ascorbic-acid and vanoxerine

The present study examined the mechanisms by which 3,4-methylenedioxymethamphetamine (MDMA) produces long-term neurotoxicity of striatal dopamine neurones in mice and the protective action of the dopamine uptake inhibitor GBR 12909. MDMA (30 mg/kg, i.p.), given three times at 3-h intervals, produced a rapid increase in striatal dopamine release measured by in vivo microdialysis (maximum increase to 380 +/- 64% of baseline). This increase was enhanced to 576 +/- 109% of baseline by GBR 12909 (10 mg/kg, i.p.) administered 30 min before each dose of MDMA, supporting the contention that MDMA enters the terminal by diffusion and not via the dopamine uptake site. This, in addition to the fact that perfusion of the probe with a low Ca(2+) medium inhibited the MDMA-induced increase in extracellular dopamine, indicates that the neurotransmitter may be released by a Ca(2+) -dependent mechanism not related to the dopamine transporter. MDMA (30 mg/kg x 3) increased the formation of 2,3-dihydroxybenzoic acid (2,3-DHBA) from salicylic acid perfused through a probe implanted in the striatum, indicating that MDMA increased free radical formation. GBR 12909 pre-treatment attenuated the MDMA-induced increase in 2,3-DHBA formation by approximately 50%, but had no significant intrinsic radical trapping activity. MDMA administration increased lipid peroxidation in striatal synaptosomes, an effect reduced by approximately 60% by GBR 12909 pre-treatment. GBR 12909 did not modify the MDMA-induced changes in body temperature. These data suggest that MDMA-induced toxicity of dopamine neurones in mice results from free radical formation which in turn induces an oxidative stress process. The data also indicate that the free radical formation is probably not associated with the MDMA-induced dopamine release and that MDMA does not induce dopamine release via an action at the dopamine transporter.

Topics: Animals; Ascorbic Acid; Body Temperature; Calcium; Corpus Striatum; Dopamine; Dopamine Uptake Inhibitors; Ferrous Compounds; Free Radicals; Hydroxybenzoates; Lipid Peroxidation; Male; Mice; Microdialysis; N-Methyl-3,4-methylenedioxyamphetamine; Piperazines; Rats; Salicylic Acid; Synaptosomes; Time Factors

Electrochemically modified carbon-fiber electrodes were used to assess the effects of indirect (amphetamine and GBR-12909) as well as direct D1 (SKF-38393) and D2 (quinpirole) dopamine agonists on extracellular ascorbate in the neostriatum of awake, behaving rats. Relative to controls, 2.5 mg/kg d-amphetamine and 20.0 mg/kg GBR-12909 produced marked behavioral activation concomitant with a significant increase in ascorbate. Comparable effects were observed following the combined administration of 10.0 mg/kg SKF-38393 and 1.0 mg/kg quinpirole, but not after either of these drugs alone. Thus, behavioral activation and release of neostriatal ascorbate were closely related to the concurrent stimulation of both D1 and D2 dopamine receptors.

Topics: 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; Amphetamine; Animals; Ascorbic Acid; Behavior, Animal; Corpus Striatum; Dopamine Agents; Electrochemistry; Electrodes; Ergolines; Male; Neurotransmitter Uptake Inhibitors; Piperazines; Quinpirole; Rats; Rats, Inbred Strains; Receptors, Dopamine; Stereotaxic Techniques; Stimulation, Chemical

The selectivity of Nafion-coated, carbon-fiber electrodes was evaluated for the voltammetric detection of dopamine in the presence of 3,4-dihydroxyphenylacetic acid (DOPAC) and ascorbate, which are interferant anions in the brain. Nafion coating was applied to both polished carbon-disk electrodes and electrochemically modified electrodes. During in vitro testing, polished disk electrodes showed the greatest selectivity for dopamine at the fastest scan rate tested (300 V s-1), but the drift in signal made slow changes in dopamine difficult to determine. Electrochemically modified electrodes already provide an ascorbate wave distinct from that for dopamine, but Nafion coating actually decreased dopamine selectivity with respect to DOPAC. In vivo testing was carried out in the neostriatum of urethane-anesthetized rats in response to drug- or stimulation-induced increases in dopamine transmission. Administration of haloperidol (0.5 mg kg-1) followed by GBR 12909 (20 mg kg-1), which is known to cause a 10-fold increase in extracellular dopamine, failed to produce a selective signal for dopamine when measured voltammetrically. Comparable results were obtained following administration of amphetamine (2.5 mg kg-1), which also increases dopamine overflow. Voltammetric detection of dopamine was possible, however, during electrical stimulation of dopaminergic afferents in the medial forebrain bundle. Thus, voltammetry with Nafion-coated electrodes is best suited to the measurement of transient changes in extracellular dopamine rather than the relatively prolonged changes in dopamine overflow produced by various drugs.

Topics: 3,4-Dihydroxyphenylacetic Acid; Amphetamine; Animals; Ascorbic Acid; Brain; Carbon; Corpus Striatum; Dopamine; Electric Stimulation; Electrochemistry; Electrodes; Fluorocarbon Polymers; Haloperidol; Kinetics; Male; Neurotransmitter Uptake Inhibitors; Piperazines; Rats; Rats, Inbred Strains

The inhibition of uptake of [3H] dopamine and [3H] 1-methyl-4-phenylpyridine (MPP+) was examined in mouse striatal synaptosomal preparations. Kinetic analysis indicated that ascorbic acid is a noncompetitive inhibitor of [3H] MPP+ uptake. No inhibition of [3H] dopamine uptake is observed. The dopamine uptake blockers, GBR-12909, cocaine, and mazindol strongly inhibit (IC50 less than 1 uM) both [3H] dopamine and [3H] MPP+ transport. Nicotine, its metabolites, and other tobacco alkaloids are weak inhibitors (IC50 greater than 1 mM) except 4-phenylpyridine and lobeline, which are moderate inhibitors (IC50 = 3 to 40 uM) of both [3H] dopamine and [3H] MPP+ uptake. These similarities in potencies are in agreement with the suggestion that [3H] MPP+ and [3H] dopamine are transported by the same carrier. The differences observed in the alteration of dopaminergic transport and mazindol binding by ascorbic acid suggest that ascorbic acid's effects on [3H] MPP+ transport are related to translocation and/or dissociation processes occurring subsequent to the initial binding event.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Ascorbic Acid; Biological Transport; Cocaine; Corpus Striatum; Dopamine; Kinetics; Mazindol; Mice; Nicotine; Piperazines; Pyridines; Synaptosomes