fg-9041 and domoic-acid

Our objective was to characterize the mechanism of action of intrastriatal infusion of domoic acid on extracellular dopamine levels, using in vivo dialysis in conscious and freely moving rats. The local infusion of domoic acid (500 microM) caused an increase (567.9+/-142.5%, versus basal) in dopamine extracellular levels associated with a decrease in its metabolites: dihydroxyphenylacetate (DOPAC) and homovanillate (HVA) (47.3+/-4.4% and 33.8+/-4.2%, respectively, compared to basal). Infusion of the amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/kainate (AMPA/kainate) receptor antagonist, 6,7-dinitroquinoxaline-2,3-dione (DNQX; 200 microM) reversed the effect of domoic acid infusion on striatal dopamine levels. However, the infusion of the selective non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, dizocilpine (MK-801; 50 microM), did not change significantly the effect of domoic acid on dopamine extracellular levels. In conclusion, based on results with a microdialysis technique, we suggest that domoic acid may act through AMPA/kainate receptors in striatum.

Topics: 3,4-Dihydroxyphenylacetic Acid; Animals; Corpus Striatum; Dizocilpine Maleate; Dopamine; Excitatory Amino Acid Antagonists; Homovanillic Acid; Kainic Acid; Male; Microdialysis; Neuromuscular Depolarizing Agents; Quinoxalines; Rats; Rats, Sprague-Dawley; Receptors, Glutamate

This study aimed at testing if, and under which conditions, long-lasting cytosolic calcium responses can be induced in dissociated embryonic brain cells exposed to alpha-amino-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor agonists. Rat brainstem cells (gestation days 13-14; mean crown-rump lengths 8-11 mm) were mechanically dissociated and loaded with the fluorescent calcium marker Fluo-3 after in vitro delays ranging from 20 min to 6 days. The cells were exposed to various concentrations of AMPA, domoic acid or kainic acid. The evoked fluorescence changes, indicating variations of cytosolic calcium, were recorded and analysed either with a video-microscope or a laser cytometer. Even at the earliest stages, non-desensitizing (or partly desensitizing) calcium responses to AMPA were found. In addition, sequential exposure to AMPA followed either by domoic acid, or by AMPA in the presence of aniracetam, revealed the existence of cells bearing predominantly desensitizing receptors. The non-desensitizing as well as desensitizing response components were blocked by 6,7-dinitroquinoxaline-2,3-dione (DNQX). When the experiments were conducted at 24 degrees C, the cytosolic calcium levels generally returned close to pre-stimulus baseline levels after washout. In contrast, when the working temperature was slightly raised (to 27 degrees C), complex secondary calcium rises were observed not only during prolonged stimulation, but also after short agonist application. The calcium modulation might be correlated with some form of cellular "learning" in the embryonic brain. Under particular conditions, where the regulation processes are either switched off by cell programmes or simply overloaded, the cascade of events comprising secondary calcium rises may lead to cell death.

Topics: alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Animals; Biological Transport; Brain Stem; Calcium; Cells, Cultured; Cytosol; Hot Temperature; Kainic Acid; Neurons; Quinoxalines; Rats; Rats, Sprague-Dawley; Receptors, AMPA; Signal Transduction; Time Factors

Kainic acid caused a marked decrease of the electrically evoked release of [3H]dopamine from rat striatal slices 4 days after its injection (10 nmol/microliters) into the corpus striatum. This damage was prevented by the non-N-methyl-D-aspartate (non-NMDA) receptor antagonist 6,7-dinitroquinoxaline-2,3-dione (DNQX) when co-injected with kainic acid into the striatum. Prior systemic administration of the NMDA selective antagonists (cis-4-phosphonomethyl-2-piperidine carboxylic acid (CGS 19755), dizocilpine (MK-801) and ketamine did not alter the kainate effect. Previous destruction of the cortico-striatal pathway abolished the kainate-induced decrease of [3H]dopamine release. When injected into the striatum, domoic acid or alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) mimicked kainic acid and damaged the dopaminergic nigro-striatal afferents. The [3H]dopamine release evoked by electrical stimulation of slices of frontal cortex was unaffected following local injections of kainic acid. Taken together, the results indicate that AMPA/kainate receptors play a key role in the impairment of [3H]dopamine release caused by kainate in the striatum. However, the kainic acid effect is probably indirect since it appears to require the availability of endogenous glutamate originating from cortico-striatal afferents.

Topics: alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Animals; Corpus Striatum; Dizocilpine Maleate; Dopamine; Electric Stimulation; Kainic Acid; Ketamine; Male; N-Methylaspartate; Neuromuscular Depolarizing Agents; Neurons, Afferent; Pipecolic Acids; Quinoxalines; Rats; Rats, Sprague-Dawley