Document Detail

Progesterone withdrawal reduces paired-pulse inhibition in rat hippocampus: dependence on GABA(A) receptor alpha4 subunit upregulation.
MedLine Citation:
PMID:  12522171     Owner:  NLM     Status:  MEDLINE    
Withdrawal from the endogenous steroid progesterone (P) after chronic administration increases anxiety and seizure susceptibility via declining levels of its potent GABA-modulatory metabolite 3alpha-OH-5alpha-pregnan-20-one (3alpha,5alphaTHP). This 3alpha,5alpha-THP withdrawal also results in a decreased decay time constant for GABA-gated current assessed using whole cell patch-clamp techniques on pyramidal cells acutely dissociated from CA1 hippocampus. The purpose of this study was to test the hypothesis that the decreases in total integrated GABA-gated current observed at the level of the isolated pyramidal cell would be manifested as a reduced GABA inhibition at the circuit level following hormone withdrawal. Toward this end, adult, female rats were administered P via subcutaneous capsule for 3 wk using a multiple withdrawal paradigm. We then evaluated paired-pulse inhibition (PPI) of pyramidal neurons in CA1 hippocampus using extracellular recording techniques in hippocampal slices from rats 24 h after removal of the capsule (P withdrawal, P Wd). The population spike (PS) was recorded at the stratum pyramidale following homosynaptic orthodromic stimulation in the nearby stratum radiatum. The threshold for eliciting a response was decreased after P Wd, and the mean PS amplitude was significantly increased compared with control values at this time. Paired pulses with 10-ms inter-pulse intervals were then applied across an intensity range from 2 to 20 times threshold. Evaluation of paired-pulse responses showed a significant 40-50% reduction in PPI for PS recorded in the hippocampal CA1 region after P Wd, suggesting an increase in circuit excitability. At this time, enhancement of PPI by the benzodiazepine lorazepam (LZM; 10 microM) was prevented, while pentobarbital (10 microM) potentiation of PPI was comparable to control levels of response. These data are consistent with upregulation of the alpha4 subunit of the GABA(A) receptor (GABAR) as we have previously shown. Moreover, the reduced PPI caused by P Wd was prevented by suppression of GABAR alpha4-subunit expression following intraventricular administration of specific antisense oligonucleotides (1 microg/h for 72 h). These results demonstrating a reduction in PPI following P Wd suggest that GABAergic-mediated recurrent or feed-forward inhibition occurring at the circuit level were decreased following P Wd in female rats, an effect at least partially attributable to alterations in the GABAR subunit gene expression.
Fu-Chun Hsu; Sheryl S Smith
Publication Detail:
Type:  Journal Article; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Journal of neurophysiology     Volume:  89     ISSN:  0022-3077     ISO Abbreviation:  J. Neurophysiol.     Publication Date:  2003 Jan 
Date Detail:
Created Date:  2003-01-10     Completed Date:  2003-03-26     Revised Date:  2014-09-13    
Medline Journal Info:
Nlm Unique ID:  0375404     Medline TA:  J Neurophysiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  186-98     Citation Subset:  IM    
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MeSH Terms
Action Potentials / drug effects
Excitatory Postsynaptic Potentials / drug effects
GABA Modulators / pharmacology
Hippocampus / cytology,  drug effects,  physiology*
Lorazepam / pharmacology
Neural Inhibition / drug effects*
Neurons / drug effects,  physiology
Oligonucleotides, Antisense / pharmacology
Progesterone / pharmacology*
Rats, Long-Evans
Receptors, GABA-A / genetics,  metabolism*
Substance Withdrawal Syndrome / physiopathology*
Up-Regulation / drug effects
Grant Support
AA-12958/AA/NIAAA NIH HHS; DA-09618/DA/NIDA NIH HHS; R01 AA012958/AA/NIAAA NIH HHS; R01 AA012958-01/AA/NIAAA NIH HHS; R01 AA012958-02/AA/NIAAA NIH HHS; R01 DA009618/DA/NIDA NIH HHS; R01 DA009618-05A2/DA/NIDA NIH HHS; R01 DA009618-06/DA/NIDA NIH HHS; R01 DA009618-07/DA/NIDA NIH HHS
Reg. No./Substance:
0/GABA Modulators; 0/Oligonucleotides, Antisense; 0/Receptors, GABA-A; 4G7DS2Q64Y/Progesterone; O26FZP769L/Lorazepam

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