APART from its role in fast inhibitory transmission, only neurotrophic effects have been reported following activation of the GABAA receptor. Here, we show that n-butyl-β-carboline-3-carboxylate and n-methyl-β-carboline-3-carboxamide, which are negative allosteric modulators of the GABAA receptor acting at the benzo-diazepine site, are neurotoxic for cerebellar granule neurones in culture. The β-carboline-induced neuronal death is apoptotic since DNA internucleosomal fragmentation was induced and the neurotoxicity could be prevented by inhibitors of mRNA or protein synthesis. As GABA and benzodiazepine ligands (diazepam and Ro 15–1788) protect cerebellar granule cells against β-carboline-induced toxicity, these data raise the possibility that the interaction between the β-carbolines and the GABAA receptor is the triggering event leading to neuronal apoptosis.