title: Bromocriptine, an ergot alkaloid, inhibits excitatory amino acid release mediated by glutamate transporter reversal.
abstract: 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.
authors.affiliation: Biological Research Laboratories, Daiichi-Sankyo Co., Ltd., Tokyo, Japan. shirasaki.yasufumi.n7@daiichisankyo.co.jp
authors.forename: Yasufumi
authors.initials: Y
authors.lastname: Shirasaki
authors.forename: Masunobu
authors.initials: M
authors.lastname: Sugimura
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Sato
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism; D015153:Blotting, Western; D001971:Bromocriptine / Q000494:pharmacology*; D002460:Cell Line; D018491:Dopamine Agonists / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D027342:Excitatory Amino Acid Transporter 2 / Q000378:metabolism*; D018846:Excitatory Amino Acids / Q000037:antagonists & inhibitors*; D018698:Glutamic Acid / Q000378:metabolism; D006801:Humans; D051379:Mice; D014162:Transfection
chemical_list: D018491:Dopamine Agonists; D018691:Excitatory Amino Acid Antagonists; D027342:Excitatory Amino Acid Transporter 2; D018846:Excitatory Amino Acids; D001971:Bromocriptine; D018698:Glutamic Acid