38 replies to this topic

[musicman4534]

Hello hello! This thread is to discuss and collect information on HDAC inhibition, its effects, how it works, its safety, and how to best use it. We should also discuss the various HDAC inhibitors, like vorinostat, dosages, methods, etc.

 

To start off, I wrote an introductory article on HDAC inhibitors and how they relate to nootropics enthusiasts here.

 

I linked to a couple articles on HDAC inhibition from my article that also act as a great introduction to HDAC inhibition used toward memory, learning and fear extinction. Here they are.

 

Things I wish to accomplish in this thread include posting studies on and discussing the mechanics of how HDAC inhibition works, the mechanisms of how long-term memories are formed, how fear and anxiety memories are different than other memories, and explanations of how HDAC inhibition works for specific effects. Since HDACi is a new subject and operates differently in the body than most other nootropics (and other drugs in general for that matter), I think explaining the mechanics behind how they work can be useful for those that are curious. Otherwise, we will hash out the effects and uses of various HDAC inhibitors as they come up and are used more anyway. So far under ten people in the nootropics community have used these incredibly unique drugs, so the story and feel of what they are is not very solidified yet, but as more people use them we'll get a good feel of what they do, how they act and what they're good for. Luckily, we actually have a good bit of in-depth studies done on the subject to back our experimenting down to the exact biochemical processes taking place. It is looking like it will be a very promising field of research.

 

For those of you that are new to doing more in-depth research into compounds and mechanisms, I use PubMed for all my research. What I do is I search for a topic, say HDAC inhibitor fear extinction, I read an article I like (or skim), and then either find an article this one lists in its sources, or just go back to my search and find another one. Unfortunately I wasn't thinking enough ahead and didn't copy all the articles I read on HDAC inhibition. Hence, one of the reason for this thread... a place where I and we can collect articles, anything, on HDAC inhibition, as a sort of easy peasy reference that people can come to for information.

 

I will just say one thing to start things off before I head to bed about HDAC inhibition's uniqueness as far as nootropics go... HDAC inhibition is very different in the way it works compared to the way most if not all other nootropics work. Most nootropics work through things like supplementation, like Alpha-GPC, receptor binding, binding to other membrane proteins like a transporter, as a ligand where it changes the way a protein acts, or even as a transcription factor where it can bind directly to DNA affecting the transcription of genes. The unique thing about HDAC inhibition is that it affects things after transcription has already started taking place. DNA must loosen from histones (what DNA is wrapped around and organized on) to be transcribed, and then when transcription should stop HDAC comes along and tightens the DNA back onto the histone (a very simplified explanation...). By blocking a bit of HDAC using an HDAC inhibitor, we can lengthen the amount of time transcription takes place, strengthening the effect. This is how people have child-like learning abilities while on an HDAC inhibitor. It is also how it can extinguish fear, although there are other factors affecting this as well, which have been briefly talked about elsewhere but we'll get to here too. HDAC is getting at the core of transcription, increasing it directly (and somewhat selectively...). This is why HDAC inhibitors are unique and deserve our attention, as well as other epigenetic modulators like the sirtuins (a type of HDAC inhibitor) or DNMT inhibitors, but only HDAC inhibitors are implicated strongly in long-term memory and fear extinction.

[gamesguru]

Table 1

Common HDAC, HAT and DNMT modulators derived from natural sources

Natural inhibitor References

HDAC    Allyl mercaptan Nian et al. (2008)  Amamistatin Fennell and Miller (2007)  Apicidin Darkin-Rattray et al. (1996)  Azumamide E Maulucci et al. (2007)  Caffeic acid Waldecker et al. (2008)  Chlamydocin Brosch et al. (1995)  Chlorogenic acid Bora-Tatar et al. (2009)  Cinnamic acid Bora-Tatar et al. (2009)  Coumaric/hydroxycinnamic acid Waldecker et al. (2008)  Curcumin Bora-Tatar et al. (2009)  Depudecin Kwon et al. (1998)  Diallyl disulfide Lea et al. (1999)  Equol Hong et al. (2004)  Flavone Bontempo et al. (2007)  Genistein Kikuno et al. (2008)  Histacin Haggarty et al. (2003)  Isothiocyanates Ma et al. (2006)  Largazole Ying et al. (2008)  Pomiferin Son et al. (2007)  Psammaplin Pina et al. (2003)  SAHA (Vorinostat) Richon et al. (1998)  S-allylmercaptocysteine Lea et al. (2002)  Sulforaphane Myzak et al. (2004)  Trapoxin (Kijima et al. 1993)  Ursolic acid Chen et al. (2009)  Zerumbone Chung et al. (2008)

HAT  Allspice Lee et al. (2007)  Anarcardic acid Balasubramanyam et al. (2003), Ghizzoni et al. (2010)  EGCG Choi et al. (2009a)  Curcumin Balasubramanyam et al. (2004), Marcu et al. (2006)  Gallic acid Choi et al. (2009b)  Garcinol Balasubramanyam et al. (2004)  Quercetin Ruiz et al. (2007)  Sanguinarine Selvi et al. (2009)  Plumbagin Ravindra et al. (2009)

DNMT  Genistein Day et al. (2002)  EGCG Fang et al. (2003)  Psammaplins Pina et al. (2003)  Quercetin, fisetin, myricetin Lee et al. (2005)  Caffeic acid Lee and Zhu (2006)  Chlorogenic acid Lee and Zhu (2006)  Curcumin Moiseeva et al. (2007)  Parthenolide Liu et al. (2009)  Mahanine Sheikh et al. (2010)

SAHA Suberoylanilide hydroxamic acid, EGCG epigallocatechin gallate

 

taken from: "Epigenetics and memory: causes, consequences and treatments for post-traumatic stress disorder and addiction"

Epigenetic mechanisms have similarly been implicated in drug addiction. Both acute and chronic cocaine administration increase histone acetylation on H3 and H4 in the NAc, a critical brain region associated with reward (Kumar et al. 2005). Mice that lack class 1 HDAC1, but not HDAC2 or HDAC3, in the NAc specifically show deficits in cocaine-induced locomotor sensitization (Kennedy et al. 2013). Knockout of HDAC1 in the striatum attenuates amphetamine-induced desensitization of the c-fos gene, an immediate early response gene that is rapidly induced in the striatum following acute exposure to psychostimulants (Renthal et al. 2008). Epigenetic changes have been implicated in the transition from drug use to drug addiction, as well as in chronic stress, through the activity of HDAC5 (Renthal et al. 2007). Mice that received site-specific injections of the HDAC class I and II inhibitor suberoylanilide hydroxamic acid (SAHA) to the NAc during place conditioning show enhancements in cocaine-induced CPP (Renthal et al. 2007). This group also found that a single injection of cocaine in mice chronically exposed to cocaine induced HDAC5 expression, an effect not present following a single dose of cocaine in naïve mice. Conversely, overexpression of HDAC5 using HSV-mediated transgene expression attenuates cocaine-induced CPP (Renthal et al. 2007). Similarly, chronic, but not acute, social defeat downregulates Hdac5 mRNA in the NAc (Renthal et al. 2007). Taken together, these findings strongly suggest that HDAC5 regulates behavioral responses to cocaine.

 

DNA methylation is also involved in modulating responses to drugs of abuse. DNMT3a has been found to be upregulated 4 h following both acute and chronic cocaine administration, but is downregulated 24 h later (LaPlant et al. 2010). Injection of the DNA methylation inhibitor RG108 to the NAc enhanced cocaine-induced CPP and cocaine-induced locomotor sensitivity at a dose that decreased methylation globally (LaPlant et al. 2010). Conversely, viral-mediated overexpression of DNMT3a in the NAc attenuated cocaine-induced CPP (LaPlant et al. 2010). Epigenetic regulation has also been observed in experiments looking at non-psychostimulants, including heroin. Heroin induces phosphoacetylation of H3 in the NAc, and intra-accumbal injection of TSA increases heroin-induced CPP, suggesting increased reward salience (Sheng et al. 2011).

