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The Journal of Neuroscience, August 15, 2001, 21(16):6069-6076

The Activation of Dopamine D4 Receptors Inhibits Oxidative Stress-Induced Nerve Cell Death

Kumiko Ishige, Qi Chen, Yutaka Sagara, and David Schubert

Cellular Neurobiology Laboratory, The Salk Institute for Biological Studies, La Jolla, California 92037

Oxidative stress is thought to be the cause of nerve cell death in many CNS pathologies, including ischemia, trauma, and neurodegenerative disease. Glutamate kills nerve cells that lack ionotropic glutamate receptors via the inhibition of the cystine-glutamate antiporter x, resulting in the inhibition of cystine uptake, the loss of glutathione, and the initiation of an oxidative stress cell death pathway. A number of catecholamines were found to block this pathway. Specifically, dopamine and related ligands inhibit glutamate-induced cell death in both clonal nerve cell lines and rat cortical neurons. The protective effects of dopamine, apomorphine, and apocodeine, but not epinephrine and norepinephrine, are antagonized by dopamine D4 antagonists. A dopamine D4 agonist also protects, and this protective effect is inhibited by U101958, a dopamine D4 antagonist. Although the protective effects of some of the catecholamines are correlated with their antioxidant activities, there is no correlation between the protective and antioxidant activities of several other ligands. Normally, glutamate causes an increase in reactive oxygen species (ROS) and intracellular Ca²⁺. Apomorphine partially inhibits glutamate-induced ROS production and blocks the opening of cGMP-operated Ca²⁺ channels that lead to Ca²⁺ elevation in the late part of the cell death pathway. These data suggest that the protective effects of apomorphine on oxidative stress-induced cell death are, at least in part, mediated by dopamine D4 receptors via the regulation of cGMP-operated Ca²⁺ channels.

Key words: HT22 cells; cell death; apomorphine; apocodeine; dopamine D4 receptors; glutamate; cGMP

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Copyright © 2001 Society for Neuroscience  0270-6474/01/21166069-08$05.00/0

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