Research Sheds Light on Mechanism by Which Long-Term Anti-Anxiety Drug Use Affects the Brain

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

Source: ANSTO

ANSTO health researchers have 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 could lead to cognitive impairment in vulnerable individuals.

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

The study suggested that the anti-anxiety drug was not acting on nerve cells directly 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 interfering with dendritic spines (small protrusions from the neurons at the tip of which the synaptic connections to other nerve cells are located).

“This observation is important because long-term use of anti-anxiety medication is thought to contribute to an acceleration of dementia and how that might occur was not known,” said co-author ANSTO Prof. Richard Banati.

“The knowledge gained in this work by a large international team helps in the development of anti-anxiety drugs without such detrimental cognitive effects. The specific experiment looked closely into how the long-term use of anti-anxiety drugs, such as diazepam, can alter the complex wiring of the brain.

“We have neurons and each neuron connects 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 makes up a substantial part of the brain and is actually directly influencing the functioning of neural networks. The compound that was studied, diazepam, didn’t go directly to the long spines and synaptic connections between the nerve cell itself, but to the microglia.

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

There are a number of serious illness conditions, such as dementia but notably also those characterized by often extreme or prolonged fatigue, such as we see now in ‘long COVID’ or after accidental or therapeutic radiation exposure, where we know that the immune system responds very strongly.

“If the connections between neurons are severed by the activity of the microglial cells, then it’s almost like unplugging neural connections, and that would explain, how very subtle changes could drive a further progression of dementia, or—more speculatively—cause severe fatigue.

“The conceptual significance of the work for me is that it shows us that we might want to view the brain not only as a telephone switchboard with point-to-point connections but as a switchboard in an unusual environment.”

Credit: ANSTO News

You can think of the collective motion of the microglial cells as being similar to what occurs in lava lamps. The microglial cells create an amorphous but still locally confined dynamic, like bubbles that go up and then down when driven by heat.

And this ever-shifting, localized activity can interfere with the more static wire connections, in extreme cases, perhaps comparable to small, local cable melts that affect the whole system which otherwise looks fine.

The overlapping of the immune system (glial cells) and the nervous system (neurons) is important in understanding the underlying cellular mechanism.

This shows the outline of a head
The overlapping of the immune system (glial cells) and the nervous system (neurons) is important in understanding 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 shows itself in a dynamic equilibrium in which connections are formed by the nervous system and modulated or even severed by cells of the immune system.

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

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

Based on the findings, the authors concluded, that as a consequence of anti-anxiety drug use (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 psychopharmacology research news

Author: Press Office
Source: ANSTO
Contact: Press Office – ANSTO
Image: The image is in the public domain

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


Abstract

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

Benzodiazepines are widely administered drugs to treat anxiety and insomnia. In addition to tolerance development and abuse liability, their chronic use may cause cognitive impairment and increase the risk for dementia. However, the mechanism by which benzodiazepines might contribute to persistent 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 γ-aminobutyric acid type A receptors, which alters microglial morphology, and phagocytosis of synaptic material.

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

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  1. Jane, no one our age should be taking regularly. Based on much prior reading about benzodiazepines (and my own experience) I’d advise to wean yourself off very, very gradually (like over the course of months), and expect your brain to feel a little weird for awhile.
    Your memory loss could well be mainly from the effects of the Ativan in your system. Don’t be alarmed just yet; get the meds cleared out and see how it goes. Be patient though, and I emphasize the need to cut back in VERY small increments, each increment several days at a time. And if you want company, search online for a forum in which people, young and old, discuss their experiences weaning themselves off.

  2. I have taken Ativan for sleep and occasional anxiety for many years. I am 70 yeaold, and have been experiencing memory loss that unnerves me. If I discontinue Ativan, will my memory improve, or is this permanent?

  3. Big pharma and big med know all this already years and years and years ago but kept prescribing these poisons so they could make their trillions and they keep doing it to this day. They need to be sued. I took antidepressants for years and benzos off and on for years and those medications not only mess up your brain but your entire body. Big pharma big med and big food are humongous monsters and deserve to be in prison!!!!!!

    1. The problem with Big Pharma is humanity – the politicians, the political parties, the government agencies, corrupt people in disease awareness and treatment advocacy organizations, the media (ads=$), and marketing agencies. I worked in Big Pharma. So sickened by it, I have been unable to return to work for years, losing *much* income and ruining my retirement. The attitude of Big Pharma employees, from top to bottom, is greed, disguised with self-justifying word salad statements. I worked in marketing consulting. I always had multiple customers. Every other customer was in a Corporate Integrity Agreement with the government when we signed them up. The gov’t was basically telling them to go the chalkboard and write 1000 times “I will not lie or promote corruption.” They did this by making the guilty corp force *all* of its employees to watch boring films and read boring papers on how not to be corrupt or bad. Sometimes this had to be done every year. Multiply that by a few customers who are required to have contractors also do the “training” and you end up with marketing consultants taking 20 hours of training or so several times a year. And it always ended up coming out of your personal time. That is a reflection of the regularity of corruption.

      Big Pharma managers always frame their marketing discussions in trying to “inform” patients and doctors. They are not trying to do that. They are obviously trying to get doctors to prescribe more with the effect that if the marketing campaign is maximally successfully, docs will reduce competitor subscriptions and increase prescriptions (“Rx’s”) for the brad being market. That is the goal with ZERO attempt to ensure it only happens when it benefits the patient. Of course, the companies DID make efforts to track what ad they showed on your TV, what ad your TV heard on the radio in the background (yes, that tech is in use!), what websites you went to within 5 minutes after the ad, etc. They could do that but not be bothered to ask if this was harmful.

      We were sending duplicate emails to the same doctors sometimes 500 times within half a year. That is not education. It is brain-washing and also trying to out-do the competitors attempts at brain-washing. Then you have the sales reps. Hoo-boy, you should have seen the first day when a sales force was gathered. My, what very young, attractive people plus a few old, very convincing sales people. These people were hired to sell, not inform. I used to help design their driving routes and call and sample drop frequencies. Nothing in that was designed to find out which patients needed the right medication. It was always oriented to name-dropping and getting the doctor to promise to think of the brand when the patient asked questions. It helped the docs were given lunches, trips, etc. Some were paid to help with the drug marketing campaign development, with the magical side effect these docs wrote a lot of prescriptions. The field is highly regulated, but it is still a joke how US medicine works. Big Pharma exists to extract money from sick people. It does not exist to help them.

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