THALAMIC DEFICIENCY IN NOREPINEPHRINE RELEASE DETECTED VIA INTRACEREBRAL MICRODIALYSIS - A SYNAPTIC DETERMINANT OF SEIZURE PREDISPOSITION IN THE GENETICALLY EPILEPSY-PRONE RAT

Seizure predisposition in the genetically epilepsy-prone rat (GEPR) is caused by a combination of central nervous system abnormalities inclu ding deficiencies in the number of noradrenergic terminals and in the amount of norepinephrine (NE) released per terminal. Heretofore, estim ates of a synaptic deficiency in NE concentration have been obtained f rom indirect indices. The present study uses intracerebral microdialys is to provide a direct demonstration of deficiency in extracellular NE levels in the GEPR brain. Under anesthesia, guide cannulae were stere otaxically placed over thalami of severe seizure GEPRs (GEPR-9s) and n on-epileptic control rats. After recovery from surgery, dialysis probe s were inserted intrathalamically and the animals were allowed to move about freely. Artificial cerebrospinal fluid (ACSF) was perfused at 1 mul/min and 30-min samples were collected for analysis on HPLC with e lectrochemical detection. Desipramine (5 muM in ACSF for 2 h), yohimbi ne (5 muM in ACSF for 2 h) or KCl (100 mM in ACSF for 1 h) was adminis tered through the dialysis fiber after a stable NE baseline was establ ished. Significantly diminished in vivo NE release from the thalamus w as seen in response to all treatments in GEPR-9s when compared with no n-epileptic controls. These observations coupled with earlier findings of deficits in postsynaptic receptor density and signal transduction support the hypothesis that noradrenergic transmission in the GEPR con tributes to seizure predisposition through a failure to provide a norm al level of protection against seizure initiation and spread.