SCHILD REGRESSION-ANALYSIS OF ANTIDEPRESSANT AND BICUCULLINE ANTAGONIST EFFECTS AT THE GABA(A) RECEPTOR

We showed previously that antidepressants inhibit GABA-stimulated Cl-3 6(-) uptake in rat cerebral cortex. In this study Schild analysis was used to determine if antidepressants are competitive antagonists or al losteric modulators at GABA(A) receptors, GABA concentration-response curves for Cl-36(-) uptake take in rat cerebral cortex were generated in the absence or presence of different concentrations of the followin g antidepressants: amitriptyline, amoxapine, mianserin, and also the G ABA(A) receptor antagonist, bicuculline. The pA(2) values for amitript yline, 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 max imum effect produced by GABA to stimulate chloride influx was decrease d by both antidepressants and bicuculline. It is concluded that neithe r the antidepressants studied nor bicuculline are pure competitive GAB A antagonists at the GABA(A) receptor-chloride-ionophore complex in th e rat cerebral cortex.