The phenomenon of contingent tolerance to carbamazepine (CBZ) with the amygdala-kindled seizure paradigm was discovered by Dr. Weiss of the Section on Psychobiology. Tolerance in this model is a contingent process, since it only develops in rats treated with CBZ before the kindling stimulation, and not in rats treated after the stimulation. Receptor autoradiography utilizing various radioligands that bind to different components of the GABA-A receptor system and in situ hy- bridization with oligonucleotides that recognize different subunits of the GABA-A receptor were performed. Kindling increased binding to benzodiazepine, convulsant, and GABA recognition sites and diazepam-insensitive [3-H]Ro 15-4513 binding in the dentate gyrus. Rats tolerant to CBZ showed decreased [3-H]muscimol and diazepam-insensitive [3-H]Ro 15-4513 binding compared with non- tolerant rats, whereas [3-H]flunitrazepam and [35-S]TBPS binding remained elevated. Kindling also increased mRNA for the a-4, b-1, and b-3 subunits (but no change in a-1 and a-2). There was a selective decrease in the a-4 subunit in CBZ-tolerant rats compared with non- tolerant rats. Messenger RNA (mRNA) for the mineralocorticoid (MR) and glucocorticoid (GR) receptors was analyzed in rats made contingent tolerant to CBZ. The MR mRNA in the dentate gyrus was increased in all three kindled groups (vehicle, CBZ-tolerant, and CBZ-non-tolerant) as compared with the two non-kindled control groups (vehicle sham and CBZ sham). However, the expression of GR mRNA was increased only in the vehicle kindled and CBZ-non-tolerant kindled groups. The GR mRNA in the CBZ- tolerant animals was not different from that of the two sham groups. The significance of the project lies in the elucidation of the anticonvulsant mechanism of action of carbamazepine, as well as in the identification of biochemical and molecular substrates of electrical kindling.
