Treatment with an antisense oligodeoxynucleotide to the GABA A receptor γ2 subunit increases convulsive threshold for β-CCM, a benzodiazepine ‘inverse agonist’, in rats

Abstract

The γ 2 subunit of the γ-aminobutyric acid type-A (GABA A) receptor is associated with the actions of benzodiazepines and related drugs. A phosphorothioate-modified antisense oligodeoxynucleotide directed against the γ 2 subunit was given by i.c.v. injection (18 μg in 2 μl saline) to male Sprague-Dawley rats every 12 h for 3 days. Controls received the corresponding sense oligodeoxynucleotide. 4–6 h after the last i.c.v. treatment, rats were given methyl-β-carboline-3-carboxylate (β-CCM), a benzodiazepine ‘inverse agonist’, by slow i.v. infusion. Compared to naive rats, the β-CCM threshold dose was not affected by the sense oligodeoxynucleotide, but was increased 87% in antisense oligodeoxynucleotide-treated rats. The treatment had no effect on the seizure threshold for picrotoxin. Both antisense and sense oligodeoxynucleotide treatments slightly increased the threshold for strychnine seizures. The results suggest that antisense oligodeoxynucleotide treatment altered GABA A receptor composition and interfered with the actions of a benzodiazepine receptor ligand in vivo, and may provide a tool for studying regulation of receptor structure and function.