Allosteric modulation of t-[ 35S]butylbicyclophosphorothionate binding in rat brain by melatonin

In order to clarify melatonin's pharmacological interaction with central γ-aminobutyric acid (GABA) receptors, its effects on the binding of t-[ 35S]butylbicyclophosphorothionate ([ 35S]TBPS), which specifically labels GABA-gated chloride channels, was examined in the rat brain. Saturation binding studies indicated that the effect of melatonin (500 μM) was due to a significant decrease in binding site density (B max) while the dissociation constant (K d) was unchanged. The central-type benzodiazepine (BZ) receptor site antagonist Ro15-1788 (flumazenil) did not reverse the effect of melatonin but blocked the effect of diazepam, indicating that central-type BZ sites do not mediate the effects of melatonin. Since the ability to allosterically inhibit TBPS binding is characteristic of GABA-positive ligands, these findings provide further evidence that the pharmacological effects of melatonin involve enhancement of central GABAergic activity.