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 including deficiencies in the number of noradrenergic terminals and in the amount of norepinephrine (NE) released per terminal. Heretofore, estimates of a synaptic deficiency in NE concentration have been obtained from indirect indices. The present study uses intracerebral microdialysis to provide a direct demonstration of deficiency in extracellular NE levels in the GEPR brain. Under anesthesia, guide cannulae were stereotaxically placed over thalami of severe seizure GEPRs (GEPR-9s) and non-epileptic control rats. After recovery from surgery, dialysis probes were inserted intrathalamically and the animals were allowed to move about freely. Artificial cerebrospinal fluid (ACSF) was perfused at 1 microliter/min and 30-min samples were collected for analysis on HPLC with electrochemical detection. Desipramine (5 microM in ACSF for 2 h), yohimbine (5 microM in ACSF for 2 h) or KCl (100 mM in ACSF for 1 h) was administered through the dialysis fiber after a stable NE baseline was established. Significantly diminished in vivo NE release from the thalamus was seen in response to all treatments in GEPR-9s when compared with non-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 contributes to seizure predisposition through a failure to provide a normal level of protection against seizure initiation and spread.
Department of Basic Sciences, University of Illinois College of Medicine, Peoria 61656.
Q S
QS
Yan
P C
PC
Jobe
J W
JW
Dailey
D000704:Analysis of Variance; D000818:Animals; D003891:Desipramine / Q000494:pharmacology; D003956:Dialysis / Q000379:methods*; D004827:Epilepsy / Q000378:metabolism* / Q000503:physiopathology; D005260:Female; D009638:Norepinephrine / Q000032:analysis / Q000378:metabolism*; D011189:Potassium Chloride / Q000494:pharmacology; D051381:Rats; D013788:Thalamus / Q000187:drug effects / Q000378:metabolism*; D013997:Time Factors; D015016:Yohimbine / Q000494:pharmacology
D015016:Yohimbine; D011189:Potassium Chloride; D003891:Desipramine; D009638:Norepinephrine