Premium
Chronic Intermittent Ethanol Treatment in Rats Increases GABA A Receptor α4‐Subunit Expression: Possible Relevance to Alcohol Dependence
Author(s) -
Mahmoudi Mithra,
Kang MaengHee,
Tillakaratne Niranjala,
Tobin Allan J.,
Olsen Richard W.
Publication year - 1997
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.1997.68062485.x
Subject(s) - endocrinology , chemistry , medicine , hippocampal formation , forebrain , kindling , pentylenetetrazol , dentate gyrus , muscimol , hippocampus , pharmacology , receptor , gabaa receptor , central nervous system , neuroscience , biology , stimulation , epilepsy , anticonvulsant
Chronic administration of ethanol to rats on an intermittent regimen, for 60 repeated intoxicating doses and repeated withdrawal episodes, results in a long‐lasting kindling phenomenon. This involves an increasing severity of withdrawal, including a reduced threshold to seizures produced by the GABA A antagonist, pentylenetetrazol. We have shown previously that muscimol‐evoked 36 Cl − efflux and paired‐pulse inhibition (involving GABA A ‐mediated recurrent inhibition) were decreased persistently in the CA1 region of hippocampal slices from chronic intermittent ethanol (CIE)‐treated rats. We now report elevated levels of mRNA in forebrain for the α4 subunit of the GABA A receptor (GABAR), considered to be a constituent of pharmacologically and physiologically novel subtypes of GABARs. Using in situ hybridization with digoxigenin‐labeled RNA probes, we show that at 2 days withdrawal, 60‐dose CIE leads to a significant 30% increase in α4 subunit mRNA levels in the dentate gyrus, 46% increase in the CA3, and 26% increase in the CA1 regions. In contrast, there was no significant change in the mRNAs for the α5 subunit or glutamic acid decarboxylase 67 in the same regions. This study suggests that GABAR subunit‐selective alterations occur after CIE treatment, possibly resulting in the alteration of the subunit composition of GABARs, with presumably altered physiological functions. This plasticity of GABARs may contribute to the increased withdrawal severity, reduced hippocampal inhibition, and increased seizure susceptibility of this animal model of human alcohol dependence.