The neurosteroid environment in the hippocampus exerts bi-directional effects on seizure susceptibility in mice.
The progesterone derivative allopregnanolone (ALLO) rapidly potentiates gamma-aminobutyric acid(A) (GABA(A)) receptor mediated inhibition. The present studies determined whether specific manipulation of neurosteroid levels in the hippocampus would alter seizure susceptibility in an animal model genetically susceptible to severe ethanol (EtOH) withdrawal, Withdrawal Seizure-Prone (WSP) mice. Male WSP mice were surgically implanted with bilateral guide cannulae aimed at the CA1 region of the hippocampus one week prior to measuring seizure susceptibility to the convulsant pentylenetetrazol (PTZ), given via timed tail vein infusion. Bilateral intra-hippocampal infusion of ALLO (0.1 microg/side) was anticonvulsant, increasing the threshold dose of PTZ for onset to myoclonic twitch and face and forelimb clonus by 2- to 3-fold. In contrast, infusion of the 5 alpha-reductase inhibitor finasteride (FIN; 2 microg/side), which decreases endogenous ALLO levels, exhibited a proconvulsant effect. During withdrawal from chronic EtOH exposure, WSP mice were tolerant to the anticonvulsant effect of intra-hippocampal ALLO infusion, consistent with published results following systemic injection. Finally, administration of intra-hippocampal FIN given only during the development of physical dependence significantly increased EtOH withdrawal severity, measured by handling-induced convulsions. These findings are the first demonstration that bi-directional manipulation of hippocampal ALLO levels produces opposite behavioral consequences that are consistent with alterations in GABAergic inhibitory tone in drug-naive mice. Importantly, EtOH withdrawal rendered WSP mice less sensitive to ALLO's anticonvulsant effect and more sensitive to FIN's proconvulsant effect, suggesting an alteration in the sensitivity of hippocampal GABA(A) receptors in response to fluctuations in GABAergic neurosteroids during ethanol withdrawal.
Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR 97239, USA. gilillan@ohsu.edu
Katherine R
KR
Gililland-Kaufman
Michelle A
MA
Tanchuck
Matthew M
MM
Ford
John C
JC
Crabbe
Amy S
AS
Beadles-Bohling
Christopher
C
Snelling
Gregory P
GP
Mark
Deborah A
DA
Finn
D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase / Q000378:metabolism; D058891:5-alpha Reductase Inhibitors; D020268:Alcohol-Induced Disorders, Nervous System / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D000818:Animals; D000927:Anticonvulsants / Q000378:metabolism / Q000494:pharmacology; D003292:Convulsants / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004827:Epilepsy / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D018120:Finasteride / Q000494:pharmacology; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010433:Pentylenetetrazole / Q000494:pharmacology; D011280:Pregnanolone / Q000378:metabolism*; D013375:Substance Withdrawal Syndrome / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology
D058891:5-alpha Reductase Inhibitors; D000927:Anticonvulsants; D003292:Convulsants; D004791:Enzyme Inhibitors; D018120:Finasteride; D011280:Pregnanolone; D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase; D010433:Pentylenetetrazole