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 r ecently 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 releas e of DA in the striatum, the authors hypothesized that riluzole could antagonize DA release in this structure. Methods: Assay for DA release Consisted of superfusing H-3-DA preloaded synaptosomes with artificia l cerebrospinal fluid (1 ml/min 37 degrees C) and measuring the radioa ctivity obtained from 1-min fractions over 22 min, first in the absenc e of any treatment (spontaneous release, 8 min), then in the presence of depolarizing agents combined with riluzole (0.1-100 mu M, 5 min), a nd finally with no pharmacologic stimulation (9 min), The following de polarizing agents were tested: KCl(9, 15 mM), veratridine (0.01-1 mu M ), N-methyl-D-aspartate (NMDA, 0.1-1 mM), kainate (0.1-1 mM), and nico tine (0.01-0.5 mM). Assay for DA uptake was performed by measuring the radioactivity incorporated in synaptosomes incubated with H-3-DA (44 nM; 5 min; 37 degrees C). Results: All depolarizing agents produced a significant, concentration-related increase from basal H-3-DA release, Riluzole was found to decrease the release induced by veratridine (1 mu M), NMDA(1 mM), and kainate (1 mM) in a significant, concentration- related manner (IC50 = 9.5 mu M, 1.6 mu M, and 5.8 mu M for veratridin e, NMDA, and kainate, respectively). In contrast, it did not affect th e release elicited by either KCI or nicotine, Riluzole had no signific ant effect on the specific H-3-DA uptake. Conclusions: Riluzole produc ed a potent blockade of the release of DA mediated by activation of pr esynaptic sodium channels, NMDA, and kainate receptors, Depression of glutamate transmission together with blockade of DA release may contri bute to the actions of this agent in vitro.