4 replies to this topic

[Daniel Cooper]

So I'm trying to working through some withdrawal issues from Eszopiclone (Lunesta) and think I may be slipping towards PAWS (I'll give it another month before I make that call).

 

Looking at what can possibly be done to decrease recovery time.  I'm wondering if increasing BDNF might be beneficial?  Depending on who you ask PAWS is either caused by a down regulation of GABA receptors or a pathological change in the conformation of the receptors. 

 

Perhaps increasing BDNF might be useful in the case of receptor down regulation?  In any case, increased BNDF is correlation with improved mood and lower levels of depression, which certainly would have some utility in treating PAWS.  

 

Anyone have any opinions, informed or otherwise, on this?

 

 

 

[gamesguru]

Perhaps there is some glutaminergic dysregulation needing correction?
 

The Availability of Surface GABA_B Receptors Is ... Controlled by Glutamate in Central Neurons

http://www.ncbi.nlm....les/PMC3259848/

 

NAD+-dependent glutamate dehydrogenase reveals cofactor specificity [more NAD+ ---> less glutamate]

http://www.ncbi.nlm....pubmed/22068154

 

Effects of N-Acetylcysteine on Nicotinamide Dinucleotide Phosphate [so, something to increase NAD+/NADH ratio]

http://www.ncbi.nlm....les/PMC3282981/

 

 

Not suggesting it as the best solution, but nicotine increases GABA-A receptors.

 

History of cigarette smoking is associated with higher limbic GABAA receptor availability

http://www.ncbi.nlm....pubmed/23247185

 

[Duchykins]

No BDNF nothing.  Leave your glutamate alone.  This is exactly the wrong time to do anything that enhances excitatory neurotransmission.

 

GABAergics need tapering.  There is no better way to get the brain back to normal on a path of least suffering, period.  If you no longer have access to the z-drug then you should be going the OTC route of magnesium & potassium, taurine, GABA, B vitamins, probiotics, teas.    You don't have to megadose anything, this is just about making that ugly slope less steep.

 

These might pique your interest though.  They certainly caught mine and right now I'm using essential oils (lemon, lemongrass, lavender, by nose not mouth), to suddenly decrease my ativan use since I'm an asshole with little patience for tapering.  It's working better than I thought (I originally assumed it would be bullshit).

 

 

 

 

http://www.ncbi.nlm....pubmed/21767622

 

Journal of Ethnopharmacology, 2011

 

The GABAergic system contributes to the anxiolytic-like effect of essential oil from Cymbopogon citratus (lemongrass).

 

ETHNOPHARMACOLOGICAL RELEVANCE:

The essential oil (EO) from Cymbopogon citratus (DC) Stapf is reported to have a wide range of biological activities and is widely used in traditional medicine as an infusion or decoction. However, despite this widely use, there are few controlled studies confirming its biological activity in central nervous system.

MATERIALS AND METHODS:

The anxiolytic-like activity of the EO was investigated in light/dark box (LDB) and marble-burying test (MBT) and the antidepressant activity was investigated in forced-swimming test (FST) in mice. Flumazenil, a competitive antagonist of benzodiazepine binding and the selective 5-HT(1A) receptor antagonist WAY100635 was used in experimental procedures to determine the action mechanism of EO. To exclude any false positive results in experimental procedures, mice were submitted to the rota-rod test. We also quantified some neurotransmitters at specific brain regions after EO oral acute treatment.

RESULTS:

The present work found anxiolytic-like activity of the EO at the dose of 10mg/kg in a LDB. Flumazenil, but not WAY100635, was able to reverse the effect of the EO in the LDB, indicating that the EO activity occurs via the GABA(A) receptor-benzodiazepine complex. Only at higher doses did the EO potentiate diethyl-ether-induced sleeping time in mice. In the FST and MBT, EO showed no effect. Finally, the increase in time spent in the light chamber, demonstrated by concomitant treatment with ineffective doses of diazepam (DZP) and the EO, revealed a synergistic effect of the two compounds. The lack of activity after long-term treatment in the LDB test might be related to tolerance induction, even in the DZP-treated group. Furthermore, there were no significant differences between groups after either acute or repeated treatments with the EO in the rota-rod test. Neurochemical evaluation showed no amendments in neurotransmitter levels evaluated in cortex, striatum, pons, and hypothalamus.

CONCLUSIONS:

The results corroborate the use of Cymbopogon citratus in folk medicine and suggest that the anxiolytic-like effect of its EO is mediated by the GABA(A) receptor-benzodiazepine complex.

 

 

http://www.ncbi.nlm....pubmed/16780969

 

Behavioural Brain Research, 2006  

 

Lemon oil vapor causes an anti-stress effect via modulating the 5-HT and DA activities in mice.