 

Both stress and exposure to drugs of abuse induce epigenetic changes that result in persistent behavioral changes, some of which may contribute to the formation of a drug addiction or a stress-related psychiatric disorder. It is therefore of great interest to find new therapeutic options to treat these disorders, and the use of agents that promote extinction as a promising new class of drugs.

 

Nat Neurosci. 2010 Nov; 13(11): 1319–1323.

DNA methylation and Memory Formation

Jeremy J. Day and J. David Sweatt

 

Introduction

Memory formation and storage require long-lasting changes within memory-related neuronal circuits. Recent evidence indicates that DNA methylation may serve as a contributing mechanism in memory formation and storage. These emerging findings both suggest a role for an epigenetic mechanism in learning and long-term memory maintenance, and raise apparent conundrums and questions. For example, it is unclear how DNA methylation might be reversed during the formation of a memory, how changes in DNA methylation alter neuronal function to promote memory formation, and how DNA methylation patterns differ between neuronal structures to enable both consolidation and storage of memories. This perspective will evaluate the existing evidence supporting a role for DNA methylation in memory, discuss how DNA methylation may affect genetic and neuronal function to contribute to behavior, propose several future directions for the emerging subfield of neuroepigenetics, and begin to address some of the broader implications of this work.

 

J Neurosci. 2013 Apr 10;33(15):6423-33. doi: 10.1523/JNEUROSCI.5107-12.2013.

Phosphorylation of cofilin regulates extinction of conditioned aversive memory via AMPAR trafficking.

Wang Y¹, Dong Q, Xu XF, Feng X, Xin J, Wang DD, Yu H, Tian T, Chen ZY.

 

Abstract

Actin dynamics provide an important mechanism for the modification of synaptic plasticity, which is regulated by the actin depolymerizing factor (ADF)/cofilin. However, the role of cofilin regulated actin dynamics in memory extinction process is still unclear. Here, we observed that extinction of conditioned taste aversive (CTA) memory led to temporally enhanced ADF/cofilin activity in the infralimbic cortex (IrL) of the rats. Moreover, temporally elevating ADF/cofilin activity in the IrL could accelerate CTA memory extinction by facilitating AMPAR synaptic surface recruitment, whereas inhibition of ADF/cofilin activity abolished AMPAR synaptic surface trafficking and impaired memory extinction. Finally, we observed that ADF/cofilin-regulated synaptic plasticity was not directly coupled to morphological changes of postsynaptic spines. These findings may help us understand the role of ADF/cofilin-regulated actin dynamics in memory extinction and suggest that appropriate manipulating ADF/cofilin activity might be a suitable way for therapeutic treatment of memory disorders.

 

Neurobiol Learn Mem. 2013 Oct; 105: 107–116.

The ubiquitin–proteasome system as a critical regulator of synaptic plasticity and long-term memory formation

Timothy J. Jarome and Fred J. Helmstetter^*

 

Abstract

Numerous studies have supported the idea that de novo protein synthesis is critical for synaptic plasticity and normal long-term memory formation. This requirement for protein synthesis has been shown for several different types of fear memories, exists in multiple brain regions and circuits, and is necessary for different stages of memory creation and storage. However, evidence has recently begun to accumulate suggesting that protein degradation through the ubiquitin–proteasome system is an equally important regulator of memory formation. Here we review those recent findings on protein degradation and memory formation and stability and propose a model explaining how protein degradation may be contributing to various aspects of memory and synaptic plasticity. We conclude that protein degradation may be the major factor regulating many of the molecular processes that we know are important for fear memory formation and stability in the mammalian brain.

 

[musicman4534]

Here are some articles and studies focusing on HDAC inhibition's implications with fear extinction, PTSD, and general mental well-being, long-term memory enhancement aside, all which can be translated to address its implications in other fear-based problems like anxiety, avoidance, or even types of depression and age-related problems as the second study mentions.

 

 

HDAC inhibitors as cognitive enhancers in fear, anxiety and trauma therapy: where do we stand?

 

A novel strategy to treat anxiety and fear-related disorders such as phobias, panic and PTSD (post-traumatic stress disorder) is combining CBT (cognitive behavioural therapy), including extinction-based exposure therapy, with cognitive enhancers. By targeting and boosting mechanisms underlying learning, drug development in this field aims at designing CBT-augmenting compounds that help to overcome extinction learning deficits, promote long-term fear inhibition and thus support relapse prevention. Progress in revealing the role of epigenetic regulation of specific genes associated with extinction memory generation has opened new avenues in this direction. The present review examines recent evidence from pre-clinical studies showing that increasing histone acetylation, either via genetic or pharmacological inhibition of HDACs (histone deacetylases) by e.g. vorinostat/SAHA (suberoylanilide hydroxamic acid), entinostat/MS-275, sodium butyrate, TSA (trichostatin A) or VPA (valproic acid), or by targeting HATs (histone acetyltransferases), augments fear extinction and, importantly, generates a long-term extinction memory that can protect from return of fear phenomena. The molecular mechanisms and pathways involved including BDNF (brain-derived neurotrophic factor) and NMDA (N-methyl-D-aspartate) receptor signalling are just beginning to be revealed. First studies in healthy humans are in support of extinction-facilitating effects of HDAC inhibitors. Very recent evidence that HDAC inhibitors can rescue deficits in extinction-memory-impaired rodents indicates a potential clinical utility of this approach also for exposure therapy-resistant patients. Important future work includes investigation of the long-term safety aspects of HDAC inhibitor treatment, as well as design of isotype(s)-specific inhibitors. Taken together, HDAC inhibitors display promising potential as pharmacological adjuncts to augment the efficacy of exposure-based approaches in anxiety and trauma therapy.

→ source (external link)

 

 

Histone deacetylases in memory and cognition.

Over the past 30 years, lysine acetylation of histone and nonhistone proteins has become established as a key modulator of gene expression regulating numerous aspects of cell biology. Neuronal growth and plasticity are no exception; roles for lysine acetylation and deacetylation in brain function and dysfunction continue to be uncovered. Transcriptional programs coupling synaptic activity to changes in gene expression are critical to the plasticity mechanisms underlying higher brain functions. These transcriptional programs can be modulated by changes in histone acetylation, and in many cases, transcription factors and histone-modifying enzymes are recruited together to plasticity-associated genes. Lysine acetylation, catalyzed by lysine acetyltransferases (KATs), generally promotes cognitive performance, whereas the opposing process, catalyzed by histone lysine deacetylases (HDACs), appears to negatively regulate cognition in multiple brain regions. Consistently, mutation or deregulation of different KATs or HDACs contributes to neurological dysfunction and neurodegeneration. HDAC inhibitors have shown promise as a treatment to combat the cognitive decline associated with aging and neurodegenerative disease, as well as to ameliorate the symptoms of depression and posttraumatic stress disorder, among others. In this review, we discuss the evidence for the roles of HDACs in cognitive function as well as in neurological disorders and disease. In particular, we focus on HDAC2, which plays a central role in coupling lysine acetylation to synaptic plasticity and mediates many of the effects of HDAC inhibition in cognition and disease.

→ source (external link)

 

Novel therapeutic approach for the treatment of post-traumatic stress disorder (PTSD): facilitating fear extinction.

