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Depression Meds Regulate the Brain

For years, pharmaceutical treatment of depression has focused on regulating or restoring the release of the neurotransmitter serotonin. However, the basic biological mechanism by which the medications help to alleviate symptoms has been poorly understood.

New research from the University of Pittsburgh suggests the drugs work by acting on a specific serotonin receptor which plays a key role in regulating the response of a particular area of the brain.

Scientists believe depression medications work on the serotonin receptor called the 5-HT1A autoreceptor, which plays a key role in regulating the response of the amygdala.

The findings, published in the journal Nature Neuroscience, also provide a model of how specific changes in 5-HT1A autoreceptors and associated amygdala reactivity may impact a person’s risk for developing depression. Much like a rheostat, these serotonin receptors regulate the brain’s emotional responses and may contribute to one’s vulnerability for depression and other psychiatric disorders.

The amygdala is a critical component of brain circuitry that processes clues from the environment about potential threats and generates appropriate behavioral and physiological responses – such as the “fight or flight” response – to these challenges. Research has indicated that depression and other mood disorders, such as anxiety, are associated with emotional brain circuitry problems involving the amygdala.

The 5-HT1A autoreceptor is located on the surface of serotonin neurons, which are responsible for producing the serotonin neurotransmitter and delivering it to several areas of the brain, including the amygdala.

The effect serotonin release has is varied and complex, due to the number of different serotonin receptors found in these brain regions. In contrast, the 5-HT1A autoreceptor on serotonin neurons in the brain stem is rather uniform: it reduces the neuron’s activity and its subsequent release of serotonin to downstream targets, a process called negative feedback inhibition. As more serotonin is released and becomes available in the brain, the neurotransmitter also acts on these 5-HT1A autoreceptors, which in turn work to reduce serotonin release.

In brain imaging studies of 20 normal subjects, the team of investigators found that individuals who had higher concentrations of the 5-HT1A autoreceptor, as assessed by positron emission tomography (PET), also had significantly reduced activity in their amygdala, which was measured by functional magnetic resonance imaging (fMRI). Moreover, the concentration of the 5-HT1A autoreceptor accounted for 30 to 44 percent of the differences in the reactivity of the amygdala among individuals.

“There’s a significant inverse relationship between the density of the 5-HT1A autoreceptor and the amygdala’s reactivity to threatening stimuli, and this mechanism appears to be reflecting the effects of the 5-HT1A on the negative feedback loop that controls the release of serotonin,” said study leader Ahmad R. Hariri, Ph.D., assistant professor of psychiatry and director of the Developmental Imaging Genetics Program at the University of Pittsburgh School of Medicine and Western Psychiatric Institute and Clinic.

“This observation could be important in understanding a key molecular pathway that may make some people more vulnerable for developing depression or other psychiatric disorders. In our normal subjects, we saw a pattern that suggests the reactivity of the amygdala is regulated by the capacity for negative feedback regulation of serotonin release through the 5-HT1A autoreceptor. Moreover, the pattern suggests that higher levels of serotonin, associated with reduced autoreceptor density and negative feedback, is linked with greater amygdala reactivity,” he added.

The study is one of the few to collect data in research subjects using these two different imaging methods, allowing for more complete interpretations to be drawn about the relationship between molecular changes in the brain and differences in behavior.

In earlier studies, Dr. Hariri and colleagues established a brain basis for a gene variant and its relationship to behavior, finding greater amygdala reactivity in people carrying a form of a gene that leads to reduced expression of the serotonin transporter, who, because of this variation, are more vulnerable to developing depression in the face of stressful and difficult life circumstances.

Recently, other researchers have noted that this same genetic variation is associated with reduced 5-HT1A density. Moreover, alterations in 5-HT1A autoreceptor density and amygdala reactivity have been documented in depression, and studies suggest that the class of drugs known as selective serotonin reuptake inhibitors (SSRIs) may evoke an antidepressant effect by acting on both the 5-HT1A autoreceptor and amygdala reactivity. Taken together, Dr. Hariri’s latest findings may be important for understanding the molecular mechanisms underlying the effects of the serotonin transporter gene variation on amygdala reactivity.

“Antidepressants, especially the SSRIs, which increase the availability of serotonin, may actually be working by shifting the availability of 5-HT1A autoreceptors and, as a consequence, modulating the reactivity of the amygdala. Such shifts may drive the improvements in depressed mood and affect that result from SSRI treatment,” explained Dr. Hariri, who plans to conduct additional studies in both healthy volunteers and patients with depression in order to better understand the specific biological pathways that contribute to risk for the condition as well as predict treatment response.

Source: University of Pittsburgh Medical Center

Depression Meds Regulate the Brain

Rick Nauert PhD

Rick Nauert, PhDDr. Rick Nauert has over 25 years experience in clinical, administrative and academic healthcare. He is currently an associate professor for Rocky Mountain University of Health Professionals doctoral program in health promotion and wellness. Dr. Nauert began his career as a clinical physical therapist and served as a regional manager for a publicly traded multidisciplinary rehabilitation agency for 12 years. He has masters degrees in health-fitness management and healthcare administration and a doctoral degree from The University of Texas at Austin focused on health care informatics, health administration, health education and health policy. His research efforts included the area of telehealth with a specialty in disease management.

APA Reference
Nauert PhD, R. (2018). Depression Meds Regulate the Brain. Psych Central. Retrieved on January 20, 2019, from
Scientifically Reviewed
Last updated: 8 Aug 2018
Last reviewed: By a member of our scientific advisory board on 8 Aug 2018
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