[Re...] Posted February 7, 2018 Share Posted February 7, 2018 Hello, dm123. I agree with you. I think these technologies represent blunt instruments right now. Some people with undamaged CNS's might have some positive benefits with current technology, but for us, I think it's a 'no-go'. There are, as you said, way too many variables and unknowns. It is an interesting read that helps broaden our knowledge to some degree but sadly offers no real solutions. I think in time that there may be more precision and specificity that comes with this technology but we'll have to wait for much more research to be concluded. -RST Hi RST, my sentiments exactly. I think ketamine is a more well proven therapy. Please see the citation below. I'm going to post a summary of what the model is, thus far, as the next paper , so that people can jump in without being too confused. Please tell your fellow BBs about this research. I want it to help people. There's also tons of information and papers in these pages..... The summary is going to tie in the GABAb receptor, and helps confirm the validity of the model relative to the neurogenesis component of the model. I think you are spot on, when you mentioned you think aberrant neurogenesis is what's perpetuating your symptoms, at least in part. A fellow BB sent me this a while back (he knows who he is, and thank you!). In the neurogenesis research, I had already stumbled on the GABAb receptor several times. One point of encouragement for you: As I said before, neurogenesis and Neuroplasticity are not one way streets. Aberrant neurogenesis can be reversed over time. Get the negative stress out of your life for now. Another very important point is that GABAbRs are very stable (population density and conductance density) relative to stimulation and modulation , unlike GABAaRs, which are very sensitive to modulation (i.e. PAMs). So you need not be concerned with the receptor itself. The information below certainly is not new information, but it's necessary to know in your case in light of the model ..... https://www.ncbi.nlm.nih.gov/pubmed/11408520 The anticonvulsant, antihyperalgesic agent gabapentin is an agonist at brain gamma-aminobutyric acid type B receptors negatively coupled to voltage-dependent calcium channels. Bertrand S1, Ng GY, Purisai MG, Wolfe SE, Severidt MW, Nouel D, Robitaille R, Low MJ, O'Neill GP, Metters K, Lacaille JC, Chronwall BM, Morris SJ. Author information Quote Abstract Gabapentin (Neurontin, Pfizer Global R & D) is a novel anticonvulsant, antihyperalgesic, and antinociceptive agent with a poorly understood mechanism of action. In this study, we show that gabapentin (EC50 2 microM) inhibited up to 70 to 80% of the total K+-evoked Ca2+ influx via voltage-dependent calcium channels (VD-CCs) in a mouse pituitary intermediate melanotrope clonal mIL-tsA58 (mIL) cell line. mIL cells endogenously express only gamma-aminobutyric acid type B (GABA(B)) gb1a-gb2 receptors. Moreover, activity of the agonist gabapentin was dose dependently and completely blocked with the GABA(B) antagonist CGP55845 and was nearly identical to the prototypic GABA(B) agonist baclofen in both extent and potency. Antisense knockdown of gb1a also completely blocked gabapentin activity, while gb1b antisense and control oligonucleotides had no effect, indicating that gabapentin inhibition of membrane Ca2+ mobilization in mIL cells was dependent on a functional GABA(B) (gb1a-gb2) heterodimer receptor. In addition, during combined whole cell recording and multiphoton Ca2+ imaging in hippocampal neurons in situ, gabapentin significantly inhibited in a dose-dependent manner subthreshold soma depolarizations and Ca2+ responses evoked by somatic current injection. Furthermore, gabapentin almost completely blocked Ca2+ action potentials and Ca2+ responses elicited by suprathreshold current injection. However, larger current injection overcame this inhibition of Ca2+ action potentials suggesting that gabapentin did not predominantly affect L-type Ca2+ channels. The depressant effect of gabapentin on Ca2+ responses was coupled to the activation of neuronal GABA(B) receptors since they were blocked by CGP55845, and baclofen produced similar effects. Thus gabapentin activation of neuronal GABA(B) gb1a-gb2 receptors negatively coupled to VD-CCs can be a potentially important therapeutic mechanism of action of gabapentin that may be linked to inhibition of neurotransmitter release in some systems. End quote Just want to throw a general THANK YOU your way, dm123. Great stuff. I remember reading the very article you cited some time ago but had lost track of it in my haphazard computer filing system. BTW, I'm reading a very interesting piece on Alzheimer's treatment right now that is thought provoking in light of what we are all experiencing. While it is very different, there are also some interesting correlations. I'll write something on it as soon as i've finished reading the literature. I also want to add a big thank you to "F&F", You know who you are and how much you have contributed and it is greatly appreciated. -RST Link to comment Share on other sites More sharing options...
[cs...] Posted February 7, 2018 Share Posted February 7, 2018 Thanks a Lot dm123 for sparing your time for us. Sorry being lazy to update my Profile here, when i was given first six shots of loading doses in june2017 i started to have pain right in my stomach, this website educate me and i straight left PPI it was Esomaprazole and pain in the stomach stooped, since then i never took any PPI, i sometime feel acidity and kept on taking Zantac which i also in Mid of January 2018, from 20th april 2017 to August 2017 i kept on taking sertraline SSRI, i stopped taking that one as well in august 2017, only medication i m on till todate is 'Atenolol' a bete block for my blood pressure. I was given Vitamin D3 tablets by prescription now to try on, tried yesterday two one in the after noon and other in night and again started to have intestinal problems, today i just took half of the D3 tablet which equal to 200UI to check how it goes on. D3 tablet also have Calcium in it, tablet called Adcel Doctors are not willing to give me anymore b12 injections although my b12 levels are now 413 and they said its above the reference range 180 so we can not continue treatment. Self injection is the option i m left with i think to buy injections from Germany. I live in UK ( Swindon) My Stool Culture was done in June 2017 and came back with below results Pathology Investigations FAECAL CULTURE Faeces appearance Semiformed. FAECAL WET PREPARATION No Cysts of Giardia lamblia seen. FAECAL MICROSCOPY No Cryptosporidia Oocysts seen. FAECAL CULTURE No Salmonella species isolated. No Shigella species isolated. No Campylobacter species isolated No Esc.coli 0157 isolated. No Vibrio species isolated. No Shigella species isolated. No Campylobacter species isolated No Esc.coli 0157 isolated. No Vibrio species isolated. FAECAL CONCENTRATION No ova or cysts seen. Another Test showed which was taken on the second day of first stool test FAECAL CALPROTECTIN FAECAL CALPROTECTIN 289 ug/g FAECAL CALPROTECTIN COMMENT Faecal calprotectin suggests organic pathology. Refer urgently to gastroenterology. Just before this test on 24 may colonoscopy was and and on 19th May my CT scan was done also, they did Endoscopy on 10 April 2017 none of this showed any celiac or other problems, my stool test above showed i have IBD, but doctor said this test is not a relaiable test and they could not see anything in Colonoscopy and Endoscopy biopsies as well, also CT Scan was normal, on 18th of January 2018 to double check again and to verify once again what stool test showed they did Wireless Capsule Endoscopy and yesterday doctor told me its normal, When u say Parasites is there any separate test for that, do you mean a Candida testing, i asked doc to test for Candida and said i m trying to catch a straw as nothing is there, and on my GP level they can not do any Candida testing i have to see consultant again. Magnesium levels were checked on 28th September 2017 and it came back as below Serum magnesium level Serum magnesium level 0.95 mmol/L [0.7 - 1.0] Shall i take some Magnesium Vitamins? I know post will become quite long i m sorry but because i m worried and its always get very hard to get all answers by doctors as they look at my face as i have gone crazy Could you check my Below Results of CBC ( Complete blood count) does it indicate anything or its normal they will keep fluctuating. Blood Test Taken on 8th June 2017 ( CBC Results ) At that time i