This project focuses on elucidating changes in the expression of mRNAs of peptides during amygdala kindling. The neuropeptides seem to be impor- tant modulators of excitatory and inhibitory neurotransmitters, and may have pro- and/or anticonvulsant properties. Following kindled seizures, the expression of peptide mRNAs (TRH, ENK, DYN, NPY) may increase or decrease, depending on the peptide, in limbic areas known to be important in seizures. Each has a different pattern of activation or inhibition at the various stages of kindling, suggesting that each plays a different role in the kindling process. The expression of the peptide mRNAs is also altered in different brain regions at different times. For in- stance, TRH, ENK and NPY mRNAs are increased in the dentate gyrus and entorhinal, piriform and perirhinal cortices four hours after a seizure, and remain elevated in the cortices but not in the dentate gyrus 24 hours after a seizure. A unique and significant alteration of TRH mRNA with contingent tolerance to CBZ has been found. In rats that are tolerant to the anticonvulsant effects of CBZ, the TRH mRNA increases usually found following a seizure are not seen. However, at the same time, TRH receptor binding is de- creased in all rats with kindled seizures, whether or not they are tolerant. The significance of this dramatic effect for CBZ contingent tolerance will be studied in the future. Interestingly, the pattern of TRH mRNA expression most closely resembles that of c-fos. This suggests that c-fos and TRH expression in kindling may be related and co-localized in certain populations of cells. Indeed, in situ double labeling of TRH mRNA with an oligonucleotide probe and an antibody for the Fos protein and Fos-related antigens demonstrates that the vast majority of Fos labeled cells are also labeled with TRH mRNA following a kindled seizure. This suggests that Fos may act as a tran- scription factor for TRH during kindling.
