Neurosteroids alter GABA-A receptor subunit gene expression and the action of ethanol on mesocortical dopamine neurons

Biggio G;DAZZI, LAURA;FOLLESA, PAOLO

2003-01-01

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Abstract

Chronic exposure of neurons in culture to progesterone (PROG) or its metabolite allopregnanolone (AP) results in decreases in the abundance of different GABA-A receptor subunits. These changes were accompained by decreases in the efficacies of BZs and b-carbolines on the modulation of GABA-evoked Cl-currents. Exposure (5 days) to ethanol (ETH) elicited similar but not identical changes in the expression of these subunits. Withdrawal from PROG and ETH resulted in an increase in the abundance of a4 subunit mRNA, in the restoration of receptor sensitivity to the negative modulatory action of b-carbolines and a positive receptor responsiveness to flumazenil. These results suggest the possible synergistic action between ETH and AP in modulating the functional activity of specific neuronal populations, such as the mesocortical and mesolimbic dopamine (DA) neurons which are involved in the modulation of addictive effects of ETH. Consistent with this conclusion injection of PROG (5 mg/kg i.p. 5 days) increased the brain content of AP and potentiated the biphasic effect of acute ETH on DA output in the rat prefrontal cortex and nucleus accumbens. Both these effects are abolished by finasteride. Given that finasteride abolished also the enhancement of AP elicited by both ETH and stress while potentiating the stress-induced increase in cortical DA output, our results suggests that AP may play a crucial role in the action of ETH on neurons that contribute to a vulnerability to alcohol abuse. The synergistic action of ETH and AP in modulating central dopaminergic neurons might help to clarify the neurochemistry of ETH addiction.