Abstracts

Chronic electroconvulsive treatment (ECT) exerts both anticonvulsant and antidepressant effects. The latter involves dorsal raphe (DR) -hippocampal serotonergic projection and postsynaptic 5HT1A receptors. We studied possible role of serotonergic transmission in the ECT-mediated inhibition of seizures. Adult Wistar rats were used. Depletion of serotonin was achieved by parachloroamphetamine (PCA, 60 mg/kg i.p.), and was verified by immunofluorescence in sections of DR and the hippocampus. ECT consisted of 7 daily corneal minimal electroconvulsive shocks (60 Hz, 0.2 s, 40 V). Seizures were induced by kainic acid (KA, 0.1 mcg) injected into the amygdala 12 days after PCA, and/or 1 day after the last electroshock. A selective 5HT1A agonist 8-OH-2-(d-n-propylamino)-tetralin (DPAT), or antagonist WAY100635 (0.3-10 nmole) were injected into the hippocampus 20 min prior to KA. EEG seizures were acquired using BIOPAC MP100 system and AcqKnowledge[trade] software. Total seizure duration (time between the first and the last seizure), cumulative seizure time (total seizure duration less seizure-free intervals), and average duration of single seizure were calculated. In naive rats seizures continued for 5-7 hours; each seizure lasted for 20-40 s, cumulative seizure time was 45-55 min. PCA depleted serotonin both in DR and in the hippocampus by 90%. After PCA, single seizure duration increased to 40-60 s, cumulative seizure time to 310-360 min, and total seizure duration to 9-12 hours. In naive animals, ECT increased serotonin signal in the hippocampus by 25% and significantly attenuated seizures: single seizure duration was 15-25 s, cumulative seizure time- 20-25 min, and total seizure duration- 2.5-4 hrs. However, ECT failed to attenuate seizures in PCA-pretreated rats. DPAT inhibited seizures in naive animals starting at 3 nmole. Both PCA and ECT lowered effective anticonvulsant dose of DPAT 10-fold. WAY100635 affected KA-induced seizures in neither na[iuml]ve, nor PCA animals, but abolished anticonvulsant effect of ECT. Serotonergic transmission in the hippocampus is anticonvulsant, and is required for ECT to inhibit seizures. While postsynaptic 5HT1A are not a sole target for the anticonvulsant effects of serotonin (evident as a lack of the effects of WAY100635 in naive rats), they are required for the ECT to inhibit seizures. Increased anticonvulsant efficacy of DPAT after both PCA and ECT may be attributed to previously reported 5HT1A hypersensitization. It is conceivable, that the hypersensitization of hippocampal 5HT1A and the strengthening of hippocampal serotonergic input underlie ECT-induced resistance to seizures. The data contribute to further understanding of the role of serotonergic transmission in regulating seizures, and confirm its importance as a target for anticonvulsant interventions. (Supported by NIH grants NS043409 (AM) and NS046516 (RS).)