To investigate the electrophysiological effects of the stimulation of the metabotropic excitatory amino acid receptors, we applied trans-1-amino-cyclopentane-1,3-dicarboxylate, an agonist of this type of receptors, on presumed rat dopamine cells intracellularly recorded in vitro. Trans-1-amino-cyclopentane-1,3-dicarboxylate (3-30 μM, t-ACPD) caused a sustained increase of the spontaneous firing rate and a depolarization. When the membrane potential was held at about the resting level (-50, -60 mV), by the single-electrode voltage-clamp technique, t-ACPD induced an inward current. In 57% of the tested cells the inward current was associated with a decrease of the apparent input conductance. In the remaining cells no obvious changes in membrane conductance were observed. The active form of t-ACPD, (1S,3R)-1-amino-cyclopentane-1,3-dicarboxylate [3-50 μM, (1S,3R)-ACPD] also produced a reversible inward current on the dopaminergic cells and this was antagonized by (S)-4-carboxy-3-hydroxyphenylglycine (300 μM), a selective antagonist of the (1S,3R)-ACPD-induced depolarization on central neurons. The (1S,3R)-ACPD-induced inward current was not antagonized by l-2-amino-3-phos-phonopropionic acid (100 μM), an antagonist of the t-ACPD-induced activation of inositide synthesis. 6-cyano-7-nitroquinoxaline-2,3-dione (10 μM), an alfa-amino-3-hydroxy-5-methyl-isoxazole propionic acid/kainate antagonist, dl-amino-5-phosphonopentanoic acid (30 μM), an N-methyl-d-aspartate antagonist, and scopolamine (10 μM), a muscarinic antagonist, did not significantly affect the actions of t-ACPD. A block of synaptic transmission obtained by applying tetrodotoxin failed to prevent the action of t-ACPD. The t-ACPD-induced current was inward from ~ -40 to -115 mV and in ~ 70% of the tested cells decreased in amplitude during membrane hyperpolarization. In ~ 30% of dopamine neurons t-ACPD produced a parallel inward shift of the I-V relation. The cellular response to t-ACPD did not reverse at hyperpolarized potentials in 2.5 mM and 7.5 mM extracellular potassium. It was not modified by the potassium channel blockers tetraethylammonium chloride (10-20 mM), barium (1 mM) or cesium (1-2 mM). It was present in low calcium (0.5 mM) plus magnesium (10-20 mM) or cobalt (1-2 mM). Shifting the Cl- equilibrium potential did not affect the properties of the t-ACPD-induced responses. Perfusion with a low NaCl solution (choline chloride substitution) reversibly attenuated the t-ACPD-induced inward current. Our data are consistent with the hypothesis that t-ACPD, interacting with metabotropic glutamate receptor, increases the excitability of the rat mesencephalic dopamine neurons. The t-ACPD-induced excitation may be partly attributed to an inward current that is predominately dependent on external sodium ions.
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