When people encounter trauma, medication can help prevent or minimize post-traumatic stress disorder by reducing overly powerful memories that produce severe flashbacks and nightmares. However, the treatment is only effective if the pills are taken immediately after a stressful encounter.
An enhanced approach that could prevent PTSD-strength memories from ever arising is possible, according to recent Brigham Young University research that was recently published in the International Journal of Molecular Sciences.
“We were really curious about whether some of those drugs used to reverse PTSD could be given to people we know have high risks — such as first responders or people in the military — before they experience stress, to prevent some of the cellular-level brain changes that are damaging in PTSD,”
said BYU neuroscience professor Jeff Edwards, who led the study.
Proof of Concept
After hearing his barber, a veteran of the Vietnam War, talk about seeing a war film and finding himself shouting and reliving the combat, Edwards became interested in the study of post-traumatic stress disorder.
Edwards and his colleagues utilized rats as a proof of concept to see whether PTSD pretreatment is worth pursuing in human trials. The researchers initially administered propranolol and mifepristone to some of the rats, which are widely used to treat PTSD retroactively.
They then generated PTSD-inducing chronic and acute stress by exposing the rats to constant light for two weeks and subjecting them to “social defeat,” periodically introducing a dominant rat into the space to frighten the rat subjects.
Memory Formation
After a week, they tested the rats for anxiety and looked at each rat brain’s amygdala and hippocampus, which are responsible for emotion and memory.
They were interested in how stress altered the degree of long-term potentiation (LTP), which is the strengthening of synapses or junctions between neurons that aids in memory formation. The stronger the memory, the higher the LTP; overly high long-term potentiation might indicate a PTSD-like impact.
As expected, rats undergoing stress without drug pretreatment showed huge increases in LTP, a 30–40% enhancement. However, the rats given the drugs before being subjected to social defeat had the same levels of LTP as the control group rats who were not subjected to any stress.
“The drugs brought the brain back to normal levels, how it should be working in memory formation, eliminating some of those maladaptive memories that create overly strong recall,”
Edwards said.
An Ounce of Prevention
The scientists also discovered that the stress receptors of the pretreated rats were normal after trauma, whereas the stress receptors of the untreated rats were 80% less functional.
“Preventative treatment strategies like this are often much more effective. You can think of the adage, ‘An ounce of prevention is worth a pound of cure.’ Although our work is very preliminary and in rodents, it is a piece in the puzzle that we hope will lead to better treatments for the prevention of PTSD in high-risk individuals,”
said Eric Winzenried, who worked on the project as a BYU undergraduate and is now a neuroscience Ph.D. student at Washington State University.
The next step before a human study is to gain a better understanding of how the drugs operate to minimize PTSD-like effects in rats. For example, the researchers could give the rats either propranolol or mifepristone instead of both to test if one is enough.
Abstract
Post-traumatic stress disorder (PTSD) is a complex stress-related disorder induced by exposure to traumatic stress that is characterized by symptoms of re-experiencing, avoidance, and hyper-arousal. While it is widely accepted that brain regions involved in emotional regulation and memory—e.g., the amygdala and hippocampus—are dysregulated in PTSD, the pathophysiology of the disorder is not well defined and therefore, pharmacological interventions are extremely limited. Because stress hormones norepinephrine and cortisol (corticosterone in rats) are heavily implicated in the disorder, we explored whether preemptively and systemically antagonizing β-adrenergic and glucocorticoid receptors with propranolol and mifepristone are sufficient to mitigate pathological changes in synaptic plasticity, gene expression, and anxiety induced by a modified social defeat (SD) stress protocol. Young adult, male Sprague Dawley rats were initially pre-screened for anxiety. The rats were then exposed to SD and chronic light stress to induce anxiety-like symptoms. Drug-treated rats were administered propranolol and mifepristone injections prior to and continuing throughout SD stress. Using competitive ELISAs on plasma, field electrophysiology at CA1 of the ventral hippocampus (VH) and the basolateral amygdala (BLA), quantitative RT-PCR, and behavior assays, we demonstrate that our SD stress increased anxiety-like behavior, elevated long-term potentiation (LTP) in the VH and BLA, and altered the expression of mineralocorticoid, glucocorticoid, and glutamate receptors. These measures largely reverted to control levels with the administration of propranolol and mifepristone. Our findings indicate that SD stress increases LTP in the VH and BLA and that prophylactic treatment with propranolol and mifepristone may have the potential in mitigating these and other stress-induced effects.
Reference:
- Winzenried ET, Everett AC, Saito ER, Miller RM, Johnson T, Neal E, Boyce Z, Smith C, Jensen C, Kimball S, et al. Effects of a True Prophylactic Treatment on Hippocampal and Amygdala Synaptic Plasticity and Gene Expression in a Rodent Chronic Stress Model of Social Defeat. International Journal of Molecular Sciences. 2023; 24(13):11193. doi: 10.3390/ijms241311193
Last Updated on December 21, 2023