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The Journal of Neuroscience, June 15, 2005, 25(24):5815-5823; doi:10.1523/JNEUROSCI.1120-05.2005

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Neurobiology of Disease
Dopamine Specifically Inhibits Forebrain Neural Stem Cell Proliferation, Suggesting a Novel Effect of Antipsychotic Drugs

Tod E. Kippin,¹ Shitij Kapur,² and Derek van der Kooy¹

Departments of ¹Medical Genetics and Microbiology and ²Psychiatry, University of Toronto, Toronto, Ontario, Canada M5S 1A8

Neurogenesis has been implicated in antidepressant drug action and animal models of depression, suggesting that proliferating cells play a role in psychiatric disorders. Similar studies using antipsychotic drugs have yielded conflicting results, perhaps because of the lack of focus on specific cell types. We examine the effect of haloperidol on neural stem cells (NSCs), the ultimate precursors for adult cell genesis. We show that haloperidol increases NSC numbers, resulting in more progenitors and more new neurons and glia in the adult rat brain. The increase in NSCs by haloperidol is dependent on central dopamine D₂ receptors, and these receptors are expressed by NSCs. D₂ receptor stimulation in vitro inhibits NSC proliferation, which is reversed by haloperidol. Thus, haloperidol increases adult mammalian brain proliferation by antagonizing dopamine at D₂ receptors on NSCs. These findings demonstrate a direct link between neural activity and NSC proliferation and implicate cell genesis in antipsychotic drug effects.

Key words: haloperidol; proliferation; dopamine receptor; dopamine; neuronal progenitor cell; neurogenesis; stem cells

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Received Nov 15, 2004; accepted April 27, 2005.

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