CONCLUSION
The results presented here show that a mild stress such as the handling manipulation during the experimental procedure decreases the density of low affinity GABA receptors in the rat cerebral cortex. These data indicate that, in order to study the involvement of the GABAergic system in the physiological response to stress, we have to take into account the emotional state of the animals during the experiment. Accordingly, electrical foot-shock decreases the total number of low affinity GABA receptors in the cerebral cortex of handling-habituated rats, but is ineffective in the cerebral cortex of naive animals. Most likely, the reason that explains the failure of foot-shock to affect GABA receptors in naive rats is that, for rats not habituated to handling, the manipulation before sacrifice constitutes a stressful stimulus responsible for the supramaximal decrease in low affinity GABA receptors. It has been proposed that benzodiazepines exert their antianxiety effect by enhancing the GABAergic transmission in the brain (4,7,35). The finding that the in vitro addition of diazepam, ZK 93423, and ZK 91296 reverses the changes produced by foot-shock on GABA receptors inc’icates that benzodiazepine receptors are involved in the action of stress on GABA receptors. This conclusion is also supported by the finding that those /3-carboline esters that bind with high affinity to the benzodiazepine receptors (5,6) and produce experimental anxiety in animals (14,15,23,25,27,30) and panic attacks in humans (16), share with stress (handling or foot-shock) the capability to down-regulate GABA receptors. Altogether these results indicate that cortical low affinity GABA receptors, coupled to benzodiazepine receptors, play a critical role in the regulation of emotional states. Compelling evidence indicates that in neuronal membranes the GABA receptor is part of a supramolecular complex that includes a chloride ionophore (24). Our experiments have shown that the function of the GABA receptor-coupled chloride channel is also modified by stress. Thus foot-shock reduces СГ efflux from cortical synaptoneurosome preparations of handling-habituated rats, but is ineffective in the same preparation from naive rats. These results, taken together with our previous findings, indicate that the GABAergic system plays a major role in anxiety and suggest that some emotional states related to stress and anxiety may result from a diminished GABAergic transmission at the level of the GABA/ benzodiazepine receptor/chloride ionophore complex.
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