was never given any b12 shots my b12 at this point was 102 and folate was 6.3 Haemoglobin concentration 147 g/L [130.0 - 170.0] Red blood cell count 5.02 10*12/L [4.5 - 6.5] PCV 0.439 [0.4 - 0.54] Mean cell volume 87.0 fL [83.0 - 101.0] Mean cell haemoglobin level 29.3 pg [27.0 - 32.0] Mean cell haemoglobin concentration 335 g/L [315.0 - 360.0] Total white blood count 5.3 10*9/L [4.0 - 10.0] Neutrophil count 3.04 10*9/L [2.0 - 7.0] Percentage neutrophil count 57.4 Lymphocyte count 1.71 10*9/L [1.0 - 3.0] Percentage lymphocyte count 32.3 Monocyte count - observation 0.42 10*9/L [0.2 - 1.0] Percentage monocyte count 7.9 Eosinophil count - observation 0.09 10*9/L [0.02 - 0.5] Percentage eosinophil count 1.7 Basophil count 0.04 10*9/L [0.0 - 0.1] Percentage basophil count 0.7 Platelet count - observation 317 10*9/L [150.0 - 400.0] Mean platelet volume 9.3 fL Blood Test Taken on 24 of September 2017 ( CBC Results) after about three months of b12 six shots , B12 at this point was 646 and folate 14.1 Haemoglobin concentration 149 g/L [130.0 - 170.0] Red blood cell count 5.13 10*12/L [4.5 - 6.5] PCV 0.447 [0.4 - 0.54] Mean cell volume 87.0 fL [83.0 - 101.0] Mean cell haemoglobin level 29.0 pg [27.0 - 32.0] Mean cell haemoglobin concentration 334 g/L [315.0 - 360.0] Total white blood count 5.6 10*9/L [4.0 - 10.0] Neutrophil count 3.15 10*9/L [2.0 - 7.0] Percentage neutrophil count 56.2 Lymphocyte count 1.86 10*9/L [1.0 - 3.0] Percentage lymphocyte count 33.3 Monocyte count - observation 0.41 10*9/L [0.2 - 1.0] Percentage monocyte count 7.3 Eosinophil count - observation 0.13 10*9/L [0.02 - 0.5] Percentage eosinophil count 2.3 Basophil count 0.05 10*9/L [0.0 - 0.1] Percentage basophil count 0.9 Platelet count - observation 297 10*9/L [150.0 - 400.0] Mean platelet volume 9.0 fL Blood Test Taken on 24 of Jan 2018 - CBC Results Recently prior to this i was given another shot of b12 on 31-10-2017 , B12 now is 413 and folate is 17.1 Full blood count Haemoglobin concentration 133 g/L [130.0 - 170.0] Red blood cell count 4.50 10*12/L [4.5 - 6.5] PCV 0.381 [0.4 - 0.54] Below low reference limit Mean cell volume 85.0 fL [83.0 - 101.0] Mean cell haemoglobin level 29.6 pg [27.0 - 32.0] Mean cell haemoglobin concentration 350 g/L [315.0 - 360.0] Total white blood count 4.1 10*9/L [4.0 - 10.0] Neutrophil count 1.76 10*9/L [2.0 - 7.0] Below low reference limit Percentage neutrophil count 42.9 Lymphocyte count 1.73 10*9/L [1.0 - 3.0] Percentage lymphocyte count 42.2 Monocyte count - observation 0.45 10*9/L [0.2 - 1.0] Percentage monocyte count 11.0 Eosinophil count - observation 0.11 10*9/L [0.02 - 0.5] Percentage eosinophil count 2.8 Basophil count 0.05 10*9/L [0.0 - 0.1] Percentage basophil count 1.1 Platelet count - observation 208 10*9/L [150.0 - 400.0] Mean platelet volume 9.9 fL My Last CBS makes me stressed and worried that something is going on wrong in my body that is why when i compare CBC reading from previous readings its going down. Thanks & Regards Shahid Hi Shahid, i think it's evident that the b12 deficiency was due in part to the 2 years you were on the PPI. Zantac also interferes with b12 absorption as well. I'm glad you are at 413. The low range end for b12 (~170 here in USA and 180 where you are at) is set too low. Japan has low range as 500. By the time you get to 170-180 you are very deficient. Mine got down to 140 a long time back. Regarding parasite testing, the tests you had were microscopic pathology tests. The newer DNA PCR testing is much more sensitive, but these tests are expensive. Giardiasis is hard to catch on the microscopic tests as well as crypto, and blasto. I don't want to post links here and create fear. You can google and research "DNA PCR stool parasite" and find the information yourself. Several years back this is what i had to do, and I had the DNA tests done and got treated aggressively. Candida is included in these tests, but everyone has candida. Mine was high but I was told that its only dangerous if it goes systemic, i.e. Through a break in the intestinal wall, which you don't have. I'm not a doctor, and can't give medical advice, but your Latest CBC looks fine, especially given your doctor has said so. Regarding magnesium, since you are no longer on the PPI, you should be ok, but extracellular Mg tests (the one that you had) are not helpful in diagnosing mg deficiency. Intracellular RBC is much more useful, but since you are no longer on the PPI, i don't think it's necessary. Regarding the CALPROTECTIN 289 ug/g It is high, but since your colonoscopy came back ok, that's a really good sign, i.e. No damage. So you don't have, crohns or UC. This is very good news, but doesn't solve your issue. One last thing. PPIs do create dysbiosis, or bacterial imbalance. They can run all kinds of fancy tests, but a probiotic will help. It takes a long time to recolonize some bacteria. I also take Saccharomyces boulardii, which is a foreign bacteria, that does not colonize, and has to be taken every day. You will also want to research on the topic "neurogastroenterology and gut motility ". Most of the lastest research in IBS and IBD is in this area. http://www.jnmjournal.org/journal/view.html?uid=1014&vmd=Full& https://www.ncbi.nlm.nih.gov/pubmed/24474234 Link to comment Share on other sites More sharing options...
[Te...] Posted February 14, 2018 Author Share Posted February 14, 2018 dm123, could you explain this to me: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2343457/ In what way would benzos play a part in this? I was reading this also: New medical research suggests that drinking apple cider vinegar can help cure acid reflux, lower blood pressure, improve diabetes, and support weight loss. The benefits of apple cider vinegar come from it’s powerful healing compounds which include acetic acid, potassium, magnesium, probiotics and enzymes. So how does ACV help lower your blood pressure you ask? In the body we have a system called the, Renin-Angiotensin System or RAS. This system helps regulate our blood pressure, cardiac function, and also kidney function. Renin-Angiotensin becomes angiotensin I and then is converted in the lungs to angiotensin II. Angiotensin II mediates vasoconstriction as well as aldosterone release from the adrenal glands resulting in sodium retention, and increased blood pressure. A study published in the journal of, “Bioscience, Biotechnology, and Biochemistry” looked at the effect that apple cider vinegar has on blood pressure if it is introduced into your diet. The results of the research suggested that consumption of acetic acid, a component found in apple cider vinegar, caused a significant reduction in hypertension. According to the researchers the acetic acid lowers you blood pressure by decreasing renin enzymes created in the kidneys. If you decrease renin then you decrease the renin-angiotensin hormone which is responsible for increased blood pressure. Although there is still much research to be done into the effects of acetic acid in controlling blood pressure the initial results are very promising. The reason why I'm asking is because in March of last year I started taking ACV in salads. For about a month I did this. But I started noticing very high bp numbers and then low ones. I thought it was the ACV and quit it. (It also has histamine in it.) But I noticed that suddenly my bp went way down and stayed pretty much down for three months until I, unfortunately, overdid it with coffee. I just thought it went down because something had improved in my body. Now I'm taking ACV again. It suddenly dawned on me that maybe it was due to the ACV that my bp went down last year. I find that ACV causes anxiety in the morning so I take it at noon and at night. I just take 1 Tbsp. I just started doing this and am hoping that it lowers my bp again. What part do benzos play in this? Could it have caused my high bp due to changes in hormones and the adrenals? THANK YOU, as usual!!! Link to comment Share on other sites More sharing options...
[Sw...] Posted February 15, 2018 Share Posted February 15, 2018 Terry38, thanks for this research. I have off and on tried the ACV, not seeing any big results. Maybe it is too little for not a long enough time. Well also because I have been drinking warm lemon water in the morning to help flush the kidney stones. Perhaps dm123 could shed some light on this issue. I saw me PCP today, she wants me to switch the lisinopril from 10 mg 2x per day to 20 mg in the morning. Says it may help with the daytime anxiety blood pressure rise. Sweet pea Link to comment Share on other sites More sharing options...
