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Summary: Clonidine, an FDA-approved drug commonly prescribed to treat blood pressure disorders and ADHD, shows promise in mitigating the effects of post-traumatic stress disorder.
source: Medical College of Georgia at Augusta University
There is new evidence that a 50-year-old blood pressure drug may find a new target as a treatment to mitigate the often life-altering effects of the increasingly common PTSD, scientists say.
Clonidine is commonly used as a medicine for high blood pressure and for ADHD. It’s also already being studied for PTSD because clonidine works on adrenergic receptors in the brain, perhaps 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 the consolidation of traumatic memory.
Clonidine’s related drug, guanfacine, which also activates these receptors, has also been studied in PTSD. Conflicting clinical trial results sideline clonidine, which has shown promise in PTSD, along with guanfacine, which has not.
Scientists at the Medical College of Georgia at Augusta University say it’s time for a new look at clonidine.
They have laboratory evidence that while the two drugs bind to the same receptors, they do different things there, says Qin Wang, M.D., Ph.D., a neuropharmacologist and founding director of the Alzheimer’s Therapeutic Discovery Program at MCG.
Their results are published in the journal Molecular psychiatry suggest that clonidine may provide immediate treatment for significant numbers of people emerging from the current pandemic with PTSD, as well as from longer-established causes such as wars and other violence.
Large-scale clinical trials of clonidine in PTSD are warranted, the researchers write. Their research also suggests that other new therapies may 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 engineered mice as well as neurons derived from human stem cells that have the ability to produce many types of cells.
In the hippocampus, the center of learning and memory, they found that a new adrenergic receptor axis called ɑ2A is essential for 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 hallmarks of PTSD.
In this axis, they found that the protein spinophilin interacts with cofilin, which is known to control the protrusions of neurons’ synapses, called dendritic spines, where memories are consolidated and stored.
A single neuron can have hundreds of these spikes, which change shape based on brain activity and whose change affects the strength of the synapse, the connection 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 thin profile to a more spongy-like shape. .
“The mushroom spine is very important in the formation of your memory,” says corresponding author Wang, a Georgia Research Alliance Distinguished Scientist in Neuropharmacology. For these mushroom shapes to appear, cofilin levels must be greatly reduced at the synapse where the spines reside. That’s where clonidine comes in.
The scientists found that clonidine interfered with the release of cofilin by encouraging it to interact with the receptor, which subsequently interfered with the ability of the dendritic spine to resume its mushroom shape and retain the memory. Guanfacine, on the other hand, has no effect on this key player cofilin.
The findings help explain the disparate results in clinical trials of these two similar drugs, Wang said. In fact, when the mice received both drugs, guanfacine appeared to reduce the impact of clonidine in the essential step of reconsolidating—and thus maintaining—a traumatic memory, indicating their polar opposite effects on at least this biological function, Wang says.
There was also living evidence. In their studies, which mimicked how PTSD occurs, mice were given a mild shock, then treated with clonidine immediately after they were returned to the place where they received the shock and had to remember what happened earlier.
Clonidine-treated mice had a significantly reduced response, such as freezing in their tracks, compared to untreated mice when they were returned to the scene. In fact, their response was more like that of the mice that had never been shocked. Guanfacine had no effect on freezing behavior.
Obviously, Wang says, they can’t know for sure how well the mice remember what happened before, but apparently those treated with clonidine didn’t have the same overt response as untreated mice or those given guanfacine.
“The interpretation is that they don’t have as strong a memory,” she says, noting that the goal is not to erase memories like those from wartime, but rather to reduce their disruption in a soldier’s life.
When a memory is recalled, such as when you return to an 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 re-stabilizes or is re-consolidated. 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 lower blood levels of stress hormones you make like epinephrine (adrenaline) and norepinephrine, which do things like increase blood pressure and heart rate.
Studies like 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 group of 79 veterans with PTSD treated with clonidine, for example, found that 72% had improvement and 49% were significantly improved or very much improved with minimal side effects.
Previous basic science research has 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 percent of survivors, a similar percentage of health care workers who care for them, and roughly 20 percent of the general population, Wang says, meaning the impact on human health and health care systems can be ‘deep’.
Psychotherapy is generally considered the most effective treatment for PTSD, and some medications, such as antidepressants, can also be used, but there are limited medication options, which include only two drugs that have Food and Drug Administration approval 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 the contraction of muscle cells and other cell types, 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 changing shape affects the strength of the synapse.
The US Department of Veterans Affairs defines PTSD as a mental health problem that some people develop after experiencing or witnessing a life-threatening or traumatic event.
Although 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 PTSD. Sometimes symptoms do not appear for months after the initial event.
About this news about PTSD and psychopharmacology research
Original Research: Free access.
“Activation of a novel α2AAR-spinophilin-cofilin axis determines the effect of α2 adrenergic drugs on fear memory reconsolidationby Shalini Saggu and others. Molecular psychiatry
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 to treat PTSD has been suggested; however, this has been hampered by conflicting clinical results and a lack of mechanistic understanding of drug action.
Our studies using both genetically engineered mice and human induced pluripotent stem cell-derived neurons reveal a novel α2a adrenergic receptor (α2aAR)-spinophilin-cofilin axis in the hippocampus, which is critical for the regulation of contextual fear memory consolidation.
Furthermore, we found that two α2 ligands, clonidine and guanfacine, show differential abilities to activate this signaling axis to disrupt fear memory consolidation.
Stimulation of α2aAR with clonidine, but not guanfacine, promotes the interaction of the actin-binding protein cofilin with the receptor and with the dendritic spine protein spinophilin to induce cofilin activation at the synapse. Spinophilin-dependent regulation of cofilin is required for clonidine-induced disruption of contextual fear memory consolidation.
Our results inform the interpretation of the differential 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 shows that modulation of dendritic spine morphology may represent an effective strategy for the development of novel pharmacotherapies for PTSD.
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