Bromocriptine, a
dopamine D(2) receptor agonist, has widely been used for patients with
Parkinson's disease. The aim of the present study was to investigate the effect of
bromocriptine on
glutamate transporter. Since the astroglial
glutamate transporter GLT-1 (EAAT2) is the predominant
isoform in the forebrain, we generated EAAT2-expressing human embryonic kidney cells and immortalized mouse astrocytes. In the present studies, we observed a GLT-1-immunoreactive band and significant Na(+)-dependent d-[(3)H]
aspartate uptake. Furthermore, the
glutamate transporter inhibitors, dl-threo-beta-benzyloxyaspartic
acid (
TBOA) and
dihydrokainate (DHK), displayed a dose-dependent reduction of d-[(3)H]
aspartate uptake in both types of cells. In contrast, cells exposed to either chemical
anoxia or high KCl elicited a marked release of d-[(3)H]
aspartate, and the release was inhibited by
TBOA and DHK, implying the contribution of
glutamate transporter reversal. Interestingly, we found that
bromocriptine dose-dependently inhibits d-[(3)H]
aspartate release elicited by chemical
anoxia or high KCl, while no changes occurred in the uptake. The inhibitory action of
bromocriptine was not affected by
sulpiride, a
dopamine D(2) receptor antagonist. On the other hand,
bromocriptine had no effect on swelling-induced d-[(3)H]
aspartate release, which is mediated by volume-regulated
anion channels. In vivo studies revealed that
bromocriptine suppresses the excessive elevation of
glutamate levels in gerbils subjected to transient forebrain
ischemia in a manner similar to DHK. Taken together, these results provide evidence that
bromocriptine inhibits
excitatory amino acid release via reversed operation of GLT-1 without altering forward transport.