| First Author | Richardson-Jones JW | Year | 2010 |
| Journal | Neuron | Volume | 65 |
| Issue | 1 | Pages | 40-52 |
| PubMed ID | 20152112 | Mgi Jnum | J:167659 |
| Mgi Id | MGI:4868687 | Doi | 10.1016/j.neuron.2009.12.003 |
| Citation | Richardson-Jones JW, et al. (2010) 5-HT1A autoreceptor levels determine vulnerability to stress and response to antidepressants. Neuron 65(1):40-52 |
| abstractText | Most 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-HT(1A)) receptor gene in increased susceptibility to depression and decreased treatment response. Here we develop a new strategy to manipulate 5-HT(1A) autoreceptors in raphe nuclei without affecting 5-HT(1A) 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-HT(1A) risk allele. Furthermore, reducing 5-HT(1A) autoreceptor levels prior to antidepressant treatment is sufficient to convert nonresponders into responders. These results establish a causal relationship between 5-HT(1A) autoreceptor levels, resilience under stress, and response to antidepressants. |
