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The effect of vinpocetine, a nootropic drug with anti-ischemic potential, on the release of DA and its main metabolite, DOPAC, was investigated in striatum isolated nerve endings under resting and depolarized conditions. Vinpocetine does not modify the baseline release of DA or the exocytotic release of DA evoked by high K(+), but inhibits the release of DA evoked by veratridine reversal of the DA transporter. In addition to these results, which confirm the vinpocetine selective blockade of voltage-sensitive presynaptic Na(+) channels (VSSC) previously reported [Neurochem. Res. 24 (1999) 1585], vinpocetine increases DOPAC release either under resting, veratridine or high K(+) depolarized conditions. This latter effect, which does not involve VSSC, was characterized. The parallel determination of the released and retained catecholamine concentrations revealed that vinpocetine increases DOPAC release at the expense of internal DA in a dose-dependent manner (low microM range). In contrast to vinpocetine, the selective MAO-A inhibitor, clorgyline, increases DA and decreases DOPAC formation. The combined action of vinpocetine and clorgyline does not indicate, however, that the activation of MAO is the mechanism responsible for the increase in DOPAC caused by vinpocetine. Reserpine, although more potent and efficient than vinpocetine, qualitatively exerts the same pattern of changes on DA and DOPAC concentrations. It is concluded that, in addition to the inhibition of presynaptic VSSC permeability, which selectively inhibits the transporter-mediated release of all neurotransmitters, vinpocetine increases DOPAC by impairing the vesicular storage of DA. Our results indicate that the cytoplasm extravesicular DA is metabolized by MAO to DOPAC. Most of the DOPAC formed is exported to the extracellular medium.

The principal objective of this study is to explore the hypothesis that a blockade of Na(+) channels can prevent some of the mechanisms involved in ototoxicity. For this purpose, the potential action of the voltage sensitive Na(+) channel antagonist, vinpocetine, on the ototoxicity induced by the representative aminoglycoside antibiotic, amikacin, in guinea pigs was tested for almost half a year. Amikacin (450 mg/kg) administered daily (i.m.) for 5 days increases the thresholds of the auditory brainstem response (ABR) to the two frequencies tested (4 and 8 kHz). These threshold increases are permanent or at least long-lived, as after 40 days they are already established and are maintained until the end of the experiment (160 days after the antibiotic administration). Amikacin decreases the amplitude of ABR waves, particularly P1, and after 160 days increases the latency of ABR waves, particularly at the higher frequency tested (8 kHz). When the above amikacin regimen is followed by a daily (i.p.) vinpocetine (2 mg/kg) administration for 13 days the increase in ABR threshold and latency caused by amikacin alone is prevented. Moreover, the animals treated with amikacin alone show a decreased weight gain and a remarkable increased mortality in comparison with the group of animals post-treated with vinpocetine. We hope that the multiple beneficial effects exerted by the Na(+) channel blocker, vinpocetine, against aminoglycoside antibiotics-induced side effects could help to solve the serious limitations of the use of this type of antibiotic.

The simultaneous effect of MK-801 on the baseline- and depolarization (20 microM veratridine or 30 mM high K+)-evoked release of endogenous dopamine, glutamate (Glu), aspartate (Asp), and GABA is investigated in the same preparation of rat striatum isolated nerve endings. MK-801, in the microM range, selectively increases the baseline and high K+ depolarization-evoked release of dopamine, without causing any effect on the baseline or on the high K+-evoked release of Glu, Asp and GABA. In addition to this selective action on dopamine release, MK-801 inhibits the veratridine depolarization-evoked release of all the neurotransmitters tested, including dopamine. In SBFI and fura-2 preloaded striatal synaptosomes, MK-801 inhibits the elevation of internal Na+ (Na(i)) and the elevation of internal Ca2+ (Ca(i)) induced by veratridine depolarization. The elevation of Ca(i) induced by high K+ depolarization is unchanged by MK-801. This study reveals two separate MK-801 actions. (1) The voltage-independent action, which increases dopamine release selectively, and might contribute to the effects of MK-801 on motor coordination. (2) The voltage-dependent action, which inhibits all the veratridine-evoked responses including the evoked release of the excitatory amino acids (which are particularly concentrated in striatum nerve endings), and might contribute to the anticonvulsant and neuroprotective effects of MK-801.