Quinolinate is a weak excitant of cortical neurons in cell culture

Abstract

Defined concentrations of quinolinate (QUIN) were administered to murine cortical neurons in culture impaled for intracellular recording. In physiological recording medium containing 1 mM Mg, concentrations of QUIN up to 2 mM had minimal effect on membrane potential and input resistance; only at higher concentrations did QUIN produce consistent depolarizations, which were accompanied by apparent increases in membrane resistance. In the absence of Mg, responses to QUIN were larger and were accompanied by decreases in membrane resistance, but QUIN was still a weak neuroexcitant, exhibiting an ED 50 of greater than 1 mM. Phthalic, dipicolinic and nicotinic acids, structural analogues of QUIN, were even less potent neuroexcitants. The relationship between QUIN depolarization amplitude and membrane potential was linear in the absence of Mg, but in the presence of 1 mM Mg showed a non-linearity consistent with the voltage-dependent Mg block of N-methyl- d-aspartate (NMDA) receptor-mediated responses described by others. QUIN responses had a marked dependence on the presence of extracellular Na, and an extrapolated reversal potential of +12 mV, consistent with the large involvement of an Na influx. The responses were attenuated by the selective NMDA receptor antagonists, dl-2-amino-5-phosphonovalerate and ketamine, as well as by the broad spectrum antagonist kynurenate, but not by l-glutamate diethylester or γ- d-glutamylaminomethyl sulfonate, compounds reported to block quisqualate or kainate receptors. The present study is consistent with the suggestion of other workers that QUIN neuroexcitation is mediated in large part by an Na influx through cation permeable NMDA-activated channels, but provides new quantitative data suggesting that the potency of QUIN as a cortical neuroexcitant is low. This low potency may argue against a role for QUIN as a traditional fast excitatory neurotransmitter.