Dopamine-induced protection of striatal neurons against kainate receptor-mediated glutamate cytotoxicity in vitro.
The effects of dopamine on glutamate-induced cytotoxicity were examined using the primary cultures of rat striatal neurons. Cell viability was significantly reduced by exposure of cultures to glutamate or kainate for 24 h. In contrast, similar application of N-methyl-D-aspartate (NMDA) or alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionate (AMPA) did not induce cytotoxicity. Kainate-induced cytotoxicity was significantly inhibited by kynurenate but not by MK-801. Dopamine at concentrations of 1-100 microM dose-dependently reduced kainate-induced cytotoxicity. Forskolin also significantly reduced kainate cytotoxicity. The neuroprotective effect of dopamine was antagonized by SCH 23390, a D1 receptor antagonist, but not by domperidone, a D2 receptor antagonist. Moreover, kainate-induced cytotoxicity was prevented by SKF 38393, a D1 receptor agonist, or forskolin but not by quinpirole, a D2 receptor agonist. The patch clamp study revealed that the same striatal neurons responded to both kainate and NMDA. During voltage clamp recording, neither kainate-induced currents nor NMDA-induced currents were affected by dopamine. Moreover, dopamine did not affect glutamate- or kainate-induced Ca2+ influx measured with fura-2. These findings indicate that dopamine prevents kainate receptor-mediated cytotoxicity without affecting the kainate receptor activities and intracellular Ca2+ movement. Dopamine-induced neuroprotection may be mediated by an increased intracellular cAMP formed following activation of D1 receptors.
Amano
T
T
Department of Pharmacology, Hiroshima University School of Medicine, Japan.
Ujihara
H
H
Matsubayashi
H
H
Sasa
M
M
Yokota
T
T
Tamura
Y
Y
Akaike
A
A
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000494:pharmacology*; D018491:Dopamine Agonists / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology; D005071:Evoked Potentials / Q000187:drug effects; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D018698:Glutamic Acid / Q000633:toxicity*; D016202:N-Methylaspartate / Q000633:toxicity; D017072:Neostriatum / Q000166:cytology* / Q000187:drug effects; D009474:Neurons / Q000187:drug effects*; D018408:Patch-Clamp Techniques; D051381:Rats; D018092:Kainic Acid Receptors / Q000037:antagonists & inhibitors* / Q000187:drug effects
D002118:Calcium; D004298:Dopamine; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D018691:Excitatory Amino Acid Antagonists; D018698:Glutamic Acid; D016202:N-Methylaspartate; D018092:Kainic Acid Receptors