A vitamin as neuromodulator: ascorbate release into the extracellular fluid of the brain regulates dopaminergic and glutamatergic transmission.

Ascorbate is an antioxidant vitamin that the brain accumulates from the blood supply and maintains at a relatively high concentration under widely varying conditions. Although neurons are known to use this vitamin in many different chemical and enzymatic reactions, only recently has sufficient evidence emerged to suggest a role for ascorbate in interneuronal communication. Ascorbate is released from glutamatergic neurons as part of the glutamate reuptake process, in which the high-affinity glutamate transporter exchanges ascorbate for glutamate. This heteroexchange process, which also may occur in glial cells, ensures a relatively high level of extracellular ascorbate in many forebrain regions. Ascorbate release is regulated, at least in part, by dopaminergic mechanisms, which appear to involve both the D1 and D2 family of dopamine receptors. Thus, amphetamine, GBR-12909, apomorphine, and the combined administration of D1 and D2 agonists all facilitate ascorbate release from glutamatergic terminals in the neostriatum, and this effect is blocked by dopamine receptor antagonists. Even though the neostriatum itself contains a high concentration of dopamine receptors, the critical site for dopamine-mediated ascorbate release in the neostriatum is the substantia nigra. Intranigral dopamine regulates the activity of nigrothalamic efferents, which in turn regulate thalamocortical fibers and eventually the glutamatergic corticoneostriatal pathway. In addition, neostriatonigral fibers project to nigrothalamic efferents, completing a complex multisynaptic loop that plays a major role in neostriatal ascorbate release. Although extracellular ascorbate appears to modulate the synaptic action of dopamine, the mechanisms underlying this effect are unclear. Evidence from receptor binding studies suggests that ascorbate alters dopamine receptors either as an allosteric inhibitor or as an inducer of iron-dependent lipid peroxidation. The applicability of these studies to dopamine receptor function, however, remains to be established in view of reports that ascorbate can protect against lipid peroxidation in vivo. Nevertheless, ample behavioral evidence supports an antidopaminergic action of ascorbate. Systemic, intraventricular, or intraneostriatal ascorbate administration, for example, attenuates the behavioral effects of amphetamine and potentiates the behavioral response to haloperidol. Some of these behavioral effects, however, may be dose-dependent in that treatment with relatively low doses of ascorbate has been reported to enhance dopamine-mediated behaviors. Ascorbate also appears to modulate glutamatergic transmission in the neostriatum. In fact, by facilitating glutamate release, ascorbate may indirectly oppose the action of dopamine, though the nature of the neostriatal dopaminergic-glutamatergic interaction is far from settled. Ascorbate also may alter the redox state of the NMDA glutamate receptor thus block NMDA-gated channel function.(ABSTRACT TRUNCATED AT 400 WORDS)