 

Pharmacological agents enhancing fear extinction may be promising tools for the treatment of PTSD. Histone acetylation is involved in memory formation, and histone deacetylase (HDAC) inhibitors increase histone acetylation and subsequently enhance fear extinction. In this study, we examined whether vorinostat, an HDAC inhibitor, facilitated fear extinction, using a contextual fear conditioning (FC) paradigm. We found that vorinostat facilitated fear extinction. Next, the levels of global acetylated histone were measured by Western blotting. We also assessed the effect of vorinostat on the hippocampal levels of NMDA receptor mRNA by real-time quantitative PCR (RT-PCR). The levels of acetylated histone and NR2B mRNA, but not NR1 or NR2A mRNA, were elevated in the hippocampus 2 h after administration of vorinostat. We investigated the levels of acetylated histones and phospho-CREB (p-CREB) binding at the promoter of the NR2B gene using the chromatin immunoprecipitation (ChIP) assay followed by RT-PCR. The levels of acetylated histone and the binding of p-CREB to its binding site at the promoter of the NR2B gene were increased. These findings suggest that vorinostat in conjunction with exposure therapy can be a promising new avenue for the treatment of PTSD.

→ source (external link)

 

 

Valproic acid effects in the hippocampus and prefrontal cortex in an animal model of post-traumatic stress disorder.

Reactive oxygen species (ROS) and pro-inflammatory cytokines (PIC) are upregulated in post-traumatic stress disorder (PTSD). Histone deacetylase inhibitors (HDACi) modify genetic transcription and can diminish ROS and PIC escalation. They can also modulate levels of neurotransmitters such as catecholamines and serotonin (5-HT). Thus, this study sought to analyze the effects of the HDACi valproic acid (VA) on oxidative stress, inflammation, and neurotransmitter modulation via a predator exposure/psychosocial stress animal model of PTSD. PTSD-like effects were induced in male Sprague-Dawley rats (n=6/group×4 groups). The rats were secured in Plexiglas cylinders and placed in a cage with a cat for 1h on days 1, 11, and 40 of a 40-day stress regimen. PTSD rats were also subjected to psychosocial stress via daily cage cohort changes. At the conclusion of the stress regimen, the treatment group (PTSD+VA) and control group (Control+VA) rats were given VA in their drinking water for 30 days. The rats were then euthanized and their brains were dissected to remove the hippocampus and prefrontal cortex (PFC). Whole blood was collected to assess systemic oxidative stress. ROS and PIC mRNA and protein elevation in the PTSD group were normalized with VA. Anxiety decreased in this group via improved performance on the elevated plus-maze (EPM). No changes were attributed to VA in the control group, and no improvements were noted in the vehicle groups. Results indicate VA can attenuate oxidative stress and inflammation, enhance fear extinction, and correct neurotransmitter aberrancies in a rat model of PTSD.

→ source (external link)

 

On the resilience of remote traumatic memories against exposure therapy-mediated attenuation

How to attenuate traumatic memories has long been the focus of intensive research efforts, as traumatic memories are extremely persistent and heavily impinge on the quality of life. Despite the fact that traumatic memories are often not readily amenable to immediate intervention, surprisingly few studies have investigated treatment options for remote traumata in animal models. The few that have unanimously concluded that exposure therapy-based approaches, the most successful behavioral intervention for the attenuation of recent forms of traumata in humans, fail to effectively reduce remote fear memories. Here, we provide an overview of these animal studies with an emphasis on why remote traumatic memories might be refractory to behavioral interventions: A lack of neuroplasticity in brain areas relevant for learning and memory emerges as a common denominator of such resilience. We then outline the findings of a recent study in mice showing that by combining exposure therapy-like approaches with small molecule inhibitors of histone deacetylases (HDACis), even remote memories can be persistently attenuated. This pharmacological intervention reinstated neuroplasticity to levels comparable to those found upon successful attenuation of recent memories. Thus, HDACis—or any other agent capable of heightening neuroplasticity—in conjunction with exposure therapy-based treatments might constitute a promising approach to overcome remote traumata.

→ source (external link)

 

 

[musicman4534]

 

taken from: "Epigenetics and memory: causes, consequences and treatments for post-traumatic stress disorder and addiction"

Epigenetic mechanisms have similarly been implicated in drug addiction. Both acute and chronic cocaine administration increase histone acetylation on H3 and H4 in the NAc, a critical brain region associated with reward (Kumar et al. 2005). Mice that lack class 1 HDAC1, but not HDAC2 or HDAC3, in the NAc specifically show deficits in cocaine-induced locomotor sensitization (Kennedy et al. 2013). Knockout of HDAC1 in the striatum attenuates amphetamine-induced desensitization of the c-fos gene, an immediate early response gene that is rapidly induced in the striatum following acute exposure to psychostimulants (Renthal et al. 2008). Epigenetic changes have been implicated in the transition from drug use to drug addiction, as well as in chronic stress, through the activity of HDAC5 (Renthal et al. 2007). Mice that received site-specific injections of the HDAC class I and II inhibitor suberoylanilide hydroxamic acid (SAHA) to the NAc during place conditioning show enhancements in cocaine-induced CPP (Renthal et al. 2007). This group also found that a single injection of cocaine in mice chronically exposed to cocaine induced HDAC5 expression, an effect not present following a single dose of cocaine in naïve mice. Conversely, overexpression of HDAC5 using HSV-mediated transgene expression attenuates cocaine-induced CPP (Renthal et al. 2007). Similarly, chronic, but not acute, social defeat downregulates Hdac5 mRNA in the NAc (Renthal et al. 2007). Taken together, these findings strongly suggest that HDAC5 regulates behavioral responses to cocaine.

 

DNA methylation is also involved in modulating responses to drugs of abuse. DNMT3a has been found to be upregulated 4 h following both acute and chronic cocaine administration, but is downregulated 24 h later (LaPlant et al. 2010). Injection of the DNA methylation inhibitor RG108 to the NAc enhanced cocaine-induced CPP and cocaine-induced locomotor sensitivity at a dose that decreased methylation globally (LaPlant et al. 2010). Conversely, viral-mediated overexpression of DNMT3a in the NAc attenuated cocaine-induced CPP (LaPlant et al. 2010). Epigenetic regulation has also been observed in experiments looking at non-psychostimulants, including heroin. Heroin induces phosphoacetylation of H3 in the NAc, and intra-accumbal injection of TSA increases heroin-induced CPP, suggesting increased reward salience (Sheng et al. 2011).

 

Both stress and exposure to drugs of abuse induce epigenetic changes that result in persistent behavioral changes, some of which may contribute to the formation of a drug addiction or a stress-related psychiatric disorder. It is therefore of great interest to find new therapeutic options to treat these disorders, and the use of agents that promote extinction as a promising new class of drugs.

 

Good find. This leads me to my findings on how HDAC inhibition can quicken the onset of addiction (just don't take an HDAC inhibitor while you're getting high), but can also enhance cessation of addiction and addictive behaviors, not only through it's enhancements to learning and memory but also it's effects on MAO, COMT, neurotransmitters and transporters, etcetera. An HDAC inhibitor is a great candidate for helping coming off cocaine, and, from anecdotal reports, coffee as well. There perhaps are other applications as well with the catecholamine systems in general, monoamines, or GABA modulators like phenibut. I'll look for studies regarding these. Here are some having to do with cocaine.

 

 

The Role of Histone Acetylation in Cocaine-Induced Neural Plasticity and Behavior

 

Conclusion:

HDAC disruption by repeated cocaine use may be a key step in the transition from recreational cocaine use to compulsive drug-taking behavior. Conversely, facilitating extinction of drug-seeking behavior via HDAC inhibition, resulting in robust and persistent extinction, may yield an exciting and novel approach to therapy. Thus, continuing to examine the epigenetic mechanisms underlying the actions of drugs of abuse is paramount to understanding fundamental mechanisms as well as guiding new therapeutic approaches.

