The interaction of 5-aminolevulinic acid (ALA) with GABA(A) receptors has been proposed to underlie the neurological dysfunctions of ALA-accumulating disorders, such as acute intermittent porphyria. The effects of ALA on [3H]muscimol binding to human and rat cerebral cortical membranes were compared. ALA (0.1-10 mM) significantly inhibited the binding of [3H]muscimol (12 nM), with a similar potency in rat and human membranes (IC50 = 199 vs. 228 microM, respectively). Kinetical analysis revealed that ALA (1 mM) significantly increased the Kd and decreased the Bmax of [3H]muscimol to both rat (100 and 50%, respectively) and human (200 and 40%, respectively) membranes, indicating a mixed-type inhibition. The similarity in the potency and mechanism of the ALA-induced inhibition of muscimol binding in rat and human membranes indicate that rat studies are useful to evaluate the neurotoxic properties of ALA towards the human GABAergic system, and may help to understand the pathophysiology of porphyria.