Abstracts

Subcutaneous administration of AY-9944 (AY) during rat brain development leads to a prepubertal onset of slow spike and wave discharges (SSWD) that persist during the adult period, although the brain cholesterol returns to normal values (Neurology 2001: 56: pp 341-349; Epilepsy Research 2002: 48: pp 111-119; Epilepsia 2002: 43: pp 3-8). The SSWD in the AY model are state-dependent, going from intermittent bilaterally synchronous discharges during the awake state to a continuous spike and wave discharge during slow wave sleep, which is often interrupted by myoclonic jerks (Epilepsia 2000: 41: pp 243). Therefore, we set out to test the hypothesis that serotonin (5- HT) plays a role in the modulation of experimental atypical absence seizures. High performance liquid chromatography (HPLC) was used to measure the levels of serotonin and its metabolite (5-HIAA) in various brain regions. Serotonin metabolism was computed using the 5-HIAA/5-HT ratio and used to ascertain differences between groups of male long Evans hooded rats (n=12), treated from postnatal day (P) 2 to P20 with the cholesterol inhibitor AY (7.5 mg/Kg). Epidural electrodes were implanted for ECoG monitoring. Serotonin depletion was ascertained with para-cholorophenylalanine (PCPA), (150 mg/kg). PCPA or vehicle (n=8) were administered between 0900-1100 h during the peak of serotonin levels (Brain Res Bull 2001;54:199-205). 5-HIAA levels were elevated in AY compared to na[iuml]ve rats in the brainstem (51% increase, p [lt] 0.05, Student[apos]s t-test). AY-treated rats showed higher levels of 5-HIAA and 5-HT in cortex, thalamus and hippocampus, with a concomitant decrease in rates of serotonin turnover. PCPA treatment significantly reduced turnover rates in the thalamus of control rats when compared to naive (80 % reduction, p [lt] 0.01, Student[apos]s t Test) and markedly reduced turnover rates in all brain regions studied in AY treated rats when compared to AY-vehicle (32 [ndash] 90 % reduction, p [lt] 0.01, Student[apos]s t-test). PCPA treatment was associated with a significant decrease in the total slow spike and wave discharge (SSWD) duration from 484.42 [plusmn] 63.98 to 259.42 [plusmn]13.48 sec/hr compared to controls (p [lt] 0.01, Student[apos]s t-test). The increased levels of 5-HIAA and 5-HT and altered rates of serotonin turnover suggest that the serotinergic neurotransmission may be perturbed in the AY-9944 rat model of chronic atypical absence seizures.