Inflammation-Induced Histamine Impairs the Capacity of Escitalopram to Increase Hippocampal Extracellular Serotonin.
Abstract
Commonly prescribed selective serotonin reuptake inhibitors (SSRIs) inhibit the serotonin
transporter to correct a presumed deficit in extracellular serotonin signaling during
depression. These agents bring clinical relief to many who take them; however, a significant
and growing number of individuals are resistant to SSRIs. There is emerging evidence
that inflammation plays a significant role in the clinical variability of SSRIs, though
how SSRIs and inflammation intersect with synaptic serotonin modulation remains unknown.
In this work, we use fast in vivo serotonin measurement tools to investigate the nexus between serotonin, inflammation,
and SSRIs. Upon acute systemic lipopolysaccharide (LPS) administration in male and
female mice, we find robust decreases in extracellular serotonin in the mouse hippocampus.
We show that these decreased serotonin levels are supported by increased histamine
activity (because of inflammation), acting on inhibitory histamine H3 heteroreceptors
on serotonin terminals. Importantly, under LPS-induced histamine increase, the ability
of escitalopram to augment extracellular serotonin is impaired because of an off-target
action of escitalopram to inhibit histamine reuptake. Finally, we show that a functional
decrease in histamine synthesis boosts the ability of escitalopram to increase extracellular
serotonin levels following LPS. This work reveals a profound effect of inflammation
on brain chemistry, specifically the rapidity of inflammation-induced decreased extracellular
serotonin, and points the spotlight at a potentially critical player in the pathology
of depression, histamine. The serotonin/histamine homeostasis thus, may be a crucial
new avenue in improving serotonin-based treatments for depression.SIGNIFICANCE STATEMENT Acute LPS-induced inflammation (1) increases CNS histamine, (2) decreases CNS serotonin
(via inhibitory histamine receptors), and (3) prevents a selective serotonin reuptake
inhibitor (SSRI) from effectively increasing extracellular serotonin. A targeted depletion
of histamine recovers SSRI-induced increases in extracellular hippocampal serotonin.
Type
Journal articleSubject
HippocampusAnimals
Mice, Inbred C57BL
Mice
Inflammation
Histamine
Serotonin
Citalopram
Serotonin Uptake Inhibitors
Female
Male
Permalink
https://hdl.handle.net/10161/24073Published Version (Please cite this version)
10.1523/jneurosci.2618-20.2021Publication Info
Hersey, Melinda; Samaranayake, Srimal; Berger, Shane N; Tavakoli, Navid; Mena, Sergio;
Nijhout, H Frederik; ... Hashemi, Parastoo (2021). Inflammation-Induced Histamine Impairs the Capacity of Escitalopram to Increase Hippocampal
Extracellular Serotonin. The Journal of neuroscience : the official journal of the Society for Neuroscience, 41(30). pp. 6564-6577. 10.1523/jneurosci.2618-20.2021. Retrieved from https://hdl.handle.net/10161/24073.This is constructed from limited available data and may be imprecise. To cite this
article, please review & use the official citation provided by the journal.
Collections
More Info
Show full item recordScholars@Duke
H. Frederik Nijhout
John Franklin Crowell Distinguished Professor of Biology
Fred Nijhout is broadly interested in developmental physiology and in the interactions
between development and evolution. He has several lines of research ongoing in his
laboratory that on the surface may look independent from one another, but all share
a conceptual interest in understanding how complex traits arise through, and are affected
by, the interaction of genetic and environmental factors. 1) The control of polyphenic
development in insects. This work attempts to understand how the inse
Michael C. Reed
Arts & Sciences Distinguished Professor of Mathematics
Professor Reed is engaged in a large number of research projects that involve the
application of mathematics to questions in physiology and medicine. He also works
on questions in analysis that are stimulated by biological questions. For recent work
on cell metabolism and public health, go to sites@duke.edu/metabolism.
Since 2003, Professor Reed has worked with Professor Fred Nijhout (Duke Biology) to
use mathematical methods to understan
Alphabetical list of authors with Scholars@Duke profiles.

Articles written by Duke faculty are made available through the campus open access policy. For more information see: Duke Open Access Policy
Rights for Collection: Scholarly Articles
Works are deposited here by their authors, and represent their research and opinions, not that of Duke University. Some materials and descriptions may include offensive content. More info