→ source (external link)

 

The Neural Rejuvenation Hypothesis of Cocaine Addiction

A leading hypothesis guiding current molecular and cellular research of drug addiction conceptualizes key aspects of addiction as a form of memory, in which common neuroplasticity mechanisms that mediate normal learning and memory processes are “hijacked” by exposure to drugs of abuse to produce pathologic addiction-related memories. Such addiction-related memories are particularly robust and long-lasting and once formed, less amenable to updating. Here, we propose the Neural Rejuvenation Hypothesis of Cocaine Addiction: that repeated exposure to drugs of abuse induces some plasticity mechanisms that are normally associated with brain development within the brain’s reward circuitry, which mediate the highly efficient and unusually stable memory abnormalities that characterize addiction.

→ source (external link)

 

HDAC3-selective inhibitor enhances extinction of cocaine-seeking behavior in a persistent manner

Nonspecific histone deacetylase (HDAC) inhibition has been shown to facilitate the extinction of drug-seeking behavior in a manner resistant to reinstatement. A key open question is which specific HDAC is involved in the extinction of drug-seeking behavior. Using the selective HDAC3 inhibitor RGFP966, we investigated the role of HDAC3 in extinction and found that systemic treatment with RGFP966 facilitates extinction in mice in a manner resistant to reinstatement. We also investigated whether the facilitated extinction is related to the enhancement of extinction consolidation during extinction learning or to negative effects on performance or reconsolidation. These are key distinctions with regard to any compound being used to modulate extinction, because a more rapid decrease in a defined behavior is interpreted as facilitated extinction. Using an innovative combination of behavioral paradigms, we found that a single treatment of RGFP966 enhances extinction of a previously established cocaine-conditioned place preference, while simultaneously enhancing long-term object-location memory within subjects. During extinction consolidation, HDAC3 inhibition promotes a distinct pattern of histone acetylation linked to gene expression within the infralimbic cortex, hippocampus, and nucleus accumbens. Thus, the facilitated extinction of drug-seeking cannot be explained by adverse effects on performance. These results demonstrate that HDAC3 inhibition enhances the memory processes involved in extinction of drug-seeking behavior.

→ source (external link)

[musicman4534]

Vorinostat reverses GABA hyposensitivity and repairs cognitive pathways after alcoholism. Could then probably be used to reverse and repair GABA desensitization after phenibut use as well.

 

Hyposensitivity to gamma-aminobutyric acid in the ventral tegmental area during alcohol withdrawal: reversal by histone deacetylase inhibitors.

Putative dopaminergic (pDAergic) ventral tegmental area (VTA) neurons have an important role in alcohol addiction. Acute ethanol increases the activity of pDAergic neurons, and withdrawal from repeated ethanol administration produces a decreased sensitivity of pDAergic VTA neurons to GABA. Recent studies show that behavioral changes induced by chronic alcohol are reversed by inhibitors of histone deacetylases (HDACs). Whether HDAC-induced histone modifications regulate changes in GABA sensitivity of VTA pDAergic neurons during withdrawal is unknown. Here, we investigated modulation of withdrawal-induced changes in GABA sensitivity of pDAergic VTA neurons by HDAC inhibitors (HDACi), and also measured the levels of HDAC2, histone (H3-K9) acetylation, and GABA-Aα1 receptor (GABA (A-α1) R) subunit in VTA during ethanol withdrawal. Mice were injected intraperitoneally (ip) with either ethanol (3.5 g/kg) or saline twice daily for 3 weeks. In recordings from pDAergic VTA neurons in brain slices from ethanol-withdrawn mice, sensitivity to GABA (50-500 μM) was reduced. In brain slices from ethanol-withdrawn mice incubated with the HDACi SAHA (vorinostat) or trichostatin A (TSA) for 2 h, the hyposensitivity of pDAergic VTA neurons to GABA was significantly attenuated. There was no effect of TSA or SAHA on GABA sensitivity of pDAergic VTA neurons from saline-treated mice. In addition, ethanol withdrawal was associated with an increase in levels of HDAC2 and a decrease in histone (H3-K9) acetylation and levels of GABA (A-α1) R subunits in the VTA. Therefore, blockade of upregulation of HDAC2 by HDACi normalizes GABA hyposensitivity of pDAergic neurons developed during withdrawal after chronic ethanol treatment, which suggests the possibility that inhibition of HDACs can reverse ethanol-induced neuroadaptational changes in reward circuitry.

→ source (external link)

 

Reversal of deficits in dendritic spines, BDNF, and Arc expression in the amygdala during alcohol dependence by HDAC inhibitor treatment

Development of anxiety-like behaviors during ethanol withdrawal has been correlated with increased histone deacetylase (HDAC) activity and decreased brain-derived neurotrophic factor (BDNF) and activity-regulated cytoskeleton-associated protein (Arc) gene expression in the amygdala. Furthermore, HDAC-mediated histone modifications play a role in synaptic plasticity. In this study we used the HDAC inhibitor trichostatin A (TSA) to determine whether HDAC inhibition could prevent ethanol withdrawal-induced deficits in dendritic spine density (DSD), BDNF or Arc expression in the amygdala of rats. It was found that decreased BDNF and Arc expression in the central (CeA) and medial nucleus of amygdala (MeA), observed during withdrawal after chronic ethanol exposure, were normalized following acute TSA treatment. TSA treatment was also able to attenuate anxiety-like behaviors during ethanol withdrawal and correct the observed decrease in DSD in the CeA and MeA of ethanol-withdrawn rats. Taken together, these findings demonstrate that correcting the deficits in histone acetylation through TSA treatment also amends downstream synaptic plasticity-related deficits such as BDNF and Arc expression, and DSD in the CeA and MeA as well as attenuates anxiety-like behaviors in rats during withdrawal after chronic ethanol exposure.

→ source (external link)

 

The Class I-Specific HDAC Inhibitor MS-275 Decreases Motivation to Consume Alcohol and Relapse in Heavy Drinking Rats.

BACKGROUND:
New strategies for the treatment of alcohol dependence are a pressing need, and recent evidence suggests that targeting enzymes involved in epigenetic mechanisms seems to have great potential. Among these mechanisms, alteration of histone acetylation by histone deacetylases is of great importance for gene expression and has also been implicated in addiction. Here, we examined whether intra-cerebroventricular administration of MS-275, a class I-specific histone deacetylase inhibitor, could alter ethanol self-administration, motivation to consume ethanol, and relapse in heavy drinking rats.
METHODS:
Male Long Evans rats trained to self-administer high levels of ethanol received intra-cerebroventricular micro-infusions of MS-275 (250 µM, 500 µM, and 1000 µM) 3 hours prior to the self-administration sessions.
RESULTS:
First, we demonstrated that intra-cerebroventricular infusion of MS-275 increases acetylation of Histone 4 within the nucleus accumbens nucleus accumbens and the dorsolateral striatum. Second, we observed that MS-275 decreases ethanol self-administration by about 75%. We found that 2 consecutive daily injections are necessary to decrease ethanol self-administration. Additionally, the dose-response curve test indicated that MS-275 has a U-shape effect on ethanol self-administration with the dose of 500 µM as the most efficient dose. Furthermore, we showed that MS-275 also diminished the motivation to consume ethanol (25% decrease), and finally, we demonstrated that MS-275 reduced relapse (by about 50%) and postponed reacquisition even when the treatment was stopped.
CONCLUSIONS:
Our study confirms the potential therapeutic interest of targeting epigenetic mechanisms in excessive alcohol drinking and strengthens the interest of focusing on specific isoforms of histone deacetylases.

→ source (external link)

 

Edited by musicman4534, 15 November 2016 - 04:39 AM.

