Antidepressant Action Requires New Neurons (cont.)
By knocking out the gene that codes for a key subtype of serotonin receptor (5-HT1A), the researchers created a strain of "knockout" mice that as adults show anxiety-related traits, such as a reluctance to begin eating in a novel environment. While unaffected by chronic treatment with the SSRI fluoxetine, the knockout mice became less anxious after chronic treatment with tricyclic antidepressants, which act via another neurotransmitter, norepinephrine, suggesting an independent molecular pathway.
While chronic fluoxetine treatment doubled the number of new hippocampal neurons in normal mice, it had no effect in the knockout mice. The tricyclic imipramine boosted neurogenesis in both types of mice, indicating that the serotonin 1A receptor is required for neurogenesis induced by fluoxetine, but not imipramine. Chronic treatment with a serotonin 1A-selective drug confirmed that activating the serotonin 1A receptor is sufficient to spur cell proliferation.
Although the new findings strengthen the case that neurogenesis contributes to the effects of antidepressants, Hen cautions that ultimate proof may require a "cleaner" method of suppressing this process, such as transgenic techniques that will more precisely target toxins at the hippocampal circuits involved.
"Our results suggest that strategies aimed at stimulating hippocampal neurogenesis could provide novel avenues for the treatment of anxiety and depressive disorders," suggest the researchers.
Also participating in the study were: Luca Santarelli, Michael Saxe, Cornelius Gross, Stephanie Dulawa, Noelia Weisstaub, James Lee, Columbia University; Alexandre Surget, Catherine Belzung, Universite de Tours, France; Fortunato Battaglia, Ottavio Arancio, New York University.
In addition to NIMH and NIDA, the research was also supported by the National Alliance for Research on Schizophrenia and Depression (NARSAD).
Source: National Institute of Mental Health, National Institutes of Health (www.nih.gov), Press Release, August 07, 2003
Last Editorial Review: 8/8/2003
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