Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
4321644 | Neuron | 2010 | 13 Pages |
SummaryMost depressed patients don't respond to their first drug treatment, and the reasons for this treatment resistance remain enigmatic. Human studies implicate a polymorphism in the promoter of the serotonin-1A (5-HT1A) receptor gene in increased susceptibility to depression and decreased treatment response. Here we develop a new strategy to manipulate 5-HT1A autoreceptors in raphe nuclei without affecting 5-HT1A heteroreceptors, generating mice with higher (1A-High) or lower (1A-Low) autoreceptor levels. We show that this robustly affects raphe firing rates, but has no effect on either basal forebrain serotonin levels or conflict-anxiety measures. However, compared to 1A-Low mice, 1A-High mice show a blunted physiological response to acute stress, increased behavioral despair, and no behavioral response to antidepressant, modeling patients with the 5-HT1A risk allele. Furthermore, reducing 5-HT1A autoreceptor levels prior to antidepressant treatment is sufficient to convert nonresponders into responders. These results establish a causal relationship between 5-HT1A autoreceptor levels, resilience under stress, and response to antidepressants.
► The novel tTS/1A system yields inducible suppression of 5-HT1A autoreceptors ► Raphe firing, but not basal 5-HT levels, is affected by autoreceptor levels ► Adult autoreceptor suppression affects depression-related behavior, but not anxiety ► Response to fluoxetine is dictated by autoreceptor levels, not desensitization