[musicman4534]

Histone deacetylase inhibitors up-regulate astrocyte GDNF and BDNF gene transcription and protect dopaminergic neurons.

 

Parkinson's disease (PD) is characterized by the selective and progressive loss of dopaminergic (DA) neurons in the midbrain substantia nigra. Currently, available treatment is unable to alter PD progression. Previously, we demonstrated that valproic acid (VPA), a mood stabilizer, anticonvulsant and histone deacetylase (HDAC) inhibitor, increases the expression of glial cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF) in astrocytes to protect DA neurons in midbrain neuron-glia cultures. The present study investigated whether these effects are due to HDAC inhibition and histone acetylation. Here, we show that two additional HDAC inhibitors, sodium butyrate (SB) and trichostatin A (TSA), mimic the survival-promoting and protective effects of VPA on DA neurons in neuron-glia cultures. Similar to VPA, both SB and TSA increased GDNF and BDNF transcripts in astrocytes in a time-dependent manner. Furthermore, marked increases in GDNF promoter activity and promoter-associated histone H3 acetylation were noted in astrocytes treated with all three compounds, where the time-course for acetylation was similar to that for gene transcription. Taken together, our results indicate that HDAC inhibitors up-regulate GDNF and BDNF expression in astrocytes and protect DA neurons, at least in part, through HDAC inhibition. This study indicates that astrocytes may be a critical neuroprotective mechanism of HDAC inhibitors, revealing a novel target for the treatment of psychiatric and neurodegenerative diseases.

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[psychejunkie]

Thank you all for these interesting information;

Listing natural, supplements and drugs with HDAC inhibiting property would also be appreciated.

[musicman4534]

Thank you all for these interesting information;
Listing natural, supplements and drugs with HDAC inhibiting property would also be appreciated.

Sure thing, I've looked up natural supplements with HDAC inhibiting properties previously and made a list. I'll track down the studies. There are undoubtably others, but the main ones studied are EGCG, curcumin, resveratrol, and to a lesser extent cocoa extract. Fisetin also modulates HDAC in various ways, but is not a pan-inhibitor (it is a solid DNMT inhibitor though).
 
Curcumin actually promotes HDAC2, but pan-inhibits the others (Class I and II). Because of its HDAC2-promoting attribute, it probably isn't healthy to take curcumin if you're a smoker or have recently smoked. I talked about this in a reddit comment -- more research is needed to confirm, but better safe than sorry.
 
EGCG is the most powerful and thoroughly-inhibiting of the natural HDAC inhibitors that have been studied so far, but even as the most potent HDAC inhibitor on paper, its HDAC-inhibiting effects are still relatively weak, and overshadowed by its other properties, making most natural HDAC inhibitors not useful for the kind of work mentioned in the above studies. You'll get the benefits, but they will be weaker and shorter-lasting. I do encourage people to take natural HDAC inhibitors, though, because, as they are only weak HDAC inhibitors, you can take them everyday and reap the benefits of having some HDAC inhibition daily, along with all the other benefits that come from EGCG, resveratrol, cocoa, etc. supplementation. You won't be able to get the full fear-extinguishing effects, and won't get the full long-term memory enhancing effects. For these to occur, more potent and more selective HDAC inhibition is needed. Even valproate, which is a fairly strong HDAC inhibitor, has too many effects other than HDAC inhibition to make it a good candidate for HDACi work. This is why vorinostat is looked to as a candidate, it is a "clean" HDAC inhibitor. Perhaps stronger natural HDAC-inhibiting compounds will be found in the future.

[RobbieG]

Article on Ketamine as an HDAC inhibitor: http://www.sciencedi...16643281300538X Highlights •

Maternal deprivation lead to behavioral and neurochemical alterations.

•

Ketamine and imipramine were able to reverse depressive behavior of deprived rats.

•

The maternally deprived rats showed increased HDAC activity in nucleus accumbens.

•

Ketamine and imipramine reduced HDAC activity in nucleus accumbens.

[StevesPetRat]

Sure thing, I've looked up natural supplements with HDAC inhibiting properties previously and made a list. I'll track down the studies. There are undoubtably others, but the main ones studied are EGCG, curcumin, resveratrol, and to a lesser extent cocoa extract. Fisetin also modulates HDAC in various ways, but is not a pan-inhibitor (it is a solid DNMT inhibitor though).

It’s actually mentioned in some of the studies linked above, but butyrate is also a HDACi, type 1 and 2, I think, eg: https://www.ncbi.nlm...pubmed/12840228
In my subjective experience, at high doses (6 g+), butyrate had effects similar to vorinostat. I was unaware of the fear extinction research at the time I was trying it, though, so I didn't test a scenario like that directly.

[musicman4534]

@StevesPetRat Yes! Definitely. I talk about Butyrate a little bit in my HDACi article. Try taking it and testing its fear extinction capabilities. From what I've read, dosages high enough to produce strong and lasting fear extinction are too much and cause side effects, but you're still probably going to get the effect, and with repeated dosing could help with the permanency of effect. There are lots of studies on the benefits of butyrate's HDACi effects.

[musicman4534]

 

 

from oldmustysad sent 13 hours ago
You mention in your article about HDAC inhibitors meant directly for memory, do you have any more information on those or links to more resources on classes of HDAC's and their associated proteins?

 

Question I got asked on Reddit and decided to write about it a bit and copy it here.

 

This is an interesting question when it comes to HDAC inhibition, or any type of drug for that matter, because there's selectivity for effect, selectivity for a specific HDAC protein, and selectivity for a body part like the brain. What they found with crebinostat, an HDAC inhibitor meant specifically for cognitive improvement, isn't necessarily a selectivity for a specific body part or effect, but a selectively to inhibit only the HDAC proteins implicated with memory. It inhibits mainly HDAC1, 2, 3, and 6, similarly to vorinostat, but with even more selectivity. It doesn't inhibit HDAC4, 5, 7, and 9 as much. If you want to learn more about what the different HDAC proteins do, I'd start by taking a look at these articles I posted,

 

https://www.dropbox....inI_zh5eUa?dl=0

 

which includes crebinostat's pioneering study. If you'd like to take a closer look at specific HDAC inhibitor effects or HDAC proteins, take a look at the studies in the HDAC discussion thread on Longecity, or go to PubMed, put in a search term like the one I've put in, HDAC6 memory, and sort by relevance. This is a quick and easy way to get into the literature.

 

Other than crebinostat and neurostat, the latter of which the structure is not even known publicly yet, there hasn't been much research done to find HDAC inhibitors that act solely on memory. This is because of the overlap in selectivity regarding specific effects, body parts, and HDAC proteins.

 

Enhancing selectivity for a specific HDAC protein, like HDAC3, isn't enough to narrow it down to only acting in the brain. The HDAC proteins that act on memory, addiction, fear, etcetera also act elsewhere in the body no matter what. These are mainly HDAC1, 2, 3, and 6. Even crebinostat would act elsewhere in the body at higher dosages. There has been a lot of talk and fear about the lack of selectivity for the brain, but before I wrote my HDAC article this was one of the things I looked into.

 

The way I see it is that by taking low dosages we are already increasing selectivity for the brain. We do the same thing with every other drug/nootropic we take for the brain... we take less cocaine, less Huperzine A, less phenibut, less coffee, less Alpha-GPC than we need to to have an appreciable effect anywhere else other than the brain. if we took too much, we'd have severely overblown effects in the brain, and side-effects would begin to appear in the body. Some of the researchers studying HDAC inhibition's cognitive effects mentioned the brain as being "primed for HDAC inhibitor use." This is because the mind is sensitive to the effect. The way HDAC inhibitors are used for cancer is they are prescribed in incredibly high dosages daily, which inhibit nearly 100% of HDAC, hold open the DNA on histones system-wide for a disordinate amount of time, as well as alter HAT/HDAC and other proteins' expression system-wide. A low-dosage, acute dose of an HDAC inhibitor does not inhibit 100% of HDAC, does not hold open histones, and will barely be noticed by our cells, including our brain's, but our *mind* will notice the change in cognition. This is because there only needs to be a small increase in the amount of transcription taking place for the desired effect to occur in our minds. In this way, we're increasing selectivity for our minds by taking lower dosages.

