TY - JOUR T1 - Decreased Benzodiazepine Binding with Little Effect on γ-Aminobutyric Acid Binding in Rat Brain After Treatment with Antisense Oligodeoxynucleotide to the γ-Aminobutyric Acid<sub>A</sub> Receptor <em>Gamma</em>-2 Subunit <span class="xref-sep">,</span> JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 752 LP - 759 VL - 287 IS - 2 AU - Tai-Jun Zhao AU - Ming Li AU - Ted H. Chiu AU - Howard C. Rosenberg Y1 - 1998/11/01 UR - http://jpet.aspetjournals.org/content/287/2/752.abstract N2 - Benzodiazepine potentiation of γ-aminobutyric acid (GABA) neurotransmission is associated with the presence of agamma-2 subunit in the GABAA receptor. A method was developed to modify the gamma-2 subunit expression in adult rat brain. Unilateral intracerebroventricular (i.c.v.) infusion of a 17-base phosphorothioate-modified antisense oligodeoxynucleotide (ASO) was performed every 12 hr for 3 days. Controls were treated with a sense oligodeoxynucleotide. Parasagittal brain sections were used for quantitative autoradiographic analysis of radioligand binding. ASO treatment caused a 15% to 25% decrease of specific [3H]flunitrazepam binding in most brain areas, with statistically significant decreases in frontal cortex, cerebellar molecular layer, zona reticulata of substantia nigra and CA3 of hippocampus. In contrast, [3H]muscimol binding was not changed. [3H]GABA binding was also unchanged, except for a 10% decrease in cerebellar granule cell layer. The effect on the chloride channel of the GABAA receptor complex was examined by 4′-ethynyl-4-n-[2,3-3H2]propylbicycloorthobenzoate binding; most brain areas showed small decreases in 4′-ethynyl-4-n-[2,3-3H2]propylbicycloorthobenzoate binding. However, hippocampal regions showed much larger decreases. Binding of the adenosine A1 receptor antagonist [3H]8-cyclopentyl-1,3-dipropylxanthine was used to examine possible secondary effects of the ASO. There was a decrease in [3H]8-cyclopentyl-1,3-dipropylxanthine binding, but this was much smaller than the change in [3H]flunitrazepam binding, and no area showed a significant effect. Quantitative immunoblotting with a monoclonal antibody that recognizes GABAA receptor beta-2 andbeta-3 subunits showed no change in immunoreactivity in cerebellar tissue after ASO treatment. The results indicate a selective effect on benzodiazepine binding to GABAA receptors and a possible change in receptor subunit composition. The American Society for Pharmacology and Experimental Therapeutics ER -