NORADRENERGIC MECHANISMS FOR THE ANTICONVULSANT EFFECTS OF DESIPRAMINE AND YOHIMBINE IN GENETICALLY EPILEPSY-PRONE RATS - STUDIES WITH MICRODIALYSIS

A large body of evidence suggests that the seizure-prone state of gene tically epilepsy-prone rats (GEPRs) results, in part, from deficits in central nervous system noradrenergic function. In order to link the s ynaptic concentration of norepinephrine (NE) to seizure behavior, we e valuated the effects of both desipramine and yohimbine on convulsions and on extracellular NE and serotonin (5-HT) concentrations in the tha lamus of severe seizure GEPRs (GEPR-9s). Under anesthesia, guide cannu lae were stereotaxically placed over thalami. After recovery from surg ery, dialysis probes were inserted and the animals were placed individ ually into a plexiglass chamber where they were allowed to move about freely. Artificial CSF was perfused and samples were collected for ana lysis on HPLC with electrochemical detection. Either desipramine (10 a nd 20 mg/kg) or yohimbine (10 mg/kg) was administered i.p. after a sta ble baseline of NE or 5-HT was established. Significant increases in t he extracellular NE concentration were seen after injection of both dr ugs. Temporal linkage exists between the maximum NE increase and the m aximum decrease in audiogenic response score (ARS) for these two agent s. No significant increases in the extracellular 5-HT concentration oc curred after administration of either desipramine or yohimbine at a do se of 10 mg/kg. We conclude that these two drugs are effective anticon vulsants in GEPRs at least partially because they enhance noradrenergi c transmission.