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Study sheds light on mechanism by which long-term anti-anxiety drug use affects the brain

Overview: Study reveals a possible mechanism by which anxiolytic drugs act on the brain, leading to cognitive impairment.

Source: ANSTO

ANSTO health researchers contributed to an international study published in: Nature Neuroscience that sheds light on the mechanism by which anti-anxiety drugs act on the brain, which can lead to cognitive impairment in vulnerable individuals.

The research relied heavily on a unique laboratory model developed at ANSTO known as the “Guwiyang Wurra -TSPO knockout” (a healthy mouse lacking an evolutionary, ancient protein normally present in mitochondria, the organelle that supplies a cell with energy.Due to the importance of the protein for energy generation, its name in the Dharawal language is Guwiyang Wurra “fire mouse”).

The study suggested that the anti-anxiety drug did not act directly on nerve cells, but on microglial cells (cells of the brain’s own intrinsic immune system that can gather around nerve cells and their connections, the synapses), and that the movement of microglial cells was interfere with dendritic spines (small projections of the neurons at the end of which the synaptic connections with other nerve cells are located).

“This observation is important because long-term use of anti-anxiety medications is thought to contribute to an acceleration of dementia and how that might happen was unknown,” said ANSTO co-author Prof. Richard Banati.

“The knowledge gained in this work by a large international team is helping to develop anti-anxiety drugs without such adverse cognitive effects. The specific experiment closely examined how long-term use of anti-anxiety drugs, such as diazepam, can alter the brain’s complex wiring.

“We have neurons and each neuron is connected to another neuron by what is called a synapse. Here the research team recognized the importance of other neighboring cells, microglial cells.

“These are small and highly mobile cells that are part of the non-neuronal matrix in which nerve cells are embedded. This matrix forms a substantial part of the brain and actually directly influences the functioning of neural networks. The substance under study, diazepam, did not go directly to the long spines and synaptic connections between the nerve cell itself, but to the microglia.

“By doing this, the drug altered the normal activity of microglial cells and indirectly the maintenance function that microglia have around synaptic nerve cell connections. It’s intriguing to see how the brain’s local immune system, of which microglial cells are a part, directly participates in the overall functional integrity of the brain.

There are a number of serious disease states, such as dementia, but especially those characterized by often extreme or prolonged fatigue, as we now see with ‘long COVID’ or after accidental or therapeutic exposure to radiation, where we know that the immune system responds very strong.

“If the connections between neurons are broken by the activity of the microglial cells, it’s almost like disconnecting neural connections, and that would explain how very subtle changes can cause further progression of dementia, or – more speculatively – severe fatigue.” cause.

“The conceptual significance of the work for me is that it shows us that we may want to see the brain not just as a telephone exchange with point-to-point connections, but as a telephone exchange in an unusual environment.”

Credit: ANSTO News

You can think of the collective movement of the microglial cells as similar to what happens in lava lamps. The microglial cells create an amorphous but still locally limited dynamics, like bubbles that go up and down when driven by heat.

And this ever-changing, localized activity can interfere with the more static wire connections, in extreme cases perhaps akin to small, localized cable breaks that affect the entire system that looks otherwise fine.

The overlap of the immune system (glial cells) and the nervous system (neurons) is important to understand the underlying cellular mechanism.

This shows the circumference of a head
The overlap of the immune system (glial cells) and the nervous system (neurons) is important to understand the underlying cellular mechanism. Image is in the public domain

Both systems mediate between the internal world of the organism and the input from the environment. This self/non-self interaction manifests itself in a dynamic equilibrium in which connections are formed by the nervous system and modulated or even broken by cells of the immune system.

“Using the potent TSPO knockout mouse model provided evidence that the mitochondrial protein TSPO was involved in the remodeling of dendritic junctions by microglial cells. Anti-anxiety drugs, such as diazepam, bind with TSPO.

“In a genetically modified animal such as a TSPO knockout mouse, the side effects described for diazepam simply do not occur. Diazepam administered to laboratory models showed a reduction in dendrite spines, while these defects did not occur in the TSPO knockout model,” said Prof. banati.

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Based on the findings, the authors concluded that as a result of the use of anti-anxiety drugs (benzodiazepines), the TSPO-mediated loss of dendritic spines accelerated cognitive decline.

It was also possible that chronic use of drugs such as the benzodiazepines altered the function of microglial cells, which could promote disease-specific pathological changes in the brain.

About this research news on psychopharmacology

Author: press office
Source: ANSTO
Contact: Press agency – ANSTO
Image: The image is in the public domain

Original research: Closed access.
Long-term diazepam treatment improves microglial spine uptake and impairs cognitive performance via mitochondrial 18 kDa translocator protein (TSPO)by Yuan Shi et al. Nature Neuroscience


Long-term diazepam treatment improves microglial spine uptake and impairs cognitive performance via mitochondrial 18 kDa translocator protein (TSPO)

Benzodiazepines are widely used to treat anxiety and insomnia. In addition to tolerance development and liability for abuse, its chronic use can cause cognitive impairment and increase the risk of dementia. However, the mechanism by which benzodiazepines may contribute to sustained cognitive decline remains unknown.

Here we report that diazepam, a widely prescribed benzodiazepine, impairs the structural plasticity of dendritic spines, causing cognitive impairment in mice. Diazepam induces these deficits via the mitochondrial 18 kDa translocator protein (TSPO), rather than classical -aminobutyric acid type A receptors, which alter the microglial morphology and phagocytosis of synaptic material.

Collectively, our findings demonstrate a mechanism by which TSPO ligands alter synaptic plasticity and cause cognitive impairment as a result.

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