GABA reduces binding of ³H-methyl β-carboline-3-carboxylate to brain benzodiazepine receptors

Abstract

Benzodiazepines are thought to exert their pharmacological and clinical effects by interacting with specific receptors on neurones in the central nervous system^1–3. Originally, only benzodiazepinoid compounds were known to interact with these receptors, but recently other classes of agents have been discovered which have high affinity for benzodiazepine receptors⁴. A representative from one of these classes, ethyl β-carboline-3-carboxylate (β-CCE), was obtained from human urine by virtue of its high affinity for benzodiazepine receptors. It was hypothesized that derivatives or congeners of this β-carboline could be related to presumed endogenous ligands, the exact nature of which are unknown^3,5. Another ester of β-carboline-3-carboxylic acid, the propyl ester, PrCC, has recently been used as a radioligand for labelling benzodiazepine receptors⁶: in particular, ³H-PrCC has been observed selectively to label a BZ₁ receptor subclass⁷. Binding of PrCC to benzodiazepine receptors, however, was less enhanced by γ-aminobutyric acid (GABA) than expected^6,8. The affinity of benzodiazepines for benzodiazepine receptors is enhanced two to threefold by GABA^9–11, probably reflecting the functional coupling of benzodiazepine receptors and GABA receptors at the molecular level. Here we have investigated binding of the methyl ester of β-carboline-3-carboxylic acid (β-CCM), which by itself is a convulsant, in contrast to β-CCE and PrCC. We report that ³H-β-CCM binds to brain benzodiazepine receptors and that, in contrast to binding of ³H-diazepam, ³H-β-CCM binding is reduced by GABA in a bicuculline-sensitive manner.