 

In regards to HDAC protein selectivity, the different HDAC proteins overlap in effect. You'll read one study saying HDAC3 in implicated in addiction, then another saying that HDAC2 and 11 are implicated in addiction, and in actuality both are true... HDAC1, 2, 3, possibly 6, 11, and possibly others are all implicated in addiction, as well as DNMT1, which controls methylation. HDAC1, 2, 3, 6, and 11 all have studies linking them to long-term memory, and several are implicated in fear extinction as well... I think that what is important right now is finding an HDAC inhibitor that sticks to inhibiting class I, IIb and IV HDACs, is safe, well-studied, and doesn't have any other effects other than HDAC inhibition. A couple other Longecity users found vorinostat a couple years ago that fits this bill, and after looking into it I fully agree with them.

 

In regards to selectivity of effect, it would be near-impossible, unless we began using weird, specific brain implants that secreted HDAC inhibitors, to separate HDAC inhibition's effects on memory, learning addiction, and fear, because these are all linked to similar mechanisms. HDAC1, 2, 3 and 6 are all implicated. HDAC 6 does stand apart, however, with effects on beta-amyloid plaque and tau fibrils. Crebinostat hasn't been studied nearly as much as vorinostat, and one problem they may find is that it is lacking in certain effects dealing with addiction and fear, as the relationships between HDAC8, 9, 10 and 11 haven't been fully researched. HDAC11 is at least partially implicated in addictive behaviors, so using a more pan-inhibitor like vorinostat may be more beneficial, or a compound somewhat in between crebinostat and vorinostat that also inhibits HDAC8 and 11 to a degree, for example. In a way, the way HDAC proteins are used in the brain already increases selectivity for certain mental processes, mainly the ones I've already described... learning, memory, fear and addiction.

[musicman4534]

HDAC6 ameliorates cognitive decline associated with amyloid beta plaque and tau fibrils.

 

Histone deacetylase 6 inhibition improves memory and reduces total tau levels in a mouse model of tau deposition

→ source (external link)

 

Reducing HDAC6 ameliorates cognitive deficits in a mouse model for Alzheimer's disease

→ source (external link)

 

[musicman4534]

Here are some studies on memory and learning...

 

SAHA attenuates sevoflurane-induced learning and memory impairments in fetal mice.

→ source (external link)

 

A role for histone deacetylases in the cellular and behavioral mechanisms underlying learning and memory

→ source (external link)

 

Histone Deacetylase (HDAC) Inhibitors - Emerging Roles in Neuronal Memory, Learning, Synaptic Plasticity and Neural Regeneration

→ source (external link)

 

Epigenetic Priming of Memory Updating during Reconsolidation to Attenuate Remote Fear Memories

→ source (external link)

[musicman4534]

I briefly mentioned it above with the alcohol studies, but I just made a post on Reddit where I talk a bit more about the possibility of using HDAC inhibitors to reset phenibut tolerance. 
 

 

I've been finding some interesting studies on HDAC inhibitors. One interesting topic that is a current focus of research is HDAC inhibitors' ability to ameliorate cognitive decline related to and prevent the formation of amyloid-beta plaque and tau fibrils. HDAC6 is the protein involved in this. I've also found studies showing that HDAC4, 5, and 11 are implicated in memory and learning to one degree or another, even though most of the older studies don't mention these HDAC proteins at all. This extends the list to at least HDAC1, 2, 3, 4, 5, 6, and 11 affecting learning and memory in some way, the main ones still being HDAC1, 2, 3 and 6. HDAC6 stands out as being perhaps the only non-sirtuin HDAC protein that deals with amyloid plaques and tau fibrils. HDAC1 and 2 are highly implicated in synaptogenesis, whereas HDAC3 is less so, though still a negative regulator of memory formation, fear extinction and addiction cessation.

I found some really interesting studies that I posted in the HDAC discussion thread about how HDAC inhibitors help with addiction cessation and cognitive repair after not only cocaine abuse but alcohol abuse as well. They are able to dramatically reverse GABA hyposensitivity, as well as repair cognitive function and attenuate cravings after alcohol abuse. It looks as if HDAC inhibitors' ability to reverse the effects of alcohol abuse can be extended to phenibut as well. GABA was studied, but not voltage-dependent calcium channels, however, which phenibut also modulates (specifically α2δ-1). But, since ethanol acts as a blocker of voltage-dependent calcium channels, α2δ-1 blocking is necessary in cocaine addiction, and HDAC inhibition attenuates both alcohol and cocaine addiction, it is likely that HDAC inhibitors would be efficacious at fully attenuating phenibut tolerance, both GABA and α2δ-1 included, as well. This hasn't been studied outright and is just my theory, so please take a look and let me know what you think. I posted three studies on this in the HDAC Inhibitor discussion thread, and there were several more beyond those (they got more specific/repetitive). One important thing to note regarding this in practice is that in the HDAC/cocaine studies it is shown that tolerance and addiction are exacerbated when an HDAC inhibitor is taken along with cocaine, so it is important to make this distinction with alcohol/phenibut as well, never taking them with an HDAC inhibitor, and in fact being sure to not even take the HDAC inhibitor the day after taking phenibut as phenibut has such a long half-life. An HDACi would quicken not only the formation of addictive memories around taking a drug but the transcriptional changes that would take place in the brain from taking the drug as well. Likewise, the unlearning of addiction, repair, and return to homeostasis are increased as well when an HDAC inhibitor is taken after drug abuse and during withdrawals, working to elevate the negative effects of withdrawal symptoms as well as lifting the urge to redose (as seen in the studies).

So, it seems that there would be the added benefit of reversing tolerances to certain drugs to doing vorinostat sessions for memory or fear extinction, or the other way around depending on what your goals are.

 

 

Edited by musicman4534, 18 November 2016 - 05:13 AM.

[tolerant]

What if you are already taking a GABA agonist (such any benzodiazepine) and calcium-channel blocker (such as pregabalin), and you're not able to stop because you're on a high dose and will not be able to handle withdrawal? However, you've developed tolerance to the doses you're taking and they are no longer of any use, but you know that to quit you would need to taper for a year or thereabouts. That means you will be taking vorinostat with those drugs. Will vorinostat in this case slowly reset the tolerance, so you're able to withdraw/experience the benefits of these drugs again, or will it exacerbate the tolerance?

Edited by tolerant, 18 November 2016 - 05:52 AM.

[tolerant]

I have found an answer to my question in the above post in the following study. It suggests that HDACi works to reduce ethanol intake in ethanol-dependant rats. That is, HDACi use is not confined to periods of withdrawal, but is effective in facilitating withdrawal. Although the HDACi used is not vorinostat and the drug of dependence is not a benzodiazepine, I guess (and hope) that the conclusions can be expanded to benzodiazepines (which work through GABA agonism as does ethanol).

 

The histone deacetylase inhibitor sodium butyrate decreases excessive ethanol intake in dependent animals.

