Abstract
We showed previously that antidepressants inhibit GABA-stimulated <sup>36</sup>Cl<sup>–</sup> uptake in rat cerebral cortex. In this study Schild analysis was used to determine if antidepressants are competitive antagonists or allosteric modulators at GABA<sub>A</sub> receptors. GABA concentration-response curves for <sup>36</sup>Cl<sup>–</sup> uptake in rat cerebral cortex were generated in the absence or presence of different concentrations of the following antidepressants: amitriptyline, amoxapine, mianserin, and also the GABA<sub>A</sub> receptor antagonist, bicuculline. The pA<sub>2</sub> values for amitriptyline, amoxapine, mianserin, and bicuculline were 4.2 ± 0.2, 5.5 ± 0.3, 4.4 ± 0.1 and 6.2 ± 0.6, respectively. The respective Schild slope values were 0.7 ± 0.1, 0.6 ± 0.03, 0.7 ± 0.2 and 1.0 ± 0.3. All slope values for antidepressants differed from unity. The maximum effect produced by GABA to stimulate chloride influx was decreased by both antidepressants and bicuculline. It is concluded that neither the antidepressants studied nor bicuculline are pure competitive GABA antagonists at the GABA<sub>A</sub> receptor-chloride-ionophore complex in the rat cerebral cortex.
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