Department of Experimental Biology, Chair of Pharmacology, University of Cagliari, 09100 Cagliari, Italy
Benzodiazepines, the drugs most widely used in the treatment of anxiety, produce their pharmacological effects by regulating the interaction of GABA with its recognition site at the level of the GABA/benzodiazepine receptor com­plex (17,18). In fact, it has been shown that benzodiazepines favor, through an allosteric mechanism, the interaction between endogenously released GABA and its recognition site. Thus the anxiolytic effect of benzodiazepines may be con­sidered the consequence of the activation of the GABA receptor induced by these drugs. Accordingly, in different animal models of anxiety, the anticonflict effect of benzodiazepines is antagonized by picrotoxin and bicuculline (4,35), drugs that reduce the responsiveness of GABA receptors and have an anxiogenic effect on their own (12,27), whereas it is mimicked and potentiated by muscimol, a specific GABA receptor agonist (7). Moreover, it has been found that /S-carboline derivatives, benzodiazepine receptor ligands (5) that modulate the GABAergic function in the opposite direction to the benzodiazepines (2,6,8,11,21,26,29) have an anxiogenic effect in several animal species, man included (14-16,23, 25,27,30). Although the above studies have clearly demonstrated that the GABA/ben­zodiazepine receptor complex participates in the anxiolytic effect of benzodi­azepines, the molecular events involved in the physiopathology of stress and anxiety have still to be clarified. With the aim of clarifying this problem we have recently found that stress selectively reduces the density of low affinity GABA receptors in the cerebral cortex of the rat (1,3,9,13). This finding is consistent with the hypothesis that some emotional states related to stress and anxiety may result from a diminished GABAergic transmission at the level of the GABA/benzodiazepine receptor complex. The finding that brain GABA receptors may be modified by the emotional state of the animal before sacrifice was obtained a few years ago in our laboratory when we found that the cerebral cortex of rats habituated to the manipulations that precede sacrifice by guillotine has a higher density of low affinity GABA receptors than that of naive, nonhabituated animals (Table 1). On the basis of this result we speculated that the handling manipulation con­stitutes, for a naive animal, a stressful stimulus sufficient to induce a decrease in the density of GABA receptors. To confirm this hypothesis we studied the effect of electrical foot-shock on the binding of 3 H-GABA in the cerebral cortex of naive and handling-habituated rats. Foot-shock, delivered just before sacrifice to these two groups of rats, decreased the density of 3 H-GABA binding sites in cortical membrane preparations from handling-habituated rats, but failed to further decrease 3 H-GABA binding in those of naive ones (Table 1). From these results we concluded that handling-habituated rats represent a relatively nonstressed condition, whereas the handling of naive animals just before sacrifice or the electrical foot-shock are stressful stimuli able to cause a decrease in GABA receptors. To further clarify the molecular mechanism that mediates the decrease of GABA receptors elicited by stress we studied whether the effect of stress was mimicked by anxiogenic /J-carboline derivatives, benzodiazepine receptor ligands that down-regulate the GABAergic function (2,6,8,11,21,26,29). As shown in Table 2, the in vitro addition of different /3-carboline derivatives to cortical membrane preparations from unstressed (handling-habituated) rats decreased the number of low affinity GABA receptors to approximately the same




level found in membranes from stressed (naive) rats. This effect was reversed by the addition of either diazepam (1,2) or the benzodiazepine receptor antagonist (19) Ro 15-1788 to membranes previously incubated with anxiogenic /?-car-bolines. Thus, anxiogenic b-carbolines produce in vitro the same modification in 3 H-GABA binding as the stressful stimulus in vivo. This finding suggests that ben­zodiazepine receptors in the cerebral cortex are involved in the decrease of low affinity GABA receptors elicited by stress.

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