Riluzole Blocks Dopamine Release Evoked by N-methyl-D-aspartate, Kainate, and Veratridine in the Rat Striatum

Background: Dopamine (DA) is released in large amounts during cerebral ischemia and may exacerbate tissue damage. Riluzole (54274 RP) is a recently developed agent that depresses glutamate neurotransmission in the central nervous system (CNS) and that may protect against ischemic injury in some animal models. Because glutamate stimulates the release of DA in the striatum, the authors hypothesized that riluzole could antagonize DA release in this structure.

Methods: Assay for DA release consisted of superfusing3 H-DA preloaded synaptosomes with artificial cerebrospinal fluid (1 ml/min, 37 degree sign] Celsius) and measuring the radioactivity obtained from 1-min fractions over 22 min, first in the absence of any treatment (spontaneous release, 8 min), then in the presence of depolarizing agents combined with riluzole (0.1-100 micro Meter, 5 min), and finally with no pharmacologic stimulation (9 min). The following depolarizing agents were tested: KCl (9, 15 mM), veratridine (0.01-1 micro Meter), N-methyl-D-aspartate (NMDA, 0.1-1 mM), kainate (0.1-1 mM), and nicotine (0.01-0.5 mM). Assay for DA uptake was performed by measuring the radioactivity incorporated in synaptosomes incubated with3 H-DA (44 nM; 5 min; 37 degree sign] Celsius).

Results: All depolarizing agents produced a significant, concentration-related increase from basal3 H-DA release. Riluzole was found to decrease the release induced by veratridine (1 micro Meter), NMDA (1 mM), and kainate (1 mM) in a significant, concentration-related manner (IC50 = 9.5 micro Meter, 1.6 micro Meter, and 5.8 micro Meter for veratridine, NMDA, and kainate, respectively). In contrast, it did not affect the release elicited by either KCl or nicotine. Riluzole had no significant effect on the specific3 H-DA uptake.