Abstracts

Rationale: Our earlier studies showed that rats which develop chronic epilepsy following pilocarpine SE, exhibit behavioral deficits indicative of depression, particularly anhedonia and despair. These impairments develop as a result of consecutive dysregulation of thehypothalamo-pituitary-adrenocortical (HPA) axis, enhanced function of presynaptic 5-HT1A receptors and the diminished raphe-hippocampal serotonergic transmission. These depressive impairments are not sensitive to Fluoxetine (FLX); however, partial improvement was achieved by the protracted intrahippocampal administration of human recombinant interleukin-1 receptor antagonist (hrIL1-Ra)In the present study we examined whether in animals with epilepsy-associated depression, combined treatment with hrIL1-Ra and FLX would afford stronger therapeutic action than with hrIL1-Ra aloneMethods: LiCl and pilocarpine SE was induced in 50 days old male Wistar rats.Two months after SE, animals underwent 2 weeks of video seizure monitoring; behavioral tests for depression (forced swim test (FST) and saccharin preference test, combined dexamethasone/corticotropin releasing hormone (DEX/CRH)). Afterwards, animals received continuous,2-week long i.c.v. infusion of hrIL1-Ra (500 mcg total amount) using ALZET osmotic minipump connected to the i.c.v. cannula; FLX was injected once a day at 20 mg/kg throughout hrIL1-Ra treatment. Controls were administered respective vehicles. At the end of the treatments, animals underwent seizure monitoring, behavioral tests and DEX/CRH test again. This was followed by autoradiographic assay of functional state of raphe 5-HT1A receptors, or by electrochemical detection of serotonin release in the raphe-hippocampal pathway using fast cyclic voltammetry.Results: FLX treatment alone did not improve any of the examined parameters of depression, as compared both with vehicle-treated post-SE animals and with selves prior to treatment. Treatment with hrIl1-Ra alone induced partial improvement of depressive deficits in behavioral, neuroendocrine, biochemical and autoradiographic assays as compared with vehicle and FLX-treated post-SE rats, as well as with selves prior to the treatment. Combined administration of hrIl1-Ra and FLX brought all of the examined parameters to the levels statistically similar to those in na ve (i.e. non-epileptic) subjects. None of treatment modified frequency/incidence of spontaneous recurrent seizures.Conclusions: We suggest that in post-SE model of epilepsy-associated depression, the overexpression of hippocampal IL1-? upregulates presynaptic 5-HT1A receptor function, thus leading to the diminished serotonin release in raphe afferents. These data suggest that epilepsy patients suffering from concurrent depression, may benefit from the inclusion of hrIL1-Ra into their treatment scheme either alone, or in combination with FLX.Research supported by NIH grants: R01 NS065783 R21 MH079933