A 24-h pretreatment with BNDF enhanced excitotoxic neuronal death in cultured mouse cortical cells challenged with NMDA in the presence of extracellular Mg(2+). The GABA(A) receptor antagonist, bicuculline, enhanced NMDA toxicity in control cultures but, unexpectedly, became neuroprotective in cultures pretreated with BDNF. In contrast, drugs that activate GABA(A) receptors (e.g. muscimol, benzodiazepines, or phenobarbital) or drugs that indirectly enhance GABAergic transmission were protective in control cultures but amplified NMDA toxicity after pretreatment with BDNF. The atypical behaviour of GABAergic drugs in cultures pretreated with BDNF depended on changes in the anion reversal potential because (i) increases in extracellular Cl(-) concentrations abolished the neurotoxic action of muscimol; (ii) muscimol stimulated (36)Cl(-) efflux after pretreatment with BDNF; and (iii) exposure to BDNF reduced the expression of the neuronal K(+)/Cl(-) co-transporter, KCC2. Our data raise the concern that GABAergic drugs may become neurotoxic under conditions associated with increases in brain BDNF levels.