TREATMENT WITH AN ANTISENSE OLIGODEOXYNUCLEOTIDE TO THE GABA(A) RECEPTOR GAMMA(2) SUBUNIT INCREASES CONVULSIVE THRESHOLD FOR BETA-CCM, A BENZODIAZEPINE INVERSE AGONIST, IN RATS

The gamma(2) subunit of the gamma-aminobutyric acid type-A (GABA(A)) r eceptor is associated with the actions of benzodiazepines and related drugs. A phosphorothioate-modified antisense oligodeoxynucleotide dire cted against the gamma(2) subunit was given by i.c.v. injection (18 mu g in 2 mu l 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-beta-carboli ne-3-carboxylate (beta-CCM), a benzodiazepine 'inverse agonist', by sl ow i.v. infusion. Compared to naive rats, the -CCM threshold dose was not affected by the sense oligodeoxynucleotide, but was increased 87% in antisense oligodeoxynucleotide-treated rats. The treatment had no e ffect on the seizure threshold for picrotoxin. Both antisense and sens e oligodeoxynucleotide treatments slightly increased the threshold for strychnine seizures. The results suggest that antisense oligodeoxynuc leotide 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 funct ion.