5-HT1A autoreceptor levels determine vulnerability to stress and response to antidepressants.
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.
Department of Pharmacology, Columbia University, New York, NY 10032, USA.
Jesse W
JW
Richardson-Jones
Caryne P
CP
Craige
Bruno P
BP
Guiard
Alisson
A
Stephen
Kayla L
KL
Metzger
Hank F
HF
Kung
Alain M
AM
Gardier
Alex
A
Dranovsky
Denis J
DJ
David
Sheryl G
SG
Beck
René
R
Hen
E David
ED
Leonardo
D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology / Q000627:therapeutic use; D017660:Autoreceptors / Q000235:genetics / Q000378:metabolism*; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D003866:Depressive Disorder / Q000188:drug therapy / Q000503:physiopathology; D005473:Fluoxetine / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D018408:Patch-Clamp Techniques; D011110:Polymorphism, Genetic; D011903:Raphe Nuclei / Q000166:cytology / Q000378:metabolism; D044282:Receptor, Serotonin, 5-HT1A / Q000235:genetics / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism; D013315:Stress, Psychological / Q000378:metabolism*
D000928:Antidepressive Agents; D017660:Autoreceptors; D005473:Fluoxetine; D044282:Receptor, Serotonin, 5-HT1A; D012701:Serotonin