Histamine could be a key player in depression, according to study in
mice

Date:
August 17, 2021
Source:
Imperial College London
Summary:
Bodily inflammation dampens levels of a 'feel-good molecule' and
antidepressants' ability to boost them, according to new research
in mice.



FULL STORY ==========================================================================
The findings, from researchers at Imperial College London and University
of South Carolina, add to mounting evidence that inflammation, and the accompanying release of the molecule histamine, affects a key molecule responsible for mood in the brain -- serotonin.


==========================================================================
If replicated in humans, the findings -- which identify histamine as a
'new molecule of interest' in depression -- could open new avenues for
treating depression, which is the most common mental health problem
worldwide.

Inflammation -- a blanket term describing an immune response -- triggers
the release of histamine in the body. This increases blood flow to
affected areas to flood them with immune cells. While these effects
help the body fight infections, both long-term and acute inflammation is increasingly linked to depression. Inflammation accompanies infections
but can also be caused by stress, allergic responses and a host of chronic diseases such as diabetes, obesity, cancer and neurodegenerative diseases.

Lead author Dr Parastoo Hashemi, from Imperial's Department of
Bioengineering, said: "Inflammation could play a huge role in depression,
and there is already strong evidence that patients with both depression
and severe inflammation are the ones most likely not to respond to antidepressants.

"Our work shines a spotlight on histamine as a potential key player in depression. This, and its interactions with the 'feel-good molecule'
serotonin, may thus be a crucial new avenue in improving serotonin-based treatments for depression." Chemical messengers Serotonin, often referred
to as the 'feel-good molecule', is a key target for depression-tackling
drugs. Commonly prescribed selective serotonin reuptake inhibitors
(SSRIs) inhibit the re-absorption of serotonin in the brain, allowing
it to circulate for longer and improve mood.



========================================================================== However, although SSRIs bring relief to many who take them, a growing
number of individuals are resistant to their effects. Researchers think
one reason for this could lie in the specific interactions between
chemical messengers, or neurotransmitters, including serotonin and
histamine.

With this in mind, researchers set out to investigate the relationship
between histamine, serotonin, and SSRIs.

They created serotonin-measuring microelectrodes and put them into
the hippocampus of the brains of live mice, an area known to regulate
mood. The technique, known as fast scan cyclic voltammetry (FSCV), allowed
them to measure brain serotonin levels in real time without harming the
brain, as they are biocompatible and only five micrometers wide.

After placing the microelectrodes, they injected half the mice with lipopolysaccharide (LPS), an inflammation-causing toxin found in some
bacteria, and half the mice with a saline solution as a control.

Brain serotonin levels dropped within minutes of LPS injection, whereas
they remained the same in control mice, demonstrating how quickly
inflammatory responses in the body translate to the brain and affect
serotonin. LPS is unable to cross the protective blood-brain barrier
and could therefore not have caused this drop directly.



==========================================================================
On further examination they found that the histamine in the brain was
triggered by the inflammatory response and directly inhibited the release
of serotonin, by attaching to inhibitory receptors on the serotonin
neurons. These inhibitory receptors are also present on human serotonin neurons, so this effect might translate to people.

To counter this, the researchers administered SSRIs to the mice, but they
were much less able to boost serotonin levels than in control mice. They posited that this is because the SSRIs directly increased the amount of histamine in the brain, cancelling out its serotonin boosting action.

The researchers then administered histamine reducing drugs alongside the
SSRIs to counter histamine's inhibitory effects, and saw serotonin levels
rise back to control levels. This appears to confirm the theory that
histamine directly dampens serotonin release in the mouse brain. These histamine reducing drugs cause a whole-body reduction in histamine
and are distinct from antihistamines taken for allergies, which block histamine's effects on neurons.

A new molecule of interest The researchers say that if their work
translates to humans it could help us towards eventually diagnosing
depression by measuring chemicals like serotonin and histamine in
human brains.

They also say the findings open new avenues to explore histamine as a
causative agent of depression, including potentially developing novel
drugs that reduce histamine in the brain.

Because the work was done in animals, more research will be needed to know
if the concepts translate to humans. However, it is not currently feasible
to use microelectrodes to make similar measurements in human brains,
so the researchers are now looking at other ways to get a snapshot of
the brain by looking at other organs which use serotonin and histamine,
like the gut.

Pain, which accompanies inflammation, can also change neurotransmitter
levels - - but previous research shows that in similar models, these
changes last a few minutes, whereas the serotonin drop shown in this
research lasted much longer, ruling out pain as a reason for the
serotonin decrease.

Dr Hashemi added: "Inflammation is a whole-body response and is
therefore hugely complex. Depression is similarly complex, and the
chemicals involved are affected in myriad ways by both genetic
and environmental factors. Thus we need to look at more complex
models of depression behaviours in both mice and humans to get a
fuller picture of both histamine and serotonin's roles in depression." ========================================================================== Story Source: Materials provided by Imperial_College_London. Original
written by Caroline Brogan. Note: Content may be edited for style
and length.


========================================================================== Journal Reference:
1. Melinda Hersey, Srimal Samaranayake, Shane N. Berger, Navid
Tavakoli,
Sergio Mena, H. Frederik Nijhout, Michael C. Reed, Janet Best,
Randy D.

Blakely, Lawrence P. Reagan, Parastoo Hashemi. Inflammation-Induced
Histamine Impairs the Capacity of Escitalopram to Increase
Hippocampal Extracellular Serotonin. The Journal of Neuroscience,
2021; 41 (30): 6564 DOI: 10.1523/JNEUROSCI.2618-20.2021 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/08/210817111404.htm

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