gamma-Butyrolactone-induced absence-like seizures increase nuclear CRE- and AP-1 DNA-binding activities in mouse brain.
We examined the involvement of the GABAB receptor and the coordinated induction of nuclear transcriptional factors in experimental generalized absence seizures induced by gamma-butyrolactone (GBL) in mice. Although administration of GBL 50 mg/kg did not show any effects on behavior or ECoG pattern, higher doses of GBL (70 and 100 mg/kg, i.p.) induced behavioral changes associated with 3-6-Hz spike and wave discharges in the mice. CGP 35348, a GABAB receptor antagonist, suppressed both the GBL-induced absence seizures and the spike and wave discharges. The antiepileptic effects of CGP 35348 (200 mg/kg, i.p.) were stronger than those of ethosuximide (200 mg/kg, i.p.). Sodium valproate (100 mg/kg, i.p.) attenuated the early phase but not the late phase of the GBL-induced absence seizures. Gel-mobility assay demonstrated that administration of an effective dose of GBL for eliciting spike and wave discharges dose-dependently increased nuclear cyclic AMP-responsive element (CRE)- and activator protein 1 (AP-1) DNA-binding activities in mouse whole brain. The increases in nuclear CRE- and AP-1 DNA-binding were antagonized by CGP 35348 in a dose-dependent fashion. In addition, GABAB receptor binding assay revealed that GBL or antiepileptic drugs did not displace [3H]baclofen binding in cerebral cortical membranes. In contrast, gamma-hydroxybutyrate (GHB), an active metabolite of GBL, inhibited [3H]baclofen binding in a concentration-dependent manner. These results suggest that GABAB receptor-mediated synaptic responses are involved in GBL-induced generalized absence seizures and that the increases in nuclear CRE- and AP-1 DNA-binding activities are correlated with the GBL-induced generalized absence seizures.
Ishige
K
K
Department of Pharmacology, College of Pharmacy, Nihon University, Chiba, Japan.
Aizawa
M
M
Ito
Y
Y
Fukuda
H
H
D015107:4-Butyrolactone / Q000494:pharmacology*; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D004247:DNA / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D012640:Seizures / Q000139:chemically induced* / Q000378:metabolism; D014157:Transcription Factors / Q000187:drug effects*
D014157:Transcription Factors; D004247:DNA; D015107:4-Butyrolactone