Bi-directional changes in the levels of messenger RNAs encoding gamma-aminobutyric acidA receptor alpha subunits after flurazepam treatment.
Changes in gamma-aminobutyric acidA (GABAA) 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 GABAA 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 alpha 1, alpha 2, alpha 3, alpha 5, and alpha 6 subunits of the GABAA receptor complex. Rats were treated with flurazepam or vehicle for up to 32 days. No changes were found in the levels of alpha 1 and alpha 2 mRNA. A rapid decrease was found in the level of alpha 5 mRNA; alpha 3 mRNA was increased by 4 days of treatment and this was followed by an increase in alpha 6 levels. These results support the hypothesis that the alteration in GABAA 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.
O'Donovan
M C
MC
Department of Psychological Medicine, University of Wales College of Medicine, Cardiff, UK.
Buckland
P R
PR
Spurlock
G
G
McGuffin
P
P
D000818:Animals; D001345:Autoradiography; D001483:Base Sequence; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D005479:Flurazepam / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D008297:Male; D008969:Molecular Sequence Data; D015345:Oligonucleotide Probes; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000235:genetics*
D015345:Oligonucleotide Probes; D012333:RNA, Messenger; D011963:Receptors, GABA-A; D005479:Flurazepam