MODIFICATIONS OF GAMMA-AMINOBUTYRIC-ACID, RECEPTOR SUBUNIT EXPRESSIONIN RAT NEOCORTEX DURING TOLERANCE TO DIAZEPAM

We evaluated whether tolerance to the antagonism of bicuculline-induce d seizures by diazepam is associated with changes (i) in the content o f mRNAs encoding for gamma-aminobutyric acid, (GABA(A)) receptor subun its, (ii) in the expression density of these subunits, and (iii) in th e 1,4-benzodiazepine binding site characteristics in discrete neocorti cal structures. We found that in diazepam-tolerant rats, the content o f the mRNA encoding for the alpha 1 subunit of the GABA(A) receptor de creased in the frontoparietal motor (FrPaM) cortex and in the hippocam pus (42% and 20%, respectively) but not in the frontoparietal somatose nsory (FrPaSS) cortex, striatum, olfactory bulb, and cerebellum. In th e FrPaM cortex, gamma 2S and gamma 2L subunit mRNA contents were also decreased (48% and 30%, respectively), whereas that of alpha 5 was inc reased (30%). In the FrPaM and FrPaSS cortices as well as in cerebellu m of diazepam-tolerant rats, the content of alpha 2, alpha 3, alpha 6, beta 2, and delta subunit mRNA was unchanged, as was the content of a lpha 2, alpha 5, gamma 1, and gamma 2S subunit mRNA in the hippocampus . Furthermore, the reduction in alpha 1 subunit mRNA content in the Fr PaM cortex and the anticonvulsant tolerance to diazepam returned to co ntrol values 72 hr after termination of the protracted diazepam treatm ent. Rats receiving a treatment with imidazenil in doses equipotent an d with a schedule identical to that of diazepam failed to exhibit tole rance to the anticonvulsant action of this drug or cross-tolerance to diazepam. In these rats, the content of mRNA encoding for alpha 1, alp ha 2, alpha 3, alpha 5, alpha 6, gamma 1, gamma 2S, gamma 2L, and delt a GABA(A) receptor subunits failed to change in the FrPaM and FrPaSS c ortices, in the hippocampus, and in the other brain areas that were st udied in diazepam-tolerant rats. Although the density and affinity of [H-3]flumazenil and [H-3]imidazenil binding failed to change in the Fr PaM and FrPaSS cortices of diazepam-tolerant rats, the expression dens ity of al subunit immunogold labeling decreased by 37%, whereas that o f alpha 5, gamma 2L/S, and beta 2/3 increased by 158%, 50%, and 47%, r espectively, in the FrPaM cortex, and the density of the alpha 5 subun it selectively increased (209%) in the FrPaSS cortex. In contrast, the immunogold labeling density of the alpha 1, alpha 5, gamma 2L/S, and beta 2/3 subunits failed to change in either the FrPaM or FrPaSS corte x of rats receiving protracted imidazenil treatment.