Kainic acid stimulates excitatory amino acid neurotransmitter release at presynaptic receptors

Abstract

Kainic acid (KA), a conformationally restricted analogue of glutamic acid, exhibits potent neuroexcitatory¹ and neurotoxic properties². The mechanism of the neurotoxicity of KA, however, seems to be complex and indirect because in many brain areas neuronal vulnerability requires the integrity of excitatory afferents^3–6. Nevertheless, neurophysiological studies indicate that the neuroexcitatory effects of KA in the mammalian brain are direct⁷. We have now examined the effects of KA and other excitatory amino acids on the stimulation of cyclic GMP formation in brain slices incubated in vitro as a method for monitoring their depolarizing effects⁸. We show in the adult mouse cerebellum that the excitatory amino acid antagonist, D-α-aminoadipate (DAA)⁹, blocks the stimulation of cyclic GMP produced by N-methyl-D,L-aspartate (NMDLA) but potentiates the effects of KA. Whereas KA causes a significant release of both aspartic (Asp) and glutamic (Glu) acids by a calcium-dependent process, NMDLA is without effect; furthermore, the effects of KA on Glu release are markedly reduced in cerebellum deficient in granule cells. KA also releases Glu and Asp from hippocampal and striatal slices, indicating that this response is not unique to the cerebellum. The results are consistent with evidence that KA has direct excitatory effects on neurones⁷ but suggest that its potent neurotoxic action involves the activation of presynaptic receptors on glutamatergic and aspartergic terminals, thereby releasing Asp and Glu.