[Te...] Posted February 15, 2018 Author Share Posted February 15, 2018 Terry38, thanks for this research. I have off and on tried the ACV, not seeing any big results. Maybe it is too little for not a long enough time. Well also because I have been drinking warm lemon water in the morning to help flush the kidney stones. Perhaps dm123 could shed some light on this issue. I saw me PCP today, she wants me to switch the lisinopril from 10 mg 2x per day to 20 mg in the morning. Says it may help with the daytime anxiety blood pressure rise. Sweet pea Do you get high blood pressure in the morning? Have you gotten your cortisol checked? I was getting lower readings in the morning. I don't know why, because I wake up with a "motor" running inside. Yes, I would like dm123 to shed some light on this situation, too! How long did you take the ACV, Sweet pea? I had to take it every day for at least a month to see results, if that's what happened. Link to comment Share on other sites More sharing options...
[fr...] Posted February 15, 2018 Share Posted February 15, 2018 I'm also on 20 mg. of LIsinopril that I take in the morning. My bp in am is always fine but after I take the med it slowly goes up. I take other meds also but this is weird to me. I know these drugs also have side effects and I wonder if any of mine are related. Wish I could just stop it. I know Dr. will say no. When I go to Dr. I am always stressed and in pain so its usually upper number is high. Lower number is usually ok. Anyway, hope DM can help out with this. My potassium has slowly been going up also and he also thought the lisinopril was causing that. Thanks in advance for all you do DM God bless. Link to comment Share on other sites More sharing options...
[Te...] Posted February 15, 2018 Author Share Posted February 15, 2018 freeme, there are bp drugs that cause high potassium. It's unfortunate. I was taking Valsartan and the doctors kept talking about the high potassium. At that time I didn't realize it was the drug. One of my pills (Labetalol) can cause damage to the liver. I've run the gamut of bp problems. I know how you feel. Link to comment Share on other sites More sharing options...
[fr...] Posted February 15, 2018 Share Posted February 15, 2018 Terry, Yes my potassium has slowly gone up from in the 4's it was 5.5 which is the upper normal number so now considered high. Dr. said not to worry since kidney and liver function blood work was normal. Sodium is low and also chloride. A/G ratio I think it was was also a little high. He said not to worry. who knows but I don't trust Dr anymore. Link to comment Share on other sites More sharing options...
[Te...] Posted February 15, 2018 Author Share Posted February 15, 2018 Well, that's good that you have good kidney and liver function. I do not. And my sodium and chloride is low, too. I've been salting food for a long time, hoping that it goes up. I think it was as a result of all the pills I've been on, and it started with NSAIDS. Link to comment Share on other sites More sharing options...
[fr...] Posted February 15, 2018 Share Posted February 15, 2018 I also take NSaids so I guess I really need to cut down. I take 2 advil most days but had tried to stop. Pain is so bad that I started again but I guess I will have to stop those also. Sigh. Link to comment Share on other sites More sharing options...
[cs...] Posted February 15, 2018 Share Posted February 15, 2018 Terry38, thanks for this research. I have off and on tried the ACV, not seeing any big results. Maybe it is too little for not a long enough time. Well also because I have been drinking warm lemon water in the morning to help flush the kidney stones. Perhaps dm123 could shed some light on this issue. I saw me PCP today, she wants me to switch the lisinopril from 10 mg 2x per day to 20 mg in the morning. Says it may help with the daytime anxiety blood pressure rise. Sweet pea Hi sweet pea see my response to Terry below. Link to comment Share on other sites More sharing options...
[cs...] Posted February 15, 2018 Share Posted February 15, 2018 Terry38, thanks for this research. I have off and on tried the ACV, not seeing any big results. Maybe it is too little for not a long enough time. Well also because I have been drinking warm lemon water in the morning to help flush the kidney stones. Perhaps dm123 could shed some light on this issue. I saw me PCP today, she wants me to switch the lisinopril from 10 mg 2x per day to 20 mg in the morning. Says it may help with the daytime anxiety blood pressure rise. Sweet pea Do you get high blood pressure in the morning? Have you gotten your cortisol checked? I was getting lower readings in the morning. I don't know why, because I wake up with a "motor" running inside. Yes, I would like dm123 to shed some light on this situation, too! How long did you take the ACV, Sweet pea? I had to take it every day for at least a month to see results, if that's what happened. Hi Terry see my response below. The relationship between renin, angiotensin II and benzodiazaphines seems to be a bit complex. Link to comment Share on other sites More sharing options...
[cs...] Posted February 15, 2018 Share Posted February 15, 2018 I'm also on 20 mg. of LIsinopril that I take in the morning. My bp in am is always fine but after I take the med it slowly goes up. I take other meds also but this is weird to me. I know these drugs also have side effects and I wonder if any of mine are related. Wish I could just stop it. I know Dr. will say no. When I go to Dr. I am always stressed and in pain so its usually upper number is high. Lower number is usually ok. Anyway, hope DM can help out with this. My potassium has slowly been going up also and he also thought the lisinopril was causing that. Thanks in advance for all you do DM God bless. Hi freeme yes the lisinopril directly affects aldosterone levels and the potassium levels rising is normal with the med. Link to comment Share on other sites More sharing options...
[cs...] Posted February 15, 2018 Share Posted February 15, 2018 Terry, Yes my potassium has slowly gone up from in the 4's it was 5.5 which is the upper normal number so now considered high. Dr. said not to worry since kidney and liver function blood work was normal. Sodium is low and also chloride. A/G ratio I think it was was also a little high. He said not to worry. who knows but I don't trust Dr anymore. Hi freeme, yes as aldosterone goes down, K goes up and Na drops. I think it's importance to listen to the doctor. As you know HBP is dangerous in the long term... but I understand how you feel. Ditto here..., Link to comment Share on other sites More sharing options...
[cs...] Posted February 15, 2018 Share Posted February 15, 2018 This is a very interesting area of study because angiotensin II antagonists are being researched as anti anxiety therapies, because they seem to lower anxiety via modulation of CRH and the benzodiazaphine binding site on the GABAa receptors. In layman's terms angiotensin II receptor antagonists do this by 1. Decreasing CRF release 2. The decrease in CRF release reverses the decrease in central benzodiazaphine binding on the GABAa receptor complex, that occurs in response to negative stressors. To explain number 2 further, as you know, the stress system plays a crucial role in the model. The stress system and the GABAergic system are very tightly coupled through a few different pathways, one of which is CRH (or CRF). As you know, CRH is the hypothalamic neuromodulator that causes the pituitary to secrete ACTH, and thus the adrenals to pump out cortisol. https://en.m.wikipedia.org/wiki/Corticotropin-releasing_hormone When test subjects are negatively stressed there is a decrease in benzodiazaphine binding (as seen in stained cultures of brain slices, see citation further down) due to an increase in CRF. Angiotensin II antagonists downmodulate CRH release which in turn reverses this negative stress induced decrease in benzodiazaphines binding thereby relieving the stress induced anxiety, Renin is connected to this whole thing because renin does the following : Quote The renin enzyme circulates in the blood stream and hydrolyzes (breaks down) angiotensinogen secreted from the liver into the peptide angiotensin I. End quote Angiotensin I is cleaved to form angiotensin II. So increasing renin will typically lead to higher angiotensin II levels which would be expected to exasperate anxiety levels given the above (and below). This is via CRF modulation, CRF receptor modulation, and the CRF modulation in turn affects the GABAAR benzodiazaphine binding. So renin decreases benzodiazaphine binding indirectly. The ACV, in reducing renin (if it does do this) would be expected to reduce BP, and given the above, anxiety levels. You said “I find that ACV causes anxiety in the morning so I take it at noon and at night.” Given its purported effects on renin, I would have expected reduction in anxiety, but perhaps because cortisol and CRH is highest in the morning, this might obscure the issue (?) To answer some of your other questions, prior to getting into the details on angiotensin II antagonists: In general, prior to tolerance or withdrawal, benzodiazaphines suppress or blunt adrenal function. The best way to think of this, is that benzodiazaphines alter the hypothalamic pituitary ACTH secretion in response to stressful stimuli, effectively blunting cortisol response. This is one reason why stress resiliency deteriorates(and anxiety escalates )with chronic benzodiazaphine use, the other reason being how both benzodiazaphines and withdrawal from benzodiazaphines impair Hippocampal