during physiological conditions such as pregnancy and lactation as well as in pharmacologically induced states such as pseudopregnancy and long-term treatment with steroid derivatives or anxiolytic-hypnotic drugs. Accordingly, long-lasting exposure of GABA(A) receptors to ethanol, as well as its withdrawal, induces marked effects on receptor structure and function. These results suggest the possible synergic action between endogenous steroids and ethanol in modulating the functional activity of specific neuronal populations.
Department of Experimental Biology, Section of Neuroscience, and Center of Excellence for the Neurobiology of Dependence, University of Cagliari, 09123 Cagliari, Italy.
Paolo
P
Follesa
Francesca
F
Biggio
Stefania
S
Caria
Giorgio
G
Gorini
Giovanni
G
Biggio
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D000431:Ethanol / Q000494:pharmacology*; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007774:Lactation / Q000378:metabolism; D009473:Neuronal Plasticity; D011247:Pregnancy / Q000378:metabolism*; D011280:Pregnanolone / Q000378:metabolism* / Q000494:pharmacology; D011555:Pseudopregnancy / Q000378:metabolism; D011963:Receptors, GABA-A / Q000096:biosynthesis*
D011963:Receptors, GABA-A; D000431:Ethanol; D011280:Pregnanolone