Hypoglycemia enhances ionotropic but reduces metabotropic glutamate responses in substantia nigra dopaminergic neurons

It is widely accepted that energy deprivation causes a neuronal death that is mainly determined by an increase in the extracellular level of glutamate . Consequently an excessive membrane depolarization and a rise in the intra cellular concentration of sodium and calcium are produced. In spite of this scenario, the function of excitatory and inhibitory amino acids during an episode of energy failure has not been studied yet at a cellular level. In a model of cerebral hypoglycemia in the rat substantia nigra pars compacta, we measured neuronal responses to excitatory amino acid agonists. Under si ngle-electrode voltage-clamp mode at -60 mV, the application of the ionotro pic glutamate receptor agonists N-methyl-D-aspartate, alpha -amino-3-hydrox y-5-methyl-4-isoxazole propionic acid, kainate, and the metabotropic group I agonist (S)- 3,5-dihydroxyphenilglycine (DHPG) produced reversible inward currents in the dopaminergic cells. In addition, an outward current was ca used by the superfusion of the metabotropic GABAB agonist baclofen. Glucose deprivation enhanced the inward responses caused by each ionotropic glutam ate agonist. In contrast, hypoglycemia depressed the DHPG-induced inward cu rrent and the baclofen-induced outward current. These effects of hypoglycem ia were reversible. To test whether a failure of the Na+/K+ ATPase pump cou ld account for the modification of the agonist-induced currents during hypo glycemia, we treated the midbrain slices with strophanthidin (1-3 muM). Str ophanthidin enhanced the inward currents caused by glutamate agonists. Howe ver, it did not modify the GABA(B)-induced outward current. Our data sugges t that glucose deprivation enhances the inward current caused by the stimul ation of ionotropic glutamate receptors while it dampens the responses caus ed by the activation of metabotropic receptors. Thus a substantial componen t of the augmented neuronal response to glutamate, during energy deprivatio n, is very likely due to the failure of Na+ and Ca2+ extrusion and might ul timately favor excitotoxic processes in the dopaminergic cells.