neurogenesis (I will get into this more in another paper, but it was also presented in the Neurogenesis( PART I )paper posted earlier). After tolerance sets in benzodiazaphines actually contribute to excessive cortisone release due to the withdrawal symptoms themselves. (note in the below reference:Some of the anticonvulsants increase steroid clearance as well, effectively lowering serum steroid levels. I don’t know if benzodiazaphines could be included here, because the list of drugs are phenos and barbiturates) First, See this reference and quote below https://www.ncbi.nlm.nih.gov/pubmed/9694568 Quote abstract Since the adrenal cortex and medulla are intimately interrelated, the effects of anticonvulsant drugs may affect both of these hormonal systems. Anticonvulsants are commonly used long-term for the treatment of epilepsy, chronic pain syndromes and affective disorders. In patients where adrenal function needs to be evaluated, the clinician should be aware of the potential interactions between anticonvulsant medication and the hypothalamo-pituitary-adrenal axis. Carbamazepine, phenytoin and phenobarbitone induce the liver P450 cytochrome enzyme system and stimulate steroid clearance. Therefore, patients investigated for Cushing's syndrome may show a falsely positive dexamethasone suppression test, and patients with adrenal insufficiency on steroid replacement may require increased doses of steroids; furthermore, increased corticosteroid-binding-globulin levels are also associated with chronic anticonvulsant administration.(dm123: i.e., lowers free cortisol levels) In addition, concomitant treatment with benzodiazepines, probably acting via the GABA pathway, can also alter the ACTH/cortisol response to stressful stimuli. Direct and indirect evidence suggest that benzodiazepines, acetazolamide and magnesium sulphate can also interfere with the renin-angiotensin-aldosterone system. Finally, to our knowledge, no systemic data are yet available in the human on the effect of antiepileptics on the function of the adrenal medulla and/or catecholamine metabolism; however, as the adrenal medulla receives part of its blood supply from the cortex, it is possible that alterations of cortical hormonal composition might affect adrenal medulla function overall. End quote Next, note the bolded part above mentioning benzodiazaphines can interfere with the renin-angiotensin-aldosterone system. Let’s examine this more closely. I could not find any direct studies on this and I don’t have access to the study above to pull the references, but I found that there is a renin peripheral benzodiazaphines receptor on tissues like the heart and kidney, but PBRs are not brain GABAaRs. Here is the reference on the information in angiotensin II receptor antagonists. AT receptor antagonists are angiotensin II antagonists. Angiotensin II antagonists seem to provide anxiety relief via modulation of CRF, CRF receptors and GABAaRs. One could infer that angiotensin II can cause anxiety in very high amounts via the CRF and the benzodiazaphine binding on GABAAR mechanisms, i.e. in reverse of the antagonist. And this is what happens (see quotes below). The stress system and the GABAergic aystem are very tightly coupled and affect one another (as the model I am presenting indicates) Finally, Stress induces renin secretion. Benzodiazaphines don’t appear to directly affect renin, but they do profoundly affect the stress system according to the model that I am proposing. Thus they do indirectly affect renin secretion through the stress system This is a study on renin, stress and benzodiazaphines, showed no effect of benzodiazaphines on stress induced renin secretion. https://www.sciencedirect.com/science/article/pii/0006899385910017 Here is exactly how the angiotensin II antagonists work relative to CRF and benzodiazaphine binding capability that occurs after negative stressors. Reference https://www.nature.com/articles/1300921 Quote The main finding of this study is that pretreatment with a centrally acting Ang II AT1 receptor antagonist prevents the isolation stress-induced alterations in cortical CRF1 and benzodiazepine binding and locus coeruleus TH mRNA, and reduces anxiety in the elevated plus-maze. This indicates that AT1 receptor antagonists exert anti-stress and anti-anxiety properties by modulating three interacting cortical systems, CRF, GABAA, and norepinephrine. End quote Quote In the cortex, CRF negatively modulates the activity of the GABAAcomplex, the main central inhibitory system (Takamatsu et al, 1991; Serra et al, 1999). The CRF and GABAA systems are tightly interconnected, and in the PVN, GABAA receptors colocalize with CRF neurons (Cullinan, 2000). A similar interaction is likely to occur in the cortex. The effect of CRF1 antagonists is similar to the effect of the benzodiazepines, the classical anxiolytic compounds, which stimulate central benzodiazepine sites, part of the inhibitory GABAA receptor complex (Nutt and Malizia, 2001; Zavala, 1997; Biggio et al, 1990). Stimulation of central benzodiazepine receptors increases the affinity of GABA for its binding site through positive allosteric effects, potentiating GABAergic transmission (Zavala, 1997). Isolation (present results) or exposure to inescapable stressors such as foot shock or forced swimming (Lippa et al, 1978; Weizman et al, 1989; Medina et al, 1983) decreased benzodiazepine receptor binding in the frontal cortex. In turn, decreased benzodiazepine binding decreases GABAergic transmission, and this leads to stress-induced anxiety (Nutt and Malizia, 2001). Our finding of decreased cortical benzodiazepine receptor binding during isolation is most likely associated with the stress-induced increase in cortical CRH release. By decreasing CRF release, AT1 receptor blockade would also reverse the stress-induced decrease in central benzodiazepine binding and restore the inhibitory influence of the GABAA complex during isolation. End quote Quote Our results are not without clinical implications. Hyperactivity of the HPA axis and of CRF neurons regulating higher brain centers are confirmed findings in anxiety and in stress-related affective disorders (Bremner et al, 2000; Keck and Holsboer, 2001). We demonstrate here that inhibition of Ang II AT1 receptors is sufficient to block stress-induced changes in CRF1 receptors and to restore the inhibitory effect of the cortical GABAA system. Our hypothesis is that these effects explain the anxiolytic and anti-stress effects of centrally active AT1receptor antagonists. Our observations indicate that Ang II AT1 receptors are involved in higher regulatory mechanisms controlling the behavioral and cognitive responses to stress and anxiety. Antagonism of brain Ang II AT1receptors could open a new lead in the treatment of anxiety and other stress-related psychiatric conditions such as depression and post-traumatic stress disorder. End quote There’s a lot more information in the reference above. And this with candesartan Quote We demonstrated ing exposure to novel surroundings and access to familiar territory. In addition, candesartan pretreatment prevented the gastric ulceration produced by cold-restraint stress in rats (Bregonzio et al, 2003). This suggested that antagonism of peripheral and brain AT1 receptors could be of therapeutic relevance in the control of the stress reaction (Armando et al, 2001). End quote And this regarding correlation to anxiety and losartan Quote Overexpression of AT1 receptors in mice lacking AT2 receptors (Armando et al, 2002) associates with anxiety-like behavior (Okuyama et al, 1999). Of particular interest was the finding that peripheral administration of the AT1 receptor antagonist losartan reduces anxiety in rodents (Barnes et al, 1990). These findings suggest that AT1receptor stimulation enhances anxiety and that these receptors regulate not only the autonomic and hormonal but also the behavioral response to stress End quote Flunitrazepam mentioned in the link above is a benzodiazaphine. Link to comment Share on other sites More sharing options...
[Te...] Posted February 16, 2018 Author Share Posted February 16, 2018 THANK YOU SO MUCH for taking the time to do this and for your thoughtful approach, dm123!!! I appreciate it very, very much. I will still need to read it again so that I can try to understand it. Link to comment Share on other sites More sharing options...
[li...] Posted February 16, 2018 Share Posted February 16, 2018 dm123, Just a note: isn't CRH (and glucocorticoids) able to help with stress, as long as it's not in excess/the wrong time/way ? Link to comment Share on other sites More sharing options...
[cs...] Posted February 17, 2018 Share Posted February 17, 2018 dm123, Just a note: isn't CRH (and glucocorticoids) able to help with stress, as long as it's not in excess/the wrong time/way ? Hi liberty, yes absolutely. Everything in proper balance. During tolerance and wd, assuming no hypothalamic burnout yet, CRH will run high, as will cortisol. If stress is sustained for very long periods the hypothalamus can falter(commonly referred to as "adrenal fatigue " , a complete misnomer. Adrenal glands don't burn out unless you have autoimmune disorders like Addison's) Balance is the key. Balance between LTP and LTD, balance between inhibitory and excitatory signaling, etc. Link to comment Share on other sites More sharing options...
[cs...] Posted February 17, 2018 Share Posted February 17, 2018 Please also see a recent post in nicotine under Other Medications. I just posted today. Happy reading...... Link to comment Share on other sites More sharing options...
