Blood pressure drug holds promise for treating PTSD

Abstract: Clonidine, an FDA-approved drug commonly prescribed to treat blood pressure disorders and ADHD, shows promise in alleviating the effects of PTSD.

Source: Medical School of Georgia at Augusta University

There is new evidence that a 50-year-old blood pressure drug may find a new purpose as a treatment to ease the often life-altering effects of increasingly widespread PTSD, scientists say.

Clonidine is commonly used as a treatment for high blood pressure and ADHD. It’s also already been studied in PTSD because clonidine works on adrenergic receptors in the brain, which are probably best known for their role in the “fight or flight” heightened response state that helps keep us safe. These receptors are thought to be activated in PTSD and play a role in consolidating traumatic memories.

Clonidine’s sister drug guanfacine, which also activates these receptors, has also been studied in PTSD. Conflicting clinical trial results put clonidine, which has shown promise in PTSD, alongside guanfacine, which has not.

Scientists at the University of Georgia School of Medicine at Augusta University say it’s time to take another look at clonidine.

They have laboratory evidence that even though the two drugs bind to the same receptors, they do different things there, says Qin Wang, MD, Ph.D., a neuropharmacologist and founder of the Alzheimer’s Therapy Discovery Program at MCG.

Their results were published in the journal Molecular psychiatry suggest that clonidine could provide immediate treatment for significant numbers of people emerging from the current pandemic with PTSD, as well as from longer-term causes such as wars and other violence.

Extensive clinical trials of clonidine in PTSD are warranted, the researchers write. Their studies also show that other new therapies could be identified by looking at the effect of existing drugs on the activation of a key protein called cofilin.

The new studies looked at genetically modified mice as well as neurons derived from human stem cells, which have the ability to generate many types of cells.

In the hippocampus, the center of learning and memory, they found that a new axis on an adrenergic receptor called ɑ2A is key to maintaining fear memories in which you associate a place or situation, such as the scene of a horrific car accident or school shooting, with fear or other distressing emotions that are features of PTSD.

In this axis, they discovered that the protein spinophilin interacts with cofilin, which is known to control protrusions at the synapses of neurons called dendritic spines, where memories are consolidated and stored.

A single neuron can have hundreds of these spines that change shape based on brain activity and whose change affects the strength of the synapse, the junction between two neurons where they exchange information.

“Usually whenever there’s stimulation, good or bad, in order to remember it, you have to go through a process where the spines store the information and get bigger,” says Wang, transforming from a slender profile to a more mushroom-like shape.

“The mushroom spine is very important for the formation of your memory,” says corresponding author Wang, a Georgia Research Alliance Distinguished Scientist in Neuropharmacology. For these mushroom forms to occur, cofilin levels must be significantly reduced in the synapse where the spines are located. This is where clonidine comes into play.

The scientists discovered that clonidine interferes with the release of cofilin by causing it to interact with the receptor, which in turn interferes with the dendritic spine’s ability to re-assemble into a mushroom shape and retain memory. Guanfacine, on the other hand, had no effect on this key player cofilin.

The findings help explain the disparate results in clinical trials of these two similar drugs, Wang says. In fact, when mice were given both drugs, guanfacine appeared to reduce clonidine’s effect on the essential step of re-consolidating—and thus maintaining—the traumatic memory, suggesting their completely opposite effects on at least this biological function, Wang says.

There was also living evidence. In their studies that mimicked how PTSD occurs, mice were given a mild shock and then treated with clonidine immediately after they were returned to the place where they received the shock and were supposed to recall what happened earlier.

Clonidine-treated mice had a significantly reduced response, such as freezing in place, compared to untreated mice when returned to the scene. In fact, their response was more like mice that had never been shocked. Guanfacine had no effect on freezing behavior.

Obviously, Wang says, they can’t know for sure how much the mice remember what happened previously, but it’s clear that those treated with clonidine didn’t have the same obvious reaction as untreated mice or those given guanfacine.

“The interpretation is that they don’t have such a strong memory,” she says, noting that the goal is not to erase memories such as those from wartime, but to reduce their disruption in a soldier’s life.