 

Abstract

 

We examined the anti-stress action of the essential oils of lavender, rose, and lemon using an elevated plus-maze task (EPM), a forced swimming task (FST), and an open field task (OFT) in mice. Lemon oil had the strongest anti-stress effect in all three behavioral tasks. We further investigated a regulatory mechanism of the lemon oil by pre-treatments with agonists or antagonists to benzodiazepine, 5-HT, DA, and adrenaline receptors by the EPM and the FST. The anti-stress effect of lemon oil was significantly blocked by pre-treatment with frumazenil, benzodiazepine receptor antagonist, or apomorphine, a nonselective DA receptor agonist. In contrast, agonists or antagonists to the 5-HT receptor and the alpha-2 adrenaline receptor did not affect the anti-stress effect of lemon oil. Buspirone, DOI, and mianserine blocked the antidepressant-like effect of lemon oil in the FST, but WAY100,635 did not. These findings suggest that the antidepressant-like effect of lemon oil is closely related with the 5-HTnergic pathway, especially via 5-HT(1A) receptor. Moreover, the lemon oil significantly accelerated the metabolic turnover of DA in the hippocampus and of 5-HT in the prefrontal cortex and striatum. These results suggest that lemon oil possesses anxiolytic, antidepressant-like effects via the suppression of DA activity related to enhanced 5-HTnergic neurons.

 

 

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*Note that I don't consider these studies to be particularly strong evidence, though I didn't find any obvious shenanigans associated with these journals; but as these compounds are understudied I suppose it's better than nothing.

[gamesguru]

enhances excitatory neurotransmission.

If by enhances you mean quiets, I quite disagree.

 

I did not explain, but excess glutamate desensitizes the GABAergic system, and NAC will lower glutamate activity thereby increasing GABA-A receptor availability and restoring balance/homeostasis, which is precisely the desired goal.

[Duchykins]

http://www.ncbi.nlm....pubmed/21509169

 

Cooperation between BDNF and glutamate in the regulation of synaptic transmission and neuronal development.

 

Abstract

Ample evidence supports a role of brain-derived neurotrophic factor (BDNF) in the survival and differentiation of selective populations of neurons in the peripheral and central nervous systems. In addition to its trophic actions, BDNF exerts acute effects on synaptic transmission and plasticity. In particular, BDNF enhances excitatory synaptic transmission through pre- and postsynaptic mechanisms. In this regard, BDNF enhances glutamate release, the frequency of miniature excitatory postsynaptic currents (mEPSCs), NMDA receptor activity and the phosphorylation of NMDA receptor subunits. Our recent studies revealed a novel cooperative interaction between BDNF and glutamate in the regulation of dendritic development. Indeed, we found that the effects of BDNF on dendritic growth of cortical neurons require both the stimulation of cAMP response element-binding protein (CREB) phosphorylation by BDNF and the activation of the CREB-regulated transcription coactivator 1 (CRTC1) by glutamate. Together, these studies highlight the importance of the cooperation between BDNF and glutamate in the regulation of synaptic transmission and neuronal development.

 

 

http://www.ncbi.nlm....pubmed/12470709

 

GABA-glutamate interaction in the control of BDNF expression in hypothalamic neurons.

 

Abstract

Brain derived-neurotrophic factor (BDNF) belongs to the neurotrophin family and regulates the survival, differentiation and maintenance of function in different neuronal populations. We previously reported that glutamate increases the expression of BDNF mRNA, its four transcripts and the BDNF peptide in fetal hypothalamic neurons, essentially through NMDA receptor activation. In the present study, we investigated whether GABA interacts with glutamate in the regulation of BDNF gene expression. BDNF and Trk B (BDNF receptor) mRNAs were determined by RNAse protection assay. BDNF transcripts expression levels were evaluated by semi-quantitative RT-PCR. BDNF peptide content was analyzed by enzyme immunoassay (ELISA).We found that picrotoxin (a GABA(A) receptor antagonist) stimulated BDNF mRNA expression and that GABA decreased the glutamate-induced augmentation with no effect on the expression of mRNA encoding the BDNF receptor, Trk B. Measurements of BDNF transcripts levels showed that transcripts containing exons I and III were increased by picrotoxin, whereas those containing exons II and IV were unchanged. GABA solely diminished the glutamate-stimulated expression of transcripts containing exon III. In addition, GABA also inhibited the stimulatory effect of glutamate on BDNF peptide content. Our findings show an interaction between glutamate and GABA on BDNF expression (mRNA, transcripts and peptide) in fetal hypothalamic neurons.

