Source: Medical College of Georgia at Augusta University
Clonidine is a medication commonly used to treat high blood pressure and ADHD. It has also been studied as a potential treatment for PTSD because it acts on adrenergic receptors in the brain, which are involved in the “fight or flight” response and are thought to be activated in PTSD and play a role in the consolidation of traumatic memories. Its sister drug, guanfacine, which also activates these receptors, has also been studied for its potential use in PTSD. However, conflicting results from clinical trials have led to clonidine being set aside, along with guanfacine, which has not shown promise in PTSD. Researchers at the Medical College of Georgia at Augusta University believe it is time to revisit clonidine, as laboratory evidence suggests that while the two drugs bind to the same receptors, they have different effects.
According to research published in the journal Molecular Psychiatry, clonidine could potentially be used to treat a significant number of people with PTSD, including those who have developed the disorder as a result of the COVID-19 pandemic and those with PTSD caused by wars or other forms of violence. The researchers argue that large-scale clinical trials of clonidine in PTSD are needed and suggest that the impact of existing drugs on the activation of a protein called cofilin could potentially lead to the identification of new therapies. The studies were conducted using genetically modified mice and neurons derived from human stem cells, which can differentiate into many different cell types.
Researchers have found that a novel axis on an adrenergic receptor called ɑ2A in the hippocampus, the center of learning and memory, is essential for maintaining fear memories associated with PTSD. The axis involves the protein spinophilin interacting with cofilin, which controls protrusions on neurons called dendritic spines, where memories are consolidated and stored. These spines, which can number in the hundreds on a single neuron, change shape based on brain activity and impact the strength of the synapse, the junction between two neurons where information is exchanged. In people with PTSD, fear memories are often triggered by places or situations, such as the site of a traumatic event, that are associated with fear or other distressing emotions.
According to neuropharmacologist Qin Wang, for information to be properly memorized, there must be a process in which dendritic spines store the information and become larger, a process that requires the reduction of cofilin levels in the synapse where the spines are located. Clonidine is thought to facilitate this process by promoting the formation of mushroom-like dendritic spines, which are important for memory formation. Wang, the Georgia Research Alliance Eminent Scholar in Neuropharmacology, explains that these spines typically change from a slender shape to a more mushroom-like one in response to stimulation, whether positive or negative.
The researchers found that clonidine interferes with cofilin’s ability to exit the synapse, which in turn prevents the dendritic spines from adopting a mushroom-like shape and retaining the memory. In contrast, guanfacine had no effect on cofilin and seemed to reduce the impact of clonidine on the reconsolidation and maintenance of traumatic memories in mice. These findings may help to explain the inconsistent results of clinical trials involving these two similar drugs, and suggest that they have opposite effects on this particular biological function.
Also, they conducted studies in mice to examine the effects of clonidine and guanfacine on PTSD-like behaviors. Mice were given a mild shock and then returned to the location where the shock occurred, where they were treated with either clonidine or guanfacine. The mice that received clonidine showed a significantly reduced response, such as freezing in place, when returned to the shock location compared to untreated mice. Their response was more similar to that of mice that had not been shocked at all. In contrast, guanfacine had no effect on freezing behavior.
While it is not possible to determine exactly what the mice remember, it is clear that those treated with clonidine do not have the same overt response as untreated mice or those receiving guanfacine, according to Wang. The goal is not to erase memories, but rather to diminish their disruption in the lives of people with PTSD, such as soldiers. When a memory is recalled, the synapses holding the memory become temporarily unstable before the memory is reconsolidated. This provides an opportunity to intervene in the reconsolidation process and weaken the strength of a negative memory. Clonidine appears to be one way to do this.