Dopamine specifically inhibits forebrain neural stem cell proliferation, suggesting a novel effect of antipsychotic drugs.
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.
Kippin
Tod E
TE
Department of Medical Genetics and Microbiology, University of Toronto, Toronto, Ontario, M5S 1A8, Canada. kippin@psych.ucsb.edu
Kapur
Shitij
S
van der Kooy
Derek
D
D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects*; D004298:Dopamine / Q000494:pharmacology*; D005260:Female; D006220:Haloperidol / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000166:cytology* / Q000187:drug effects; D016548:Prosencephalon / Q000166:cytology* / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D050637:Receptors, Dopamine D3 / Q000172:deficiency / Q000187:drug effects / Q000235:genetics; D013234:Stem Cells / Q000166:cytology* / Q000187:drug effects
D014150:Antipsychotic Agents; D050637:Receptors, Dopamine D3; D006220:Haloperidol; D004298:Dopamine