[cs...] Posted February 17, 2018 Share Posted February 17, 2018 THANK YOU SO MUCH for taking the time to do this and for your thoughtful approach, dm123!!! I appreciate it very, very much. I will still need to read it again so that I can try to understand it. Sure Terry. Let us know if you have any questions. Angiotensin II antagonists to help during withdrawal? Perhaps...... Link to comment Share on other sites More sharing options...
[Te...] Posted February 17, 2018 Author Share Posted February 17, 2018 I used to take Valsartan. It was a good drug for benzo withdrawal, but it upped my potassium to the point that doctors kept commenting on it. I wish I could go back on it, but I'm already taking so many drugs, yet they don't help. They do cause a lot of side effects, though. Very difficult to get off of with this benzo anxiety... THANKS AGAIN!!! Link to comment Share on other sites More sharing options...
[cs...] Posted February 24, 2018 Share Posted February 24, 2018 I'm posting the link to the nicotine thresd in Other Medications here as well. We will get into brain neuro-anatomy is Module 4 of Neural Circuits,,and this provides a great example of some of the circuitry involved between the thalamus and the cortex. http://www.benzobuddies.org/forum/index.php?topic=197499.0 There is a nice summary of the article in that thread Link to comment Share on other sites More sharing options...
[cs...] Posted March 3, 2018 Share Posted March 3, 2018 Hi, for any late comers I hope this Summary post will help. Please note that a lot of this material is referenced in detail in earlier posts. For those who have been following, I've added more content on how the GABAbR fits into the model. RST, liberty, and others who PM'ed, I hope this helps you better understand what is going on in your CNS. Hopefully, some therapeutic applications might come out of this new frontier in understanding. Neural circuits modules 1-3 are posted. Module 4 will be the next module... Please Be well dm123 ------------------------------------ ~”To be truly humble, one can never presume and proclaim complete humility in oneself. By its very nature, the attainment of perfect humility is an elusive lifelong pursuit….”. – dm123. James 4:6 Prior to continuing with Module 4 of the neural circuits paper, I wanted to present a summary of the model up to this point. This summary also has some interesting additional insights that further validate the integrity of the model. The earlier posts in this thread contain much more detail on the individual components of the model-framework that described below. 1.Model Summary so far: Exercise, cortisol , and the stress system in general, are very powerful physiological drivers for both neuroplasticity and neurogenesis in the brain. We have already seen how profoundly cortisol, in and of itself, affects the plasticity of the brain through LTP and LTD, and it is very well established that stress, cortisol and exercise also affect the rate of neurogenesis in the plastic regions of the brain. Adult neurogenesis of the brain has been found to extend into the striatal areas of the brain (i.e., the striatum) , according to the latest research (see reference in Neurogenesis paper (PART 1)). This makes the impact of neurogenesis in the benzodiazaphine model even more profound and relevant. I’m also quite confident that significant adult neurogenesis will be found to occur in other regions of the brain, as the clinical research in this important area continues to expand and evolve. It’s no longer just about the hippocampus when it comes to neurogenesis. Stress has an even more profound effect outside of the realm of cortisol itself. Stressors, or perturbations, as they are called in the neural circuit literature, directly induce neuroplastic changes (Neuroplasticity ) in the brain. These changes manifest themselves in the strength between the neuronal synapses in a neural circuit, and in the conductance densities of the ligand-gated(ionotropic receptor) and voltage gated channels in individual neurons that are part of the neural circuit. We will explore this realm of neuroplasticity, often referred to as homeostatic plasticity , in the ongoing Neural Circuits paper. (For an introduction to ionotropic and voltage gated channels see some very early posts in this thread (called ADDENDUMs) as well as the links below. Both of these types of channels are referred to generically as ion channels in the clinical research: https://en.m.wikipedia.org/wiki/Ligand-gated_ion_channel https://en.m.wikipedia.org/wiki/Ion_channel https://en.m.wikipedia.org/wiki/Voltage-gated_ion_channel ) Conductance densities can be thought of as the rate of flow of ions through the individual ionotropic receptor channels and voltage gated channels in a neuron, when the channels are opened.. The conductance densities homeostatically vary individually in response to a perturbation; they vary by receptor type, for example sodium channels, potassium channels, and various types of other voltage gated and ionosphere channels. These changes vary from individual to individual for the same controlled perturbation, as the body tries to maintain homeostasis, and prevent a crash. The individual neurons, as constituents in a given neural circuit, plastically respond to maintain the neural circuit’s physiological functional output. We will see exactly what is meant by “physiological functional output” in the neural circuits paper. In the Gould exercise reference noted in an earlier post, we see that positive stress like exercise not only modulates neurogenesis, but also alters neurotransmitter levels (GABA for example), as well as presynaptic neurotransmitter release dynamics (this is sometimes referred to as presynaptic plasticity), positively altering the Hippocampal function via Neuroplasticity. Improved stress resiliency is one of the many neurological benefits of consistent moderate exercise. This improved stress resiliency occurs from not only a neurophysiological perspective, but also from an endocrine perspective as well. The resulting improved stress resiliency results in an improved adaptation response to everyday stressors, and this ultimately results in lower anxiety levels. The benzodiazaphine withdrawal model thus far has 3 major components to it: 1. The action potential dynamics at the individual neuron level. This is directly affected by the stress system (via LTP and LTD), the glutamatergic system, the GABAergic system, as well as a number of “other systems” that have not been presented yet. 2. The neurogenesis component, which accounts, in part, for benzodiazaphine PWS. Neurogenesis initially can be destabilized by dysfunction in the GABAergic system (alcohol or benzodiazaphines; see the alcohol study referred to in an earlier post, one of many references in this area) and perpetuated through the negative stress system.Neurogenesis is directly affected by the glutamatergic, GABAergic and stress systems, as well as many other different neurogenic modulators (including serotonin) that were briefly discussed in the Neurogenesis (PART 1) post above. 3. The neuroplasticity overlay, which includes neural circuit dynamics, and homeostatic plasticity, as well as hebbian plasticity (LTP and LTD; note this is not the same as non-hebbian glutamatergic LTP which can be associated with PWS under abrupt withdrawal). Neuroplasticity is also affected by the stress system, the GABAergic system, and the glutamatergic system, as well as many many (the list is huge!)different neuromodulators. The 3 major components above are affected by benzodiazaphines through the 3 major mechanistic systems or “pillars” alluded to above (reduced to 3 for simplicity): 1. The glutamatergic system, 2. the GABAergic system, and of course 3. the stress system. What’s interesting, and what makes the model dynamics so complex, is that each of these three pillars affect one another. Destabilizing a pillar (for example, chronic benzodiazaphine use directly destabilizes the GABAergic system) has the potential to throw the entire system off, and the stress system can perpetuate the dysfunction not only through further aberrant neurogenesis, but through its direct effects on the other two systems. The references in this area are plentiful. A few examples are below: -The stress system affects the GABAergic system via CRH, and the GABAergic system modulates CRH. CRH release that occurs in response to negative stressors can decrease central benzodiazaphine binding on GABAaRs, in certain regions of the brain, thus reducing inhibitory signaling efficiency. -Furthermore, the stress system alters Neurosteroid and corticosteroid production, which in turn affects the GABAergic system. Neurosteroids profoundly affect (modulate) the tonic GABAergic system primarily through the δ Subunit. Neurosteroids also affect (modulate) NMDARs. Corticosteroids affect LTP, and LTD and affect both the amplitudes and frequencies of inhibitory post synaptic currents. -A suprising link: The stress system directly affects NMDARs and AMPARs of the glutamatergic system. https://www.frontiersin.org/articles/10.3389/fncel.2012.00009/full Front. Cell. Neurosci., 06 March 2012 | https://doi.org/10.3389/fncel.2012.00009 Dynamic regulation of NMDAR function in the adult brain by the stress hormone corticosterone Yiu Chung Tse , Rosemary C. Bagot , and Tak Pan Wong https://www.frontiersin.org/articles/10.3389/fncel.2012.00015/full Front. Cell. Neurosci., 09 April 2012 | https://doi.org/10.3389/fncel.2012.00015 Interactions between noradrenaline and corticosteroids in the brain: from electrical activity to cognitive performance Harm J. Krugers , Henk Karst and Marian