 

Converging evidence indicates that epigenetic mechanisms are involved in drug addiction, and that enzymes involved in chromatin remodeling may represent interesting targets in addiction treatment. No study has addressed whether histone deacetylase (HDAC) inhibitors (HDACi) can reduce excessive ethanol intake or prevent relapse in alcohol-dependent animals. Here, we assessed the effects of two HDACi, sodium butyrate (NaB) and MS-275, in the operant ethanol self-administration paradigm in dependent and non-dependent rats. To characterize some of the epigenetic mechanisms associated with alcohol dependence and NaB treatment, we measured the levels of histone H3 acetylation in different brain areas of dependent and non-dependent rats, submitted or not to NaB treatment. Our results demonstrated that (1) NaB and MS-275 strongly decreased excessive alcohol intake of dependent rats in the operant ethanol self-administration paradigm but not of non-dependent rats; (2) NaB reduced excessive drinking and prevented the escalation of ethanol intake in the intermittent access to 20% ethanol paradigm; and (3) NaB completely blocked the increase of ethanol consumption induced by an alcohol deprivation, thus demonstrating a preventive effect of NaB on relapse. The mapping of cerebral histone H3 acetylation revealed a hyperacetylation in the amygdala and cortical areas in dependent rats. Interestingly, NaB did not exacerbate the hyperacetylation observed in these regions, but instead restored it, specifically in cortical areas. Altogether, our results clearly demonstrated the efficacy of NaB in preventing excessive ethanol intake and relapse and support the hypothesis that HDACi may have a potential use in alcohol addiction treatment.

 

 

[musicman4534]

I have found an answer to my question in the above post in the following study. It suggests that HDACi works to reduce ethanol intake in ethanol-dependant rats. That is, HDACi use is not confined to periods of withdrawal, but is effective in facilitating withdrawal. Although the HDACi used is not vorinostat and the drug of dependence is not a benzodiazepine, I guess (and hope) that the conclusions can be expanded to benzodiazepines (which work through GABA agonism as does ethanol).

 

The histone deacetylase inhibitor sodium butyrate decreases excessive ethanol intake in dependent animals.

 

Converging evidence indicates that epigenetic mechanisms are involved in drug addiction, and that enzymes involved in chromatin remodeling may represent interesting targets in addiction treatment. No study has addressed whether histone deacetylase (HDAC) inhibitors (HDACi) can reduce excessive ethanol intake or prevent relapse in alcohol-dependent animals. Here, we assessed the effects of two HDACi, sodium butyrate (NaB) and MS-275, in the operant ethanol self-administration paradigm in dependent and non-dependent rats. To characterize some of the epigenetic mechanisms associated with alcohol dependence and NaB treatment, we measured the levels of histone H3 acetylation in different brain areas of dependent and non-dependent rats, submitted or not to NaB treatment. Our results demonstrated that (1) NaB and MS-275 strongly decreased excessive alcohol intake of dependent rats in the operant ethanol self-administration paradigm but not of non-dependent rats; (2) NaB reduced excessive drinking and prevented the escalation of ethanol intake in the intermittent access to 20% ethanol paradigm; and (3) NaB completely blocked the increase of ethanol consumption induced by an alcohol deprivation, thus demonstrating a preventive effect of NaB on relapse. The mapping of cerebral histone H3 acetylation revealed a hyperacetylation in the amygdala and cortical areas in dependent rats. Interestingly, NaB did not exacerbate the hyperacetylation observed in these regions, but instead restored it, specifically in cortical areas. Altogether, our results clearly demonstrated the efficacy of NaB in preventing excessive ethanol intake and relapse and support the hypothesis that HDACi may have a potential use in alcohol addiction treatment.

 

Okay yeah, thanks for catching that @tolerant, I thought I read something like that but I couldn't remember where... turns out it was in one of the studies I was referencing haha

 

I also read a story of a long-time coffee drinker having his coffee tolerance disappear when he started an HDACi, and was drinking coffee the entire time, on the HDACi or not. I think cocaine may be unique in this respect because one of the ways cocaine asserts its addictive effects is actually through HDAC, leading cocaine and HDAC inhibitors to interact weirdly with each other.

 

So, it seems that if you're dependent on a GABA agonist and/or calcium channel blocker that vorinostat sessions would help to reset your tolerance to those drugs/facilitate a taper like it does with alcohol, or at least not have any ill effects. (I don't know if your dosages would then have to be lowered if they were tapered up in the beginning at all.) It would then be the same for phenibut... if you've become tolerant of phenibut, taking an HDACi with or without phenibut would help to reverse your phenibut tolerance to at least some degree, in addition to granting you its learning, memory and fear extinction benefits along with. This seems to be at least true for those that have administered daily or have become tolerant, but what effect an HDACi would have on someone taking phenibut for the first time would be I don't know. If the studies hold true for both GABA tolerance and calcium channel blocker tolerance, perhaps occasionally coadministering vorinostat with phenibut would help to stave off the building of phenibut tolerance, something all phenibut users are weary of. It would at least help dramatically on all fronts when taken separately from phenibut, as is seen in the other HDAC/addiction studies.

 

Some things we don't know yet are HDACi's interactions with other kinds of drugs... I'll have to look up more studies. There have been studies showing HDAC inhibitors do not affect amphetamine/methamphetamine.

 

What I'm going to experiment with personally, is I'm going to try doing a vorinostat session while on phenibut in order to learn social habits while in the mind frame of phenibut. I'll take notes on tolerance changes and comedowns. I'm thinking that the HDACi will at least have no ill effect, and may help prevent tolerance from building. Even if it happens the be that vorinostat helps build tolerance in early phenibut users when they're coadministered, a vorinostat session later in the week off of phenibut would work to undo it, but you will have still gained the benefits of HDACi-enhanced learning of social habits while on phenibut earlier in the week.

 

I'll look through some more studies for further information.

[musicman4534]

I'm thinking since HDAC inhibitors increase transcription, and you body is always trying to come back to homeostasis, that it will, at least, always try to pull toward equilibrium. If you've been on a benzo for a lot time, HDAC inhibitors would help pull things back to equilibrium, and this would be toward lowering tolerance, or facilitating a taper. The HDACi would at least help your body adjust quicker during the taper. If you're taking a drug for the first time and have yet to become accustomed to it, an HDAC inhibitor may quicken your body's response to it, building a tolerance, but would perhaps at the same time prevent an extreme tolerance from ever building... This is just speculation though thinking about the mechanisms of HDAC inhibition... I am going to look through the studies to find more specific information because this is really interesting me now.

 

HDAC inhibitors also affect the precesses of neurotransmitters in unique ways like lowering MAO and COMT, but increasing transporters, essentially stabilizing and protecting monoamine neurotransmission. In these ways, HDAC inhibitors have unique, protective effects downstream of direct HDAC inhibition...

 

What we do know is that when HDAC inhibitors are taken after drug cessation, they facilitate things so well that, even after cocaine abuse, withdrawal symptoms are staved off, cravings are ceased, and the body is brought back to equilibrium.

[tolerant]

Yes, that is what I was thinking. If an HDACi is taken together tolerance-inducing event, such as taking a drug for the first time or increasing the dose, it may increase tolerance. If it's taken when tolerance has already been established, it will not increase tolerance. It appears that on the contrary, it will act act to decrease tolerance. Here's a study that backs this up. Because that study is hard to read, I will quote the sentence from another study that precedes the reference to the first study: Rapid tolerance to anxiolytic effects of alcohol in rats can be reversed by TSA treatment, suggesting a role for amygdaloid HDAC-induced histone modifications in alcohol tolerance.

 

Note that the studies I posted in this post and in my post immediately preceding this one all involved ethanol as the drug of addiction and none involved vorinostat as the HDACi.

[musicman4534]

Very interesting article shared with me by oldmustysad on Reddit.

 

Link to the full PDF below.