When a memory is recalled, such as when you flash back to the intersection where you were involved in a horrific car accident, the synapses that hold the memory of what happened there become temporarily unstable or labile before the memory stabilizes or consolidates again. This natural dynamic provides an opportunity to intervene in reconsolidation and thus at least reduce the strength of the bad memory, Wang says. Clonidine seems to be one way to do this.

Adrenergic drugs like clonidine bind to receptors in the central nervous system to reduce the level of stress hormones you make in your blood, such as epinephrine (adrenaline) and norepinephrine, which act to increase blood pressure and heart rate.

Studies like the one that came out 15 years ago that looked at only guanfacine showed no benefit in PTSD. But then in 2021, a retrospective look at a cohort of 79 veterans with PTSD treated with clonidine, for example, found that 72% experienced improvement and 49% experienced significant or very significant improvement with minimal side effects.

Previous basic science studies have also shown that manipulating the adrenergic receptor can affect fear memory formation and memory, but how remains unknown.

PTSD has emerged as a major neuropsychiatric component of the COVID-19 pandemic, affecting about 30% of survivors, a similar percentage of healthcare workers who care for them, and an estimated 20% of the general population, Wang says, meaning the impact on human health and health systems could be ” deep”.

Psychotherapy is generally considered the most effective treatment for PTSD, and some medications, such as antidepressants, can be used, but there are limited drug options, including only two Food and Drug Administration-approved drugs specifically for the condition, she says. The lack of approved drugs has led to the off-label use of drugs such as clonidine.

Cofilin is a key element in helping muscle cells and other cell types to contract, as well as the flexibility of the dendritic spine cytoskeleton. A single neuron can have thousands of dendritic spines that change shape based on brain activity and whose shape change affects the strength of the synapse.

The US Department of Veterans Affairs defines post-traumatic stress disorder as a mental health problem that some people develop after experiencing or witnessing a life-threatening or traumatic event.

While problems such as feelings of tension, trouble sleeping, and/or nightmares may persist for several weeks or more after the event, if symptoms like these, as well as flashbacks and increasingly negative thoughts, persist, it is likely to be PTSD. Sometimes symptoms do not appear until months after the initial event.

About this PTSD news and psychopharmacology research

Author: Press office
Source: Medical School of Georgia at Augusta University
Contact: Press Office – Medical College of Georgia at Augusta University
Picture: The image is in the public domain

Original research: Open access.
“Activation of a novel α2AAR-spinophilin-cofilin axis determines the effect of α2 adrenergic drugs on fear memory reconsolidationby Shalini Saggu et al. Molecular psychiatry

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Abstract

Activation of a novel α2AAR-spinophilin-cofilin axis determines the effect of α2 adrenergic drugs on fear memory consolidation

Post-pandemic post-traumatic stress disorder (PTSD) has emerged as a major neuropsychiatric component of post-acute COVID-19 syndrome, but current pharmacotherapy for PTSD is limited.

The use of adrenergic drugs has been suggested for the treatment of PTSD; however, it is hampered by conflicting clinical results and a lack of mechanistic understanding of drug action.

Our studies, using both genetically modified mice and human induced pluripotent stem cell-derived neurons, reveal new α_2a adrenergic receptor (α_2aAR)-spinophilin-cofilin axis in the hippocampus that is critical for the regulation of contextual fear memory consolidation.

In addition, we found that two α₂ ligands, clonidine and guanfacine, show different abilities in activating this signaling axis to disrupt fear memory consolidation.

Stimulation α_2aAR with clonidine, but not guanfacine, promotes interaction of the actin-binding protein cofilin with the dendritic spine scaffold receptor and spinophilin to induce cofilin activation at the synapse. Spinophilin-dependent regulation of cofilin is required for clonidine-induced impairment of contextual fear memory consolidation.

Our results inform the interpretation of the different clinical observations of these two drugs on PTSD and suggest that clonidine may provide immediate treatment for PTSD symptoms associated with the current pandemic. Furthermore, our study demonstrates that modulation of dendritic spine morphology may represent an effective strategy for the development of new pharmacotherapies for PTSD.