Joels -We also know that chronic benzodiazaphine use affects serotonin, dopamine and acetylcholine levels. -The glutamatergic and GABAergic pillars are the most tightly bound via homeostatic plasticity and action potential dynamics. When viewed from the perspective of this model, it’s quite obvious why and how benzodiazaphines can adversely affect our physiology from many different angles, and why benzodiazaphine withdrawal can be protracted. The direct effects of benzodiazaphines on the unforgiving and temperamental GABAa receptor make them a particularly potent perturbation to the system model. The benzodiazaphine effects on the GABAa receptor are THE initial crack in the wall of our normally resilient physiology. The stress response system dysfunction in the form of reduced stress resiliency, is often one of the earliest collateral symptoms of benzodiazaphine withdrawal and tolerance, as things begin to unravel and fall apart. The stress system can potentially perpetuate withdrawal via aberrant negative stress related neurogenesis, even after the benzodiazaphine has been completely washed out. The action potential component is directly affected by the 3 pillars, and there are “other systems” that affect the action potential dynamics (like GPCRs such as serotonin, dopamine, acetylcholine (muscarinic receptors), and Neurosteroids, as well as neurotrophic factors like BDNF and many other neuromodulators). Some of these GPCRs, for example are directly coupled to GABAa receptors. The Benzodiazaphine effects on serotonin, dopamine and acetylcholine, thus tend to exasperate withdrawal symptoms because of the GPCR’s intrinsic effects on the neuron, and because of the GPCR’s intracellular coupling to GABAaRs. As mentioned earlier, there are many many other neuromodulators that affect neural circuit neuroplasticity, but the three most relevant ones relative to benzodiazaphine use and withdrawal are the three systems listed above. There are also a large number of growth factors, including serotonin (see earlier post)and dopamine, that affect adult neurogenesis, but for simplicity, the three systems that are affected most profoundly by benzodiazaphines are those listed above. 2.1.More on the model, GABAergic signaling, and neurogenesis….. The references in the area of neurotransmitter effects on neurogenesis are numerous. I want to very briefly focus on the “ GABAergic to neurogenesis link” (pillar number 2 to component number 2 , above) portion of the model, because this link and the link of” GABAergic to action potential dynamics”, are the most obviously affected links by benzodiazaphines (at least initially). Regarding an in depth review of the latest research on GABAa receptors and neurogenesis see the Palotto reference(2014) cited in the Neurogenesis (PART 1) paper. Abstract https://www.ncbi.nlm.nih.gov/pubmed/24999317 Full text is also available.(see Neurogenesis (PART 1)) Reiterating some of the points made in the Neurogenesis (PART 1) paper posted earlier: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5043052/ Thinking after Drinking: Impaired Hippocampal-Dependent Cognition in Human Alcoholics and Animal Models of Alcohol Dependence Miranda C. Staples and Chitra D. Mandyam Front Psychiatry. 2016; 7: 162. Published online 2016 Sep 30. doi: 10.3389/fpsyt.2016.00162 1.Why is the hippocampus so dramatically affected by the “ GABAergic to neurogenesis link” in the model? Neural stem cells are abundant in the hippocampus: Quote A critically unique region of the hippocampus, the dentate gyrus (DG), contains neural stem cells that continue to divide and primarily generate functional neurons into adulthood in nearly all mammalian species (55) and have proved critical for pattern separation functionality (56). End quote 2.Do neural stem cells have GABAaRs? The answer is yes. If neural stem cells did not have GABAaRs, the link in the model (“GABAergic to neurogenesis “) would simply not exist. Some references are listed below. Also please refer to the Palloto reference cited above. From the Palotto reference: Quote In the subgranular zone (SGZ) of the DG, GABA neurotransmitter, released by a specific population of interneurons, regulates stem cell quiescence and neuronal cell fate decisions. Similarly, in the subventricular zone (SVZ), OB neuroblast production is modulated by ambient GABA. Ambient GABA, acting on extrasynaptic GABAA receptors (GABAAR), is also crucial for proper adult-born granule cell (GC) maturation and synaptic integration in the OB as well as in the DG. Throughout adult-born neuron development, various GABA receptors and receptor subunits play specific roles. Previous work has demonstrated that adult-born GCs in both the OB and the DG show a time window of increased plasticity in which adult-born cells are more prone to modification by external stimuli. One mechanism that controls this "critical period" is GABAergic modulation. Indeed, depleting the main phasic GABAergic inputs in adult-born neurons results in dramatic effects, such as reduction of spine density and dendritic branching in adult-born OB GCs. End quote There are many other references in this area of adult neural stem cells and GABAaRs. Here are a few more: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2566617/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3541438/pdf/nihms410120.pdf https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3839947/ 3.How exactly could positive modulation of the GABAaR during alcohol use, or GABAaR dysfunction following withdrawal or tapering from alcohol use, affect Hippocampal neurogenesis? This is the big question that needs to be answered to legitimize this link of the model. Hippocampus-dependent cognitive dysfunction seems to be protracted after cessation of alcohol and abstinence. Temporally, hippocampal cognitive recovery is much longer than prefrontal cortex cognitive recovery. Quotes This is most widely apparent as frontal cortex-dependent cognitive dysfunction, where executive function and decision-making are severely compromised, as well as hippocampus-dependent cognitive dysfunction, where contextual and temporal reasoning are negatively impacted. This review discusses the relevant clinical literature to support the theory that cognitive recovery in tasks dependent on the prefrontal cortex and hippocampus is temporally different across extended periods of abstinence from alcohol. Additional studies from preclinical models are discussed to support clinical findings. Finally, the unique cellular composition of the hippocampus and cognitive impairment dependent on the hippocampus is highlighted in the context of alcohol dependence. ….. It is possible that this disparity [between hippocampal and PFC recovery rates] is due to, at least in part, the ongoing adult neurogenesis in the hippocampus which occurs at a much lesser rate in the PFC of mammals [when compared to the hippocampus](146); neurons which would be generated during critical periods of withdrawal would be developing into mature neurons during a time of negative affect (147, 148), potentially resulting in a pathologic phenotype and dysfunctional characteristics (149). This problematic phenomenon would be far more impactful in a region with high neurogenesis (such as the hippocampus) as compared with a region of low or absent neurogenesis, where the typical functioning of the existing circuitry may return upon complete washout of the drug. End quote 4.And the quotes below, for more detail on the proposed mechanisms of action, involved in the aberrant morphology. This could occur with abrupt withdrawal, tolerance, or even during a non-symptom based rapid taper that does not allow time for the GABAaR to “heal” or acclimate to the successively lower daily dosages. Note that specific Subunit compositions of the GABAaR differentially modulate important stages of neurogenesis. This is one reason why different benzodiazaphines, each with their own unique Subunit binding affinity profiles, have different protracted withdrawal and withdrawal/tolerance severity characteristics for certain individuals. Quote The granule cells of the hippocampus are maintained in a quiescent [quiet or inacitve] state by the mossy fibers of the hilus viaGABA-ergic regulation [reviewed in Ref. (161)]. Evidence has demonstrated that these cells do express GABAaRs (162), as do the surrounding cells of the DG( 163, 164); therefore, not only are the granule cells sensitive to enhanced GABA-ergic transmission during exposure to chronic alcohol but are also subject to secondary regulation due to the modulation of activity of surrounding cells by alcohol’s actions on the GABAaR. As specific subunit compositions of the GABAaR can modulate important stages of neurogenesis (particularly the maintenance of quiescent cells and proliferation), this could provide a potential mechanism by which alcohol could be modulating neurogenesis in dependent individuals. During periods of alcohol intake, GABAaR function would be supported and facilitated such that quiescent cells would be maintained (165, 166) as such and proliferation would be reduced (167–169). In the acute absence of alcohol, the facilitation of GABAaR activity would be lost (dm123: due to downregulation or desensitization of the receptor; the same would occur with abrupt cessation of benzodiazaphines, and also as tolerance to the drug or alcohol develops) and quiescent cells would be allowed to proliferate, and these effects could result in increase or decrease in cell survival in the days following withdrawal (169–171). However, impaired GABA-ergic receptor function has been shown to restrict morphology[the form] of newly born cells (172), which could reduce the number of synaptic connections and network integration required for survival and function of the granule cells and, therefore, result in net reduction of the number of surviving cells during protracted abstinence (171). This finding serves as a potential argument for the reduced survival subsequent to the increased proliferation following withdrawal in dependent animals (171). End quote The implications of the above are clear and powerful. A restriction in morphology in new born cells would reduce dendritic length and spine density, ultimately reducing the number of synaptic connections , and the integration of the new neuron into the neural circuit fabric. Without synaptic connections the neuron will simply not survive. In layman’s terms these newly developing neurons are starved to death, resulting in a lower ongoing rate of neurogenesis Finally, this last part emphasizes that although it’s clear that hippocampal neurogenesis results in aberrant morphology post withdrawal, this cannot be definitively linked to the protracted cognitive dysfunction, without further studies directly linking the aberrant morphology with physiological deficits in cognition. Thus, further research is required. This is where NEW research should be conducted…… Quote Unfortunately, there is no conclusive evidence linking aberrant neurogenesis subsequent to alcohol dependence and impaired hippocampal cognitive function. Future studies will be required to demonstrate the plausibility of this mechanism as an underlying explanation for the deleterious effect of alcohol dependence on hippocampal function. Preclinical findings in animal models of alcohol exposure support the clinical observation; mechanistic studies support that this temporally differential rescue (dm123: i.e., recovery) of PFC-dependent tasks is potentially due to the neurogenic deficits in the hippocampus during abstinence, such that the birth of new neurons during periods of negative affect result in the persistence of the hippocampal-specific cognitive disparities.(dm123: a post withdrawal syndrome) Many questions remain unanswered with regard to human hippocampal function during periods of alcohol abstinence. For example, it is clear that employing cognitive therapy can support individuals in successful attempts at abstinence End quote The key takeaway is that dysfunctional GABAergic signaling (from chronic use, withdrawal, tolerance, or complete cold turkey) has the potential to start the downward spiral into what we understand as a long drawn out recovery. Regions of the brain that are highly plastic, according to this model, would be affected most severely. 2.2. GABAergic and Glutamatergic influences on neurogenesis. Not just the GABAaR….enter the GABAbR For another example, see this older (2008)reference on GABAergic and glutamatergic (2 of the 3 pillars) influences on neurogenesis. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2538920/ I found this quote particularly interesting from the reference above , because the GABAb receptor (a metabotropic receptor in the GPCR class) is often ignored in the discussions about GABAergic signaling and neurogenesis. Quote In her presentation and in the review paper in this issue (Markwardt & Overstreet-Wadiche, 2008) she explored the involvement of GABAB receptors in adult neurogenesis, a neglected topic as much research focused on chloridepermeable GABAA receptors. The starting hypothesis was that hyperpolarization via GABAB receptor-mediated activation of inward-rectifying K+ channels would counteract GABAA-mediated depolarization (dm123: note this was the hypothesis; also note that GABAa receptors are excitatory or depolarizing early on in the neuron’s development). Her results showed that GABAB receptor-mediated K+ responses are absent in newborn granule cells but it is not known if this is due to the lack of functional GABAB receptors, GIRK channels or coupling between the two. She concluded that GABAergic signalling in newly developed DGCs is optimized for depolarization-mediated functions. (dm123: i.e., GABAaR mediated signaling) End quote Note: since GABAb K+ responses are absent in newborn granule cells, this points to GABAa receptors being the primary drivers during neurogenesis via depolarization. However, GABAb receptors are also coupled to other channels like VGCCs, and IF GABAb receptors are functional in the newborn cell(we aren’t sure about this……yet!), it might have effects on neurogenesis through these other GABAb channel couplings. This area needs more research. Some answers are in the 2014 study cited below in section 2.3!! End quote In a nutshell, the quote above is basically implying that GABAa receptors, and not GABAb receptors are the major GABAergic receptor affecting neurogenesis. Remember, upon withdrawal or tolerance, the GABAa receptor recovery is typically slow and insufficient to support healthy neurophysiology. If GABAa receptors and not GABAb receptors are the primary drivers for GABAergic neurogenesis, this would explain why benzodiazaphines and other GABAa PAMS have a higher propensity to cause a PWS, than GABAb agonists. In addition, GABAa receptors in and of themselves seem to be a very temperamental receptor that does not respond well to chronic exogenous modulation (i.e., alcohol or benzodiazaphines) The above would confirm the research that implicates impaired GABAa neurogenesis as a factor in this mysterious PWS (alcohol study), and support the robustness of this proposed benzodiazaphine tolerance and wd model. But what if GABAbR agonists actually suppressed adult neurogenesis early in the neurogenic lifecycle?? … 2.3. GABAb receptors and neurogenesis. More recent clinical research…. To continue the interesting discussion above , more recent research (2014, see pdf citation below) indicates that GABAb receptor activity may actually suppress adult neurogenesis in the hippocampus. Note that the citation below states that genetic deletion or pharmacological inhibition of the GABAb receptor stimulates and increases adult neurogenesis. Furthermore the researchers found that a GABAB receptor antagonist activated quiescent (i.e. Inactive) NSCs (neural stem/progenitor cells) (i.e., increased neurogenesis), whereas a GABAB receptor agonist (baclofen) promoted NSC quiescence (inactivity).(i.e., decreased neurogenesis) http://dev.biologists.org/content/develop/141/1/83.full.pdf Quote Adult neurogenesis is tightly regulated through the interaction of neural stem/progenitor cells (NSCs) with their niche. Neurotransmitters, including GABA activation of GABAA receptor ion channels, are important niche signals. We show that adult mouse hippocampal NSCs and their progeny express metabotropic GABAB receptors. (dm123: this is the first major revelation in the article; recall the earlier 2008 study cited above, which lacked this evidence) Pharmacological inhibition of GABAB receptors stimulated NSC proliferation and genetic deletion of GABAB1 receptor subunits increased NSC proliferation and differentiation of neuroblasts in vivo. Cell-specific conditional deletion of GABAB receptors supports a cell-autonomous role in newly generated cells. Our data indicate that signaling through GABAB receptors is an inhibitor of adult neurogenesis. End quote 2.4.GABAb antagonists and antidepressant neurogenesis The quote below, is from the same reference above, regarding the antidepressant effects of GABAb antagonists (note: not agonist and not positive modulators, but direct antagonists). This antidepressant effect would be through a similar mechanism as that of pharmaceutical antidepressants: via increased neurogenesis.(see earlier post on serotonin and neurogenesis in PART 1 of the neurogenesis paper). However, the concern is that pharmaceutically antagonizing the GABAbR might produce unforeseen “side effects”, such as upregulation or sensitization of the receptor once the antagonist is washed out. However, it is known that GABAb receptors, unlike GABAa receptors, are very stable at the cell surface, at least relative to agonist stimulation. I’m not sure if the same holds true in terms of antagonist activation, but one could infer this. (Interestingly, the number of cell surface GABAbRs is primarily controlled by glutamate and not GABA activation, via crosstalk between glutamate and GABAb receptor types, in central neurons. As I mentioned earlier, these systems or pillars all affect one another in a very intricate manner….. Given the above one could surmise that during GABAb agonist-only administration, neurogenesis would be suppressed or stunted. However, after tapering the GABAb agonist, if negative stressors are mitigated, a neurogenesis-and-stress-related protracted withdrawal feedback loop would be much less likely, because the GABAbR is quick to recover. This is because the GABAbR is much more stable at the cell surface than GABAaRs are. The neurogenesis would have a much better chance of recovery in GABAb-agonist only administration, given that the receptor function does not deteriorate as in GABAa-PAM administration.. Quote NSCs become mostly quiescent during aging, and this correlates with a dramatic reduction in neurogenesis with age (Hattiangady and Shetty, 2008; Jessberger and Gage, 2008; Lugert et al., 2010). However, NSC quiescence is reversible, and this could be exploited to rejuvenate neurogenesis in the aged or damaged brain (Hattiangady and Shetty, 2008; Lugert et al., 2010). Importantly, excitation as well as specific neurotransmitters can activate the latent stem cell pool (Jhaveri et al., 2010; Lugert et al., 2010), and here we propose that GABAB receptors can contribute to this process. Therefore, manipulation