TY - JOUR
T1 - The role of pregnane neurosteroids in ethanol withdrawal
T2 - Behavioral genetic approaches
AU - Finn, Deborah A.
AU - Ford, Matthew
AU - Wiren, Kristine
AU - Roselli, Charles E.
AU - Crabbe, John Jr
N1 - Funding Information:
This work was supported by the U.S. National Institutes of Health grants AA12439 (DAF) and AA10760 (JCC, DAF, CRR, and KMW) and by the U.S. Department of Veterans Affairs (DAF, KMW, and JCC). We are very grateful to Adam Douglass, Season Long, Jessica Mair, Stacy Matthews, Brett Patterson, Michelle Tanchuck, and Naomi Yoneyama for excellent technical support.
PY - 2004/2
Y1 - 2004/2
N2 - Within the last 20 years, rapid nongenomic actions of steroid hormones have been demonstrated to occur via an interaction with ligand-gated ion channels. For example, the pregnane neurosteroid allopregnanolone (ALLOP) is a potent positive modulator of γ-aminobutyric acidA (GABA A) receptors. The physiological significance of fluctuations in endogenous ALLOP levels has been investigated with regard to disease states and the effect of therapeutic agents on ALLOP levels. Because the pharmacological profile of ALLOP is similar to that of ethanol (EtOH), the modulatory effect of pregnane neurosteroids on EtOH dependence and withdrawal will be the focus of this review. Data on the effects of chronic EtOH exposure and withdrawal on pregnane neurosteroid levels, biosynthetic enzymes, and changes in neurosteroid sensitivity will be summarized. Results from genetic animal models indicate that seizure-prone animals have a persistent decrease in endogenous ALLOP levels during EtOH withdrawal in conjunction with tolerance to ALLOP's anticonvulsant effect. Manipulation of endogenous ALLOP levels with finasteride also markedly reduced the severity of chronic EtOH withdrawal. Gene mapping studies provide a hint for an interaction between genes for GABAA receptor subunits and the biosynthetic enzyme 5α-reductase. Overall, the results are suggestive of a relationship between endogenous pregnane neurosteroid levels and behavioral changes in excitability during EtOH withdrawal, consistent with recent findings in humans. While the findings with ALLOP emphasize the therapeutic potential of neurosteroid treatment during EtOH withdrawal, the gene mapping studies suggest that pregnane neurosteroid biosynthesis may represent a target for therapeutic intervention in the treatment of alcohol dependence.
AB - Within the last 20 years, rapid nongenomic actions of steroid hormones have been demonstrated to occur via an interaction with ligand-gated ion channels. For example, the pregnane neurosteroid allopregnanolone (ALLOP) is a potent positive modulator of γ-aminobutyric acidA (GABA A) receptors. The physiological significance of fluctuations in endogenous ALLOP levels has been investigated with regard to disease states and the effect of therapeutic agents on ALLOP levels. Because the pharmacological profile of ALLOP is similar to that of ethanol (EtOH), the modulatory effect of pregnane neurosteroids on EtOH dependence and withdrawal will be the focus of this review. Data on the effects of chronic EtOH exposure and withdrawal on pregnane neurosteroid levels, biosynthetic enzymes, and changes in neurosteroid sensitivity will be summarized. Results from genetic animal models indicate that seizure-prone animals have a persistent decrease in endogenous ALLOP levels during EtOH withdrawal in conjunction with tolerance to ALLOP's anticonvulsant effect. Manipulation of endogenous ALLOP levels with finasteride also markedly reduced the severity of chronic EtOH withdrawal. Gene mapping studies provide a hint for an interaction between genes for GABAA receptor subunits and the biosynthetic enzyme 5α-reductase. Overall, the results are suggestive of a relationship between endogenous pregnane neurosteroid levels and behavioral changes in excitability during EtOH withdrawal, consistent with recent findings in humans. While the findings with ALLOP emphasize the therapeutic potential of neurosteroid treatment during EtOH withdrawal, the gene mapping studies suggest that pregnane neurosteroid biosynthesis may represent a target for therapeutic intervention in the treatment of alcohol dependence.
KW - Behavioral sensitivity
KW - Biosynthetic enzymes
KW - Functional sensitivity
KW - GABA receptor
KW - Inbred strains
KW - Selected lines
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U2 - 10.1016/j.pharmthera.2003.10.006
DO - 10.1016/j.pharmthera.2003.10.006
M3 - Review article
C2 - 14761701
AN - SCOPUS:0842324491
SN - 0163-7258
VL - 101
SP - 91
EP - 112
JO - Pharmacology and Therapeutics
JF - Pharmacology and Therapeutics
IS - 2
ER -