gamma-Butyrolactone-induced absence-like seizures increase nuclear CRE- and AP-1 DNA-binding activities in mouse brain.

Abstract

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.

• Authors: K Ishige, M Aizawa, Y Ito, H Fukuda
• Journal: Neuropharmacology (Neuropharmacology) Vol. 35 Issue 1 Pg. 45-55 (Jan 1996) ISSN: 0028-3908 [Print] England
• PMID: 8684596 (Publication Type: Journal Article)

Chemical References

• Transcription Factors
• DNA
• 4-Butyrolactone

Topics

• 4-Butyrolactone (pharmacology)
• Animals
• Binding, Competitive (drug effects)
• Brain (drug effects, metabolism)
• DNA (drug effects)
• Dose-Response Relationship, Drug
• Male
• Mice
• Mice, Inbred Strains
• Seizures (chemically induced, metabolism)
• Transcription Factors (drug effects)