 

The potential use of histone deacetylase inhibitors in the treatment of depression

Abstract

Numerous preclinical studies demonstrate that changes in gene expression in the brain occur in animal models of depression using exposure to stress, such as social defeat and leaned helplessness, and that repeated administration of antidepressants ameliorates these stress-induced changes in gene expression. These findings suggest that alteration in gene transcription in the central nervous system in response to stress plays an important role in the pathophysiology of depression. Recent advances in epigenetics have led to the realization that chromatin remodeling mediated by histone deacetylase (HDAC) is closely involved in the regulation of gene transcription. In this context, we first review several preclinical studies demonstrating the antidepressant-like efficacy of HDAC inhibitors. We then suggest the efficacy of HDAC inhibitors in treatment-resistant depression based on the mechanism of action of HDAC. Finally, we discuss the possibility of using HDAC inhibitors in patients with treatment-resistant depression.

→ source (external link)

 

Full Study PDF

 

[tolerant]

Good article. The only thing is that for depression they say you have to dose it chronically. I wonder if dosing 15 mg a day is less safe than dosing 100 mg once a week and, if so, why?

[musicman4534]

@tolerant From all the other studies and anecdotes I'd say that the effect would build up just the same with intermittent larger dosages, and might be a little safer than chronic dosing. There's a safety line somewhere in there for all of us, and I suppose we wouldn't be crossing it with very low daily dosages, somewhere around 15mg a day like you suggest. Perhaps even 5 or 10, though. PRL, which I believe is an HDAC inhibitor, is dosed safely at 5-10mg a day, but around 15mg a day people report weird side effects starting after about a week.

 

 

 

A study from incredulitor of Reddit:

 

Early-life stress-induced visceral hypersensitivity and anxiety behavior is reversed by histone deacetylase inhibition

→ source (external link)

 

It's like a mix of the fear extinction and child-like learning properties of HDAC inhibitors mixed together. Makes sense, and can be quite useful.

[tolerant]

Correction to the last paragraph of post #22. In the second study mentioned in post #20: In the second study mentioned in post #20, one of the agents that attenuated GABA hyposensitivity induced by ethanol withdrawal was in fact vorinostat.

[tolerant]

Is there anything wrong with using Sodium Butyrate as an HDACi, although it cannot do all the things that vorinostat can. And perhaps it can do things that vorinostat cannot.

Edited by tolerant, 24 November 2016 - 04:59 AM.

[tolerant]

Because I take various substances full-time and others from time to time (all legal so far), I've been doing research on their interaction with vorinostat. Below is a study that sounds a warning to anyone combining vorinostat with opiates. The good news is that the study points to curcumin can significantly reduce tolerance to opioids. The study does not focus on anxiety/depression behaviour and the drug studied is morphine, but I assume it suggests one must be really careful with regard to all opioids when taking vorinostat.

 

Epigenetic regulation of opioid-induced hyperalgesia, dependence, and tolerance in mice.

 

Abstract

Repeated administration of opioids such as morphine induces persistent behavioral changes including opioid-induced hyperalgesia (OIH), tolerance, and physical dependence. In the current work we explored how the balance of histone acetyltransferase (HAT) versus histone deacetylase (HDAC) might regulate these morphine-induced changes. Nociceptive thresholds, analgesia, and physical dependence were assessed during and for a period of several weeks after morphine exposure. To probe the roles of histone acetylation, the HAT inhibitor curcumin or a selective HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) was administered daily to groups of animals. Histone acetylation in spinal cord was assessed by Western blot and immunohistochemistry. Concurrent administration of curcumin with morphine for 4 days significantly reduced development of opioid-induced mechanical allodynia, thermal hyperalgesia, tolerance, and physical dependence. Conversely, the HDAC inhibitor SAHA enhanced these responses. Interestingly, SAHA treatment after the termination of opioid administration sustained these behavioral changes for at least 4 weeks. Histone H3 acetylation in the dorsal horn of the spinal cord was increased after chronic morphine treatment, but H4 acetylation was unchanged. Moreover, we observed a decrease in HDAC activity in the spinal cords of morphine-treated mice while overall HAT activity was unchanged, suggesting a shift toward a state of enhanced histone acetylation.
PERSPECTIVE:
The current study indicates that epigenetic mechanisms play a crucial role in opioid-induced long-lasting neuroplasticity. These results provide new sight into understanding the mechanisms of opioid-induced neuroplasticity and suggest new strategies to limit opioid abuse potential and increase the value of these drugs as analgesics.

 

 

[tolerant]

Everybody please take a note of this thread. Musicman, I'm sure you've said and repeated this before, but for those who want to line up some sort of therapy while on vorinostat, when do the effects of vorinostat kick in? Do I remember correctly that it's about 30 minutes?

Edited by tolerant, 01 December 2016 - 05:55 AM.

[KieranA001]

I heard that sodium butyrate is a HDAC inhibitor as well. Does anyone know what it's like in comparison to vorinostat?

[musicman4534]

Tolerant, good find with the opioid study. This corroborates other studies showing that starting certain substances while taking vorinostat could quicken the building of tolerance.
 
This is interesting because so far we have studies showing that HDAC inhibition will quicken building of tolerance and slow withdrawal with opioids, quicken building of tolerance but also quicken cessation of withdrawal with cocaine, and slow the building of tolerance and quicken withdrawal cessation of alcohol (and so possiblity phenibut). It seems that different substances each record their affect on the body, build tolerance and affect HDAC differently.
 
 
The Onset of vorinostat is about a half-hour, yes, so take a half-hour before.
 
 
I'll copy what I just posted in the other thread about butyrate:
 
"Concerning butyrate, I looked this up when I was exploring all the different HDAC inhibitors and making sure vorinostat was the one I wanted to go with, butyrate is an HDAC inhibitor, but a weaker one, and it also has many other effects other than HDAC inhibition, making it hard to take a high enough dose to get the effects we're exactly looking for without its other effects giving us weird side-effects. It would be beneficial to supplement, as it is used by our gut and body (it is actually produced by our gut bacteria), but we won't be able to get the clinical effects seen in the studies as easily from butyrate, especially the fear extinction. There are a good bit of studies on butyrate and learning, however, and since it is a weaker HDAC inhibitor you can take it daily, so I'd definitely recommend supplementing it or supplementing resistant starch to increase butyrate day-to-day or for when you need to get a little boost while studying. Metformin also increases butyrate by affecting our gut bacteria if anyone is interested in that. I've been taking metformin for a couple weeks now and notice a sort of clarity of mind, similar to what I saw with intranasal insulin but more subtle yet more wholesome. I should start a metformin thread, actually, because there's a lot of interesting studies with it... don't want to clog this thread with it lol."
 
Yeah there are some good studies behind butyrate, but it just isn't cut out to be a strong contender for the kind of work we talk about in these threads. It makes sense if you look at its structure, too. It is a quite simple molecule versus the classically-shaped HDAC-inhibiting structure of vorinostat that worked so well it is the basis for a lot of the other newer HDAC inhibitors. Vorinostat was based on 

 

http://imgur.com/pElamhp

 

http://imgur.com/wu40lBL

 

http://imgur.com/P3zybRP

 

Vorinostat was loosely based off of TSA, a natural compound, but once again isn't nearly as useful as vorinostat for what we need it for.

SaveSave

[musicman4534]

Everybody please take a note of this thread. Musicman, I'm sure you've said and repeated this before, but for those who want to line up some sort of therapy while on vorinostat, when do the effects of vorinostat kick in? Do I remember correctly that it's about 30 minutes?

 

This thread is awesome. The drug he used is essentially a prodrug of butyrate, so you can see that butyrate indeed does have some efficacy when it comes to fear extinction. Perhaps for anyone not able to get in on the vorinostat group buy, butyrate would be a good alternative. Also, butyrate may be a solid daily supplement as far as HDAC inhibitors go, because daily use of the stronger HDAC inhibitors is too much.