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 behaviors in both mice and humans to get a fuller picture of both
histamine and serotonin’s roles in depression.”
Source: https://www.imperial.ac.uk/news/228353/histamine-could-player-depression-according-study/
Journal article: https://www.jneurosci.org/content/41/30/6564
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