Foot‐Shock Stress and Anxiogenic β‐Carbolines Increase <i>t</i>‐[³⁵S]Butylbicyclophosphorothionate Binding in the Rat Cerebral Cortex, an Effect Opposite to Anxiolytics and γ‐Aminobutyric Acid Mimetics

Abstract

Abstract: The effect of foot‐shock stress on t ‐[ 35 S]‐butylbicyclophosphorothionate ([ 35 S]TBPS) binding to fresh unwashed membrane preparations from rat cerebral cortex was studied and was compared to those of GABA A receptor agonists and antagonists and to positive and negative modulators of the GABAergic transmission. [ 35 S]TBPS binding was increased in the cerebral cortex of rats exposed to foot shock compared to that of nonstressed rats. Scatchard analysis revealed that the effect of foot shock was due to an increase in the total number of [ 35 S]TBPS binding sites. In contrast, the in vitro addition of muscimol or GABA induced a dose‐dependent inhibition of [ 35 S]TBPS binding, an effect abolished by the concomitant addition of the GABA receptor antagonist, bicuculline, which, per se, enhanced [ 35 S]TBPS binding by 73%. Thus, bicuculline, similar to stress, increased [ 35 S]TBPS binding in the same membrane preparation. In contrast to stress, the anxiolytic and positive modulators of the GABAergic transmission (ZK 93423, ZK 91296, and di‐azepam) inhibited the specific binding of [ 35 S]TBPS in a concentration‐dependent manner. The greatest inhibitory effect was produced by ZK 93423 at 30 μ M (31% of control), followed by diazepam (54% of control) and by the partial agonist ZK 91296 (61 % of control). Scatchard plot analysis indicated that the inhibition induced by ZK 93423 and diazepam was due to a decrease in the density of [ 35 S]TBPS recognition sites. On the other hand, the anxiogenic β‐carbolines DMCM and FG 7142 mimicked the effect of stress. Thus, at a 10 μf concentration, DMCM and FG 7142 increased [ 35 S]TBPS binding by 22% and 26%, respectively. The inhibitory effect of ZK 93423, ZK 91296, and diazepam and the stimulatory effect of FG 7142 and DMCM were blocked by the benzo‐diazepine receptor antagonists Ro 15–1788 and ZK 93426. The demonstration that stress, similar to the GABA receptor antagonist bicuculline and to anxiogenic β‐carbolines and opposite to GABA agonists, anxiolytic β‐carbolines, and benzodiazepines, increases [ 35 S]TBPS binding in the rat cerebral cortex, suggests that some emotional state related to stress and anxiety may result from a diminished GABAergic transmission at the level of the GABA A /benzodiazepine receptor/chloride ionophore complex.