Neuroscience Letters, 56 (1985) 265-269 265 Elsevier Scientific Publishers Ireland Ltd. NSL 03298 SELECTIVE BLOCKADE OF BENZODIAZEPINE RECEPTORS BY Ro 15-1788 PREVENTS FOOT SHOCK-INDUCED DECREASE OF LOW AFFINITY 7-AMINOBUTYRIC ACID RECEPTORS M.G. CORDA, A. CONCAS and G. BIGGIO Institute of Biology, Chair of Pharmacology, University of Cagliari, Cagliari (Italy) (Received December 3rd, 1984; Revised version received February 15th, 1985; Accepted February 19th, 1985) Key words: stress - endogenous ligand - benzodiazepine receptors - 7-aminobutyric acid receptors - ben- zodiazepine antagonists The cerebral cortex of unstressed rats has a higher density of low affinity 7-aminobutyric acid (GABA) receptors than that of stressed animals. Stress (handling or foot shock) produces a sudden decrease in the total number of low-affinity GABA receptors in the cerebral cortex of unstressed rats but leaves unchanged the density of GABA receptors in the cortex of stressed animals. The in vivo administration of Ro 15-1788 (30 mg/kg per os), a specific benzodiazepine receptor antagonist, completely prevents the effect of footshock on the low-affinity GABA receptors. The results suggest that (a) benzodiazepine recog- nition sites are involved in the action of stress on GABA receptors, and (b) stress may release an endo- genous ligand for the benzodiazepine recognition site. Recently we have shown that stress due to handling selectively reduces the low- affinity 7-aminobutyric acid (GABA) receptors in different areas of the rat brain and, more effectively, in the cerebral cortex [1]. Thus, cerebral cortex membranes from handling-habituated rats have a higher number of low-affinity GABA receptors than naive (stressed) animals. Foot shock administered just before sacrifice lowers the den- sity of GABA receptors in handling-habituated rats to the level found in naive ones. Moreover, the addition of fl-carbolines to cortical membranes from handling-habit- uated rats also reduces the total number of low-affinity GABA receptors. Vice versa, the in vitro addition of diazepam antagonizes the changes produced by both stress (handling and foot shock) and fl-carbolines on [3H]GABA binding [2, 3, 6]. These results indicate that fl-carbolines, specific benzodiazepine recognition site ligands [4, 5], produce in vitro the same modification in [3H]GABA binding as a stressful stimulus, such as handling or foot shock does in vivo. On the basis of these results we concluded [2, 3, 6] that stress might release an endogenous ligand for benzodiazepine recognition site possessing properties similar to fl-carbolines. Accordingly, several putative ligands, which competitively inhibit [3H]diazepam binding to rat brain synaptosomes, have recently been isolated from the brain [4, 10, 13]. However, the identification of these compounds with the endog- enous ligand is still doubtful. 0304-3940/85/$ 03.30 © 1985 Elsevier Scientific Publishers Ireland Ltd.