Vorinostat - HDAC Inhibition - Fear Extinction, Learning, Memory enhancement Contribute

Joey B. Wong | earned $0.12

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Warning: These compounds have only been used for cancer so far, so other use cases are in their infancies. They are very powerful and can stop cell cycles which is how they kill cancer. They cannot be taken daily and research points to far lower doses than cancer treatment

Vorinostat is a pan-HDAC inhibitor of sorts, inhibiting HDACs 1, 2, 3, 8, 9 and more to one degree or another (mostly Class I, some Class II).

Neurostat (unknown structure, few studies) and Crebinostat (known structure, few studies) are HDAC inhibitors meant directly for memory and fear extinction, but are more expensive and harder to find than vorinostat. There are many other HDAC inhibitors, mostly used for specific types of cancer, but they are either much more expensive or not as useful

Butyrate is also an HDAC inhibitor and it is a waste product of your gut bacteria. This can be boosted, but is difficult because of the diet requirements to do so.

HDAC inhibitors are currently being research for fear extinction, and other novel uses this is because HDAC has a very novel mechanism of action which allows genes to be turned on when they should be turned off.

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“Research in 2013 supporting the HDAC - fear extinction hypothesis.

Vorinostat ameliorates impaired fear extinction possibly via the hippocampal NMDA-CaMKII pathway in an animal model of posttraumatic stress disorder.

RESULTS: Systemic administration of vorinostat with extinction training significantly enhanced fear extinction in SPS rats as compared with the controls. Furthermore, vorinostat enhanced the hippocampal levels of NR2B and calcium/calmodulin kinase II (CaMKII) α and β proteins, accompanied by increases in the levels of acetylated histone H3 and H4. CONCLUSIONS: These findings suggest that vorinostat ameliorated the impaired fear extinction in SPS rats, and this effect was associated with an increase in histone acetylation and thereby enhancement of NR2B and CaMKII in the hippocampus. Our results may provide new insight into the molecular and therapeutic mechanisms of PTSD.

How Does HDAC Inhibition Help Extinguish Fear

Fear experience is created after repeated exposure of traumatic short-term memory, happening repeatedly which then get's turned into long-term memory. If the experience is exceptionally powerful or emotional, or strongly associated with all other memories, we can't get past it.

When fearful experiences are created when are young it ends up being associated with all our other memories, which makes them exceptionally powerful, the younger you are when the memory is imprinted the stronger an impression it will leave on you.

Long-term memories are created with BDNF, this is known as consolidation. For BDNF to happen, DNA transaction has to take place.

Fear exists as a memory like any other, it is contextual in that it is linking two things together like getting an electric shock everytime a piano is heard.

In the above case, one memory exists for the piano and another memory exists for the electric shock. 

Importantly, every time a long-term memory is recalled it is reactivated, opened up again to transaction and then reconsolidated through transcription by BDNF, exactly the same way it was first turned into a long-term memory.


This moment of recall opens up a window where the context can be modified and makes the recall memory stronger.

So in our example, when the piano and electric shock happens together say 10 times, eventually the link will be strong enough to be paralyzing. You can hear the piano only and still get shit scared about an electric shock.

Long-term fear memory is very hard to overcome, the older a fear memory the harder is is to use clinical fear extinction methods to overcome fear.

This is particularly troublesome when recalling the memory itself strengthens the long-term memory, when the fear experience is traumatizing to the point where it overtakes any sort of realization that there is no actual threat.

So bullying, child abuse, hazing, soldiers returning from war all of these are setups for irreversible learned fear and helplessness.

Here is where HDAC inhibitors come into play - The window of reactivation isn't long enough to allow an update to the fear memory.

HDAC inhibitors open up the gene editing window, so we can associate the trigger of the fear e.g. loud bangs into something completely non-threatening.

You are not getting rid of the memory, but downplaying it by associating with the present instead of associating the trigger with past traumas. As recalling is a self-feedback loop, when you downplay it the fear memory gets recalled less often, thus preventing the cycle of the fear getting worst and worst.

By the way, learned fear/helplessness is evolutionary design. Learned Fear was extremely beneficial for humans to avoid certain death, even if the threat is no longer there, the fact is the threat used to be there means it was safer all together all together in the caveman days. In modern age, humans can afford to take a lot of risks (which don't have the punishment of death or exile) and is often beneficial to do so.

The HDAC inhiitor holds open the transcription window during the memory formation, enabling you to reevaluate old memories. You feel like you have no emotional baggage attached the present because the fear is now being connected to you at that moment rather than the past. This allows interesting possibilities to fear extinction but also other memory enhancing effects.

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