CONTINGENT TOLERANCE TO CARBAMAZEPINE - ALTERATIONS IN TRH MESSENGER-RNA AND TRH RECEPTOR-BINDING IN LIMBIC STRUCTURES

Tolerance to carbamazepine's anticonvuslant effects on amygdala kindle d seizures occurs contingently, that is, only when carbamazepine is gi ven prior to, but not after the seizure occurs. Biological correlates of contingent tolerance were examined using in situ hybridization and receptor binding techniques for thyrotropin-releasing hormone (TRH) mR NA and TRH receptor binding. Rats were fully kindled and given daily i njections of carbamazepine (15 mg/kg, i.p.) either 15 min before (CBZ- before) or after (CBZ-after) amygdala stimulation until the CBZ-before rats became tolerant. Kindled rats were matched so that the two group s had an equal number of seizures and doses of CBZ. Three other groups were also used for comparison: kindled rats that received vehicle inj ections, and sham-kindled animals treated with either vehicle or CBZ. Rats were sacrificed 4 h after the last seizure or sham stimulation. B oth sham-kindled rat groups had barely detectable levels of TRH mRNA. In the CBZ-after (non-tolerant) and vehicle-kindled rats, TRH mRNA lev els were increased in the dentate gyrus, pyriform, entorhinal, and per irhinal cortices. In contrast to the other kindled animals, the CBZ-be fore rats (tolerant) had dramatically diminished TRH mRNA levels bilat erally in the dentate gyrus and pyriform cortex, and ipsilateral to th e stimulation in the entorhinal cortex. Decreases in TRH receptor bind ing were demonstrated autoradiographically in the dentate gyrus and pe rirhinal cortex in all of the kindled groups with no differences betwe en tolerant and non-tolerant rats. The reported TRH mRNA alterations a re, thus, specifically associated with the development of contingent t olerance and are not attributable to either the occurence of seizures or repeated drug exposure alone. The role of TRH in carbamazepine's an ticonvulsant effects and the functional consequences of the failure of CBZ-tolerant animals to show seizure-induced increases in TRH mRNA wa rrants further investigation.