Specific antagonism of behavioral action of “uncommon” amino acids linked to motor‐system diseases

Beta‐N‐methylamino‐L‐alanine (BMAA) and beta‐N‐oxalylamino‐L‐alanine (BOAA) are chemically related amino acids present in the seeds of Cycas circinalis and Lathyrus sativus, respectively. Consumption of these seeds has been linked to Guam amyotrophic lateral sclerosis (BMAA) and lathyrism (BOAA; a form of primary lateral sclerosis). A single large dose of BOAA or BMAA causes seizures in newborn mice and postsynaptic neuronal edema and degeneration in CNS explants. We report that the acute neurotoxic actions of these amino acids are blocked selectively by specific glutamate‐receptor antagonists (administered intracerebroventricularly) (i.c.v.) prior to the amino acid. Administration of BOAA i.c.v. to neonatal mice (ED₁₀₀ = 50 μg) elicits a spectrum of time‐dependent behavioral states including arm and leg rigidity, convulsions, and resting tremor. These are blocked in a dose‐dependent manner by cis‐2,3‐piperidine dicarboxylic acid (PDA), an antagonist of quisqualate (QA)‐preferring (A₂) and kainate (KA)‐preferring (A₃) glutamate receptors (ED₅₀s; 2.8 μg, rigidity; 1.4 μg, convulsions; 2.4 μg, resting tremor). BMAA induces a transitory hyperexcitable state followed by a long‐lasting whole‐body shake/wobble (ED₁₀₀ = 1,000 μg, i.c.v.). These responses are antagonized selectively and dose‐dependently by 2‐amino‐7‐phosphonoheptanoic acid (AP7), an N‐methyl‐D‐aspartate (NMDA) or A₁ glutamate‐receptor antagonist (ED₅₀ = 0.45 μg). Taken collectively, our data indicate that the acute neuronotoxic actions of BOAA and BMAA (or a metabolite) operate through different glutamate‐receptor species. BMAA likely exerts most of its action indirectly via the A₁ glutamate receptor, while BOAA acts principally at the A₂ and/or A₃ receptor.