Serotonin-1A Receptor Gene Linked to Depression

Mouse experiment models genetic tendency for depression, poor treatment response in people
By Jeff Muise
HealthDay Reporter

WEDNESDAY, Jan. 20 (HealthDay News) -- In a mouse model, researchers were able to manipulate the level of serotonin-1A (5-HT1A) autoreceptors to affect both the mice's vulnerability to stress as well as their response to antidepressants, according to a study in the Jan. 14 issue of Neuron.

Jesse W. Richardson-Jones, Ph.D., of Columbia University in New York City, and colleagues set out to test the suspected role of 5-HT1A autoreceptors in causing anxiety and depression and inhibiting response to antidepressants, such as selective serotonin reuptake inhibitors. The researchers began by cross-breeding mice to generate a mouse genotype in which they could modulate the level of 5-HT1A receptors in raphe nuclei by exposing the mice to doxycycline (producing higher levels) or withholding doxycycline (producing lower levels).

The researchers found their 5-HT1A modulation strategy substantially affected raphe firing rates, without affecting basal forebrain serotonin levels. Mice with high levels of 5-HT1A autoreceptors exhibited a dampened physiological response to acute stress, increased behavioral despair, and no behavioral response to antidepressants, compared to mice with lower levels, which successfully modeled the experience in human patients with the 5-HT1A risk allele. By reducing 5-HT1A autoreceptor levels in advance of treatment with antidepressants, the investigators found they were able to convert non-responders into responders.

"These results establish a causal relationship between 5-HT1A autoreceptor levels, resilience under stress, and response to antidepressants," the authors write.

The study was supported in part by a grant from AstraZeneca. Also, one study author reported receiving consulting fees from pharmaceutical companies.

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