ALLOSTERIC INTERACTIONS BETWEEN GAMMA-AMINOBUTYRIC-ACID, BENZODIAZEPINE AND PICROTOXININ BINDING-SITES IN PRIMARY CULTURES OF CEREBELLAR GRANULE CELLS - DIFFERENTIAL-EFFECTS INDUCED BY GAMMA-HEXACHLOROCYCLOHEXANE AND DELTA-HEXACHLOROCYCLOHEXANE

Allosterism between gamma-aminobutyric acid (GABA), benzodiazepine and picrotoxinin recognition sites on the GABA(A) receptor was studied in primary cultures of cerebellar granule cells. The increase in [H-3]fl unitrazepam binding induced by GABA was inhibited by bicuculline and p icrotoxinin and the decrease in [S-35]t-butylbicyclophosphorothionate ([S-35]TBPS) binding mediated by GABA was reverted by bicuculline. The effects of hexachlorocyclohexanes (the convulsant gamma- and the depr essant delta-isomers, both acting at the picrotoxinin recognition site ) on GABA and benzodiazepine sites were studied. delta-Hexachlorocyclo hexane, but not the gamma-isomer (lindane), increased [H-3]flunitrazep am binding in a concentration-dependent manner (EC(50): 8.3 mu M). Thi s increase in [H-3]flunitrazepam binding was reduced by bicuculline an d picrotoxinin. The gamma-isomer reduced the increase in [H-3]flunitra zepam binding induced by GABA or delta-hexachlorocyclohexane. Neither delta- nor gamma-hexachlorocyclohexane inhibited [H-3]GABA binding. Mo reover, the inhibition of [S-35]TBPS binding induced by delta-hexachlo rocyclohexane was not reverted by bicuculline. The results obtained in this study in vitro agree with the pharmacological properties and the effects of gamma- and delta-hexachlorocyclohexane in vivo. It is conc luded that delta-hexachlorocyclohexane acts as a positive allosteric m odulator and gamma-hexachlorocyclohexane acts as a non-competitive ant agonist of the GABA(A) receptor.