CLOZAPINE AND SOME OTHER ANTIPSYCHOTIC-DRUGS MAY PREFERENTIALLY BLOCKTHE SAME SUBSET OF GABA(A) RECEPTORS

Selective blockade of a subset of GABA(A) receptors may be involved in the antipsychotic effects of Clozapine and several other antipsychoti c drugs. Seven antipsychotic drugs, and 11 drugs classified as antidep ressants that only partially reverse the inhibitory effect of 1 mu M G ABA on [S-35]TBPS binding, do not yield additive reversal when tested painwise with Clozapine, which also only partially reverses the inhibi tory effect of GABA. This suggests that all of these antipsychotic/ant idepressant drugs may block a common subset of GABA(A) receptors. DMCM and Ro 5-4864 are also partial reversers of GABA's inhibitory effect, but they yield additive reversals when tested pairwise with the antip sychotic/antidepressant drugs, and also with each other, suggesting th at DMCM, Ro 5-4864, and the antipsychotic drugs define three heterogen eous subsets of GABA(A) receptors, with variable overlap, depending on the drug. Several potent ligands for benzodiazepine binding sites can block the GABA inhibitory effects of DMCM and Ro 5-4864, but with dif ferent patterns: the ligands generally blocked DMCM less potently, but more completely than Ro 5-4864. Ro 5-4864 was not blocked by Flumazen il or CGS-8216, ligands that potently blocked DMCM. Nine additional an tipsychotic/antidepressant drugs, as well as Clozapine, and 7 ''classi cal'' GABA(A) receptor blockers, all of which reversed GABA nearly com pletely, when tested at lower concentrations that only reverse similar to 20-35%, yielded almost complete additivity when tested painwise wi th DMCM or Ro 5-4864. Another convulsant benzodiazepine, KW-1937, a po sitional isomer of Brotizolam, fully reverses the inhibitory effect of 1 mu M GABA. At a lower concentration yielding about 50% reversal, KW -1937 is completely additive with DMCM, but entirely nonadditive with Ro 5-4864. The 50% reversal obtained with KW-1937 was potently blocked by Triazolam, but with a plateau similar to that obtained with Ro 5-4 864. The results with KW-1937 suggest that its 50% reversal largely co rresponds to the reversal obtained with Ro 5-4864, and that virtually all of the [S-35]TBPS binding sites inhibited by 1 mu M GABA are coupl ed to benzodiazepine binding sites. The fraction of GABA(A) receptors preferentially blocked by all the antipsychotic/antidepressant drugs, roughly 25% of the [S-35]TBPS binding sites inhibited with 1 mu M GABA , are sensitive to KW 1937, but not to DMCM or to Ro 5-4864.