 

 

 

http://journals.plos...al.pone.0053793

 

BDNF Regulates the Expression and Distribution of Vesicular Glutamate Transporters in Cultured Hippocampal Neurons Abstract

 

BDNF is a pro-survival protein involved in neuronal development and synaptic plasticity. BDNF strengthens excitatory synapses and contributes to LTP, presynaptically, through enhancement of glutamate release, and postsynaptically, via phosphorylation of neurotransmitter receptors, modulation of receptor traffic and activation of the translation machinery. We examined whether BDNF upregulated vesicular glutamate receptor (VGLUT) 1 and 2 expression, which would partly account for the increased glutamate release in LTP. Cultured rat hippocampal neurons were incubated with 100 ng/ml BDNF, for different periods of time, and VGLUT gene and protein expression were assessed by real-time PCR and immunoblotting, respectively. At DIV7, exogenous application of BDNF rapidly increased VGLUT2 mRNA and protein levels, in a dose-dependent manner. VGLUT1 expression also increased but only transiently. However, at DIV14, BDNF stably increased VGLUT1 expression, whilst VGLUT2 levels remained low. Transcription inhibition with actinomycin-D or α-amanitine, and translation inhibition with emetine or anisomycin, fully blocked BDNF-induced VGLUT upregulation. Fluorescence microscopy imaging showed that BDNF stimulation upregulates the number, integrated density and intensity of VGLUT1 and VGLUT2 puncta in neurites of cultured hippocampal neurons (DIV7), indicating that the neurotrophin also affects the subcellular distribution of the transporter in developing neurons. Increased VGLUT1 somatic signals were also found 3 h after stimulation with BDNF, further suggesting an increased de novo transcription and translation. BDNF regulation of VGLUT expression was specifically mediated by BDNF, as no effect was found upon application of IGF-1 or bFGF, which activate other receptor tyrosine kinases. Moreover, inhibition of TrkB receptors with K252a and PLCγ signaling with U-73122 precluded BDNF-induced VGLUT upregulation. Hippocampal neurons express both isoforms during embryonic and neonatal development in contrast to adult tissue expressing only VGLUT1. These results suggest that BDNF regulates VGLUT expression during development and its effect on VGLUT1 may contribute to enhance glutamate release in LTP.

 

 

http://www.ncbi.nlm....pubmed/22886995

 

The release of glutamate from cortical neurons regulated by BDNF via the TrkB/Src/PLC-γ1 pathway.

 

Abstract

The brain-derived neurotrophic factor (BDNF) participates in the regulation of cortical neurons by influencing the release of glutamate. However, the specific mechanisms are unclear. Hence, we isolated and cultured the cortical neurons of Sprague Dawley rats. Specific inhibitors of TrkB, Src, PLC-γ1, Akt, and MEK1/2 (i.e., K252a, PP2, U73122, LY294002, and PD98059, respectively) were used to treat cortical neurons and to detect the glutamate release from cortical neurons stimulated with BDNF. BDNF significantly increased glutamate release, and simultaneously enhanced phosphorylation levels of TrkB, Src, PLC-γ, Akt, and Erk1/2. For BDNF-stimulated cortical neurons, K252a inhibited glutamate release and inhibited the phosphorylation levels of TrkB, Src, PLC-γ, Erk1/2, and Akt (P < 0.05). PP2 reduced the glutamate release from BDNF-stimulated cortical neurons (P < 0.05) and inhibited the phosphorylation levels of TrkB and PLC-γ1 (P < 0.05). However, PP2 had no effect on the phosphorylation levels of Erk1/2 or Akt (P > 0.05). U73122 inhibited the glutamate release from BDNF-stimulated cortical neurons, but had no influence on the phosphorylation levels of TrkB, Src, Erk1/2, or Akt (P > 0.05). LY294002 and PD98059 did not affect the BDNF-stimulated glutamate release and did not inhibit the phosphorylation levels of TrkB, Src, or PLC-γ1. In summary, BDNF stimulated the glutamate release from cortical neurons via the TrkB/Src/PLC-γ1 signaling pathway.

 

 

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This is all fine and dandy for someone who is normal, or someone who is a little one the slow side.

 

This is NOT what is best for someone whose glutamatergic systems are already hyperexcitable because GABA is out of whack.  That is one of the causes for benzo withdrawal symptoms in the first place, not to mention the semi-permanent or permanent effects from mild nerve damage, like tinnitus and hyperacusis (from ototoxicity).     They will make him worse before he gets better; there is no reason to chose that path when gentler and safer routes are available.  

 

NAC triggers systemic nonallergic histamine release.

There is also no need to go out of the way to reduce glutamate activity because of interactions with GSH.  Rather, he should instead try to enhance the brain's ability to clear glutamate (and make GABA).  

 

The first and ideal way to do this is reinforce his mitochondrial energy production & transport because that will lift the whole floor for him in a smoother fashion, including BDNF.

Edited by Duchykins, 05 August 2015 - 08:20 PM.