5-HT1A Autoreceptor Levels Determine Vulnerability to Stress and Response to Antidepressants

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