Abstract
Changes in γ-aminobutyric acid A (GABA A) receptor function have been observed following chronic benzodiazepine administration. The molecular mechanisms responsible are unknown, but one possibility is that benzodiazepines induce alterations in the expression of genes which encode subunits of the GABA A receptor complex, resulting in changes in the receptor structure and function. We have investigated this hypothesis by evaluating the effect of flurazepam 40 mg/kg i.p. on brain levels of the mRNAs which encode the α1, α2, α3, α5, and α6 subunits of the GABA A receptor complex. Rats were treated with flurazepam or vehicle for up to 32 days. No changes were found in the levels of α1 and α2 mRNA. A rapid decrease was found in the level of α5 mRNA; α3 mRNA was increased by 4 days of treatment and this was followed by an increase in α6 levels. These results support the hypothesis that the alteration in GABA A receptor function after benzodiazepine administration results from changes in subunit gene expression. Furthermore, the predicted consequences of the pattern of mRNA changes we have observed suggest that altered gene expression may be important in the genesis of benzodiazepine tolerance.
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