Opposite modulation of cortical N-methyl- d-aspartate receptor-mediated responses by low and high concentrations of dopamine

Abstract

To examine whether dopamine modulates cortical N-methyl- d-aspartate receptor-mediated glutamate transmission, whole-cell recordings were made from identified pyramidal cells located in layers V and VI of the medial prefrontal cortex of the rat using a slice preparation. In the presence of tetrodotoxin and the absence of Mg 2+, a brief local application of N-methyl- d-aspartate evoked an inward current which was blocked by the N-methyl- d-aspartate antagonist dizocilpine maleate but not affected by the non- N-methyl- d-aspartate antagonist 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(f)quinoxaline, suggesting that the observed current is mediated by N-methyl- d-aspartate receptors located on recorded cells. Bath application of dopamine produced opposite effects on the N-methyl- d-aspartate current depending on the concentrations of dopamine applied. At low concentrations (<50 μM), dopamine enhanced the N-methyl- d-aspartate current, whereas at higher concentrations, dopamine suppressed the current. The same concentrations of dopamine did not significantly affect the inward current induced by the non- N-methyl- d-aspartate agonist α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid. The enhancing effect of dopamine on the N-methyl- d-aspartate response was mimicked by the D 1 agonist SKF38393 and blocked by the D 1 antagonist SCH31966, whereas the suppressing effect was mimicked by the D 2 agonist quinpirole and blocked by the D 2 antagonist eticlopride. The above results suggest that dopamine at low concentrations acts preferentially on D 1-like receptors to promote N-methyl- d-aspartate receptor-mediated transmission, while at high concentrations dopamine also activates D 2-like receptors, leading to a suppression of the N-methyl- d-aspartate function. This differential modulation of N-methyl- d-aspartate function may have significant implications for understanding behaviors and disorders involving both cortical dopamine- and glutamate-mediated neurotransmission.