Currently, various treatment options, such as antidepressants or cognitive behavioral therapy, are used to treat PTSD. Selective serotonin reuptake inhibitors (SSRIs) are the only class of antidepressants approved to treat PTSD. However, the drug has the disadvantage of being slow-acting and ineffective in some patients.
Cognitive-behavioral therapies, such as eye movement desensitization and reprocessing (EMDR), are also commonly used to treat PTSD. However, such fear-reducing therapies are not effective in half of the patients. Furthermore, even with successful therapy, PTSD is well known for its potential for symptom recurrence. Recurrence of previously treated PTSD, known as “spontaneous recovery,” has been the subject of many studies.
Previously, studies have shown that activities in glutamatergic neurons are an important part of the pathophysiology of PTSD. Of particular interest are the effects of the N-methyl-D-aspartate receptor (NMDAR) on these neurons, which are responsible for controlling synaptic plasticity involved in learning and memory.
To tackle PTSD at its root, researchers from the Center for Cognition and Society of the Institute of Basic Sciences (IBS) in association with Yale University have explored the molecular mechanism of PTSD treatment. In their latest study, published in Molecular Psychiatry, the IBS team tested an experimental PTSD drug called NYX-783 on mice and examined its molecular mechanism of action. NYX-783 is a newly discovered drug that modulates NMDAR functions in neurons.
There are two rodent models of PTSD: auditory fear conditioning (AFC) and one-time sustained stress (SPS) model. For auditory fear conditioning, the rats were acclimated to an environment and subjected to a combination of sound and electric shocks to mediate fear that induces PTSD. To induce single sustained stress, some rats were exposed to multiple stressors to induce single sustained stress before fear conditioning. It should be noted that the experience of stress prior to the treatment of fear is well known to cause further difficulties in later treatment of PTSD.
The mice were then placed in a new environment and underwent a series of amnesiac procedures aimed at erasing their traumatic memories. To enhance cognitive behavioral therapy, researchers tested the performance of NYX-783 along with ketamine, a known fast-acting antidepressant. It was found that injecting mice with the drug 1 hour before fear extinction therapy provided the highest rate of treatment success.
After the treatment, the mice were monitored for freezing behavior when listening to the same sound to measure the level of fear they were experiencing. It was confirmed that the mice injected with NYX-783 lived much better than those injected with ketamine or the control with saline. The drug is particularly effective in preventing spontaneous recovery or unwanted return of PTSD. The drug worked differently depending on the sex of the mice, with female rats responding more positively to treatment than male rats.
To explore the therapeutic mechanism, these experiments were repeated together with genetic manipulation. First, it was found that NYX-783 inhibits fear memories and prevents the spontaneous recovery of those memories by modulating NMDA receptors, specifically by acting on the NMDA subunit. GluN2B. To test this, the researchers knocked down the GluN2B subunit of NMDARs by manipulating the Grin2b gene using viral vectors. As expected, the drug’s effectiveness was mostly diminished when receptors were defeated in glutamatergic neurons in the medial prefrontal cortex. In particular, the Grin2b knockdown mutant exhibited spontaneous recovery, even when it was injected with NYX-783.
On the other hand, drug performance was not affected when the same receptors were knocked down in GABAergic interneurons. Interestingly, it was found that knocking down the NMDA receptors in interneurons alone has the potential to reduce spontaneous recovery. The team believes this most likely happens through a reduction in the inhibitory effect of interneurons on primary neurons.
However, this does not completely rule out the possibility that NYX-783 acts on inhibitory neurons. The authors note, “Grin2b knockdown in interneurons without NYX-783 showed low freezing during spontaneous recovery. Because of this floor effect, we may not see a reduction in freezing. further with NYX-783 during spontaneous recovery even when NYX-783 acts via GluN2B on glutamatergic neurons.” Although it is believed that drug action on glutamatergic neurons is important more important for behavioral output, but further research may be needed to confirm this.
Ultimately, the team found that brain-derived neurotrophic factor (BDNF), which is important for synaptic plasticity, is required for memory erasure. When the authors blocked BDNF activity in the rat brain using an antibody treatment, it largely attenuated the effect of NYX-783 on inhibiting spontaneous reconstitution.
Corresponding author LEE Boyoung from the Center for Cognition and Society commented: “Together, these findings suggest that NYX-783, a novel NMDAR positive modulator, may be an effective drug for PTSD. Although clinical studies on this compound are ongoing, these findings suggest that the development of an NMDAR modulator may be a viable strategy for the treatment of PTSD.”
Source: Eurekalert