of GABAB function may be a novel approach to modulate adult hippocampal neurogenesis in vivo and during aging. Recently, GABAB receptors have attracted attention as potentially being involved in the etiology of depression, and GABAB blockade causes antidepressant-like effects (Cryan and Slattery, 2010). Given that antidepressant drugs can promote adult neurogenesis and new hippocampal neurons have been implicated in mediating some effects of antidepressants (Petrik et al., 2012), our findings are relevant for human disease. Indeed, increased proliferation in the ventral hippocampus has been suggested as a plausible mechanism for the antidepressant-like effects of chronic treatment with GABAB receptor antagonists (Felice et al., 2012). End quote 2.5.And this, describing how GABAaRs and GABAbRs coordinate with each other during adult neurogenesis. Another example of mechanisms in neurophysiology that are a delicate balancing act : Quote Together, our data suggest that metabotropic GABAB receptors are already active in the cells at the start of the adult neurogenic lineage. This may represent a novel mechanism to integrate hippocampal network activity, GABA release and NSC proliferation. Based on continued expression of GABAB subunits in more differentiated cell types, further regulation by GABAB may occur downstream of NSCs during adult hippocampal neurogenesis. Indeed, our results show that differentiation of neuroblasts is accelerated in mice lacking the GABAB1 receptor subunits, without there being a significant effect on newborn neuron survival. Notably, and in contrast to the action of the GABAB receptors, activation of GABAA receptors promotes differentiation along the neuronal lineage, survival of new neurons as well as asynaptic integration in the adult DG (Tozuka et al., 2005; Ge et al., 2006; Jagasia et al., 2009). Therefore, GABAB receptors can potentially synergize with GABAA receptors to inhibit NSC division (Song et al., 2012) and counteract the differentiation-promoting effects of GABAA receptors later within the neurogenic lineage (Tozuka et al., 2005; Ge et al., 2006). End quote The bottom line… Thus, the full story is that both GABAaRs and GABAbRs are present and active at the start of neurogenic lineage in neural stem cells. This is another illustration of the fine balancing act that is present in cellular neurophysiology and adult neurogenesis (We saw something very similar in terms of neuroplasticity and the fine balancing act between LTP and LTD, relative to cortisol levels, in an earlier post. Every physiological process in the body boils down to homeostatic balance in one form or another) 2.6.How does all of this information fit into the model? For one thing, we now realize that the“ GABAergic to neurogenesis link” in the model involves both GABAaRs and GABAbRs. The GABAaRs induce neurogenesis and the GABABRs suppress neurogenesis. The model also perhaps explains why GABAb agonists are a mixed bag as a therapeutic protocol during benzodiazaphine withdrawal and recovery (note benzodiazaphines are taken at the same time as GABAb agonists, in this scenario). There’s no doubt that GABAb agonists dramatically assist in normalizing the action potential dynamics part of the model during withdrawal. This can be a lifesaver during acute benzodiazaphine withdrawal. However, their effects on neurogenesis, in light of the reference above, implies that they could possibly impair neurogenesis in the all important Hippocampal recovery phase, post recovery. Thus, they seem to offer a very good immediate therapeutic benefit (and GABAbRs, unlike GABAaRs, are very stable at the cell surface in terms of agonist stimulation). However, GABAb agonists might present as a liability relative to neurogenesis during chronic benzodiazaphine use and during benzodiazaphine post withdrawal recovery, as the rate of neurogenesis would suffer more of a “setback”, for lack of a better term. As mentioned in the Neurogenesis (PART 1) paper, the aberrant neurogenesis along with negative reinforcing stressors, are what perpetuates withdrawal even after the benzodiazaphine is flushed from the body. This feedback also occurs during tolerance to the benzodiazaphine or during withdrawal from the benzodiazaphine, as the GABAaR is very sensitive to modulation (i.e., it can downregulate or desensitize), and the receptor takes a very long time to revert to normal. With a therapeutic GABAb agonist onboard during and post withdrawal this could partially suppress the healthy neurogenesis recovery that is required for Hippocampal neurogenic recovery. This is a necessary recovery during post withdrawal, if one hopes to regain full neurophysiological function. 3.Back to Benzodiazaphines,neurogenesis, and the GABAa receptor Given the above, GABAb antagonists appear to fosterneurogenesis, and agonists appear to suppress neurogenesis. On the other hand, tolerance and withdrawal from chronic GABAaR positive modulation has been postulated to cause aberrant neurogenesis (see alcohol study in earlier post), and this is via the drug or alcohol induced dysfunction in the GABAaRs. This study can be extrapolated to benzodiazaphines. Healthy GABAaRs, unlike GABAbRs, for the most part promote neurogenesis and are excitatory early on in the neuron’s development lifecycle. In fact, to further elaborate, benzodiazaphines, in and of themselves, seem to adversely affect neurogenesis. Benzodiazaphines tend to counteract or block antidepressant induced neurogenesis.(They also impair neurogenic LTP learning in hippocampus, so they adversely affect neuroplasticity). So impaired neurogenesis can occur even prior to tolerance or withdrawal, with just chronic benzodiazaphine use. However, most likely the impact on neurogenesis is much much less severe than in the tolerance an withdrawal phases, wherein GABAaR signaling is more severely compromised. So both withdrawal from and tolerance to benzodiazaphines and chronic use of benzodiazaphines have adverse affects on adult neurogenesis. https://www.ncbi.nlm.nih.gov/pubmed/23639432 Quote We demonstrate that 9 weeks of social isolation induces a deficit in motivational behaviour with increased anxiety as well as impairment in hippocampal neurogenesis. This was parallelled by reduced BDNF levels in the hippocampus. While treatment with fluoxetine alone for 3 weeks restored anxiety behaviour as well as progenitor cell proliferation and the generation of new hippocampal neurons, this effect was prevented by co-administration with diazepam. This suggests that co-administering benzodiazepines with antidepressants could significantly delay or prevent the cellular and behavioural improvement needed by patients. These findings indicate the need for future clinical studies designed to investigate the combined effects of benzodiazepines and antidepressants in patients. End quote Benzodiazaphines reduce anti-depressant induced neurogenesis in the DG https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4374628/ Quote Our results in mid-dentate, and to some degree anterior dentate, gyrus are consistent with murine findings that benzodiazepines counteract antidepressant-induced increases in neurogenesis by interfering with progenitor proliferation. We also confirmed, in this expanded sample, our previous finding of granule neuron deficit in untreated MD. End quote 4.What about the model and Cold Turkey cessation of benzodiazaphines? The model developed thus far is primarily for modeling benzodiazaphine withdrawal and tolerance. The model also attempts to characterize the corner case of PWS when the benzodiazaphine is properly and slowly tapered. This is a very poorly defined and sparse area of the clinical research: Why do a small percentage of people continue to suffer withdrawal symptoms long after the cessation of the drug (technically 18 months post taper), even when the drug has been tapered properly? An obvious reason is a taper that’s not symptom based. But what about the others that do a symptom based taper? These cases are what the model attempts to characterize. (Individualistic responses and recoveries from what are referred to as “neural circuit crashes” , will also be explored in the ongoing Neural circuits paper) How does the model hold up with cold turkey abrupt withdrawal from the benzodiazaphine? Two of the three pillars are directly destabilized by a cold turkey. The GABAergjc pillar is profoundly compromised at the time of abrupt cessation as the receptor has not been given any time whatsoever to “heal”. Thus the post synaptic membrane potential is highly predisposed to severe and protracted depolarization(massive chloride depletion). This sets up the neuron for long term plastic changes at the glutamatergic synapses in the form of non-hebbian long term potentiation(LTP). Thus, there are long term excitatory potentiations at glutamatergic post synaptic synapses as described in these 2 pinned excellent documents by Perserverance: Nuclear Mechanisms of the PWS syndrome Benzodiazaphine withdrawal, glutamate receptors, and LTP In a nutshell, this results in hyperexcitability of neurons throughout the brain. Stress resiliency dramatically and rapidly deteriorates. As stress resiliency deteriorates, the stress forms a feedback loop. Negative stress in the stress system (the third pillar to go down), in and of itself inhibits neurogenesis. Furthermore, persistently elevated cortisol levels (prior to hypothalamic-pituitary shutdown) induce aberrations in the delicate balance between LTP and LTD, particularly in the hippocampus, as explained in an earlier post (RST2) Hence, from the onset of the cold turkey, 2 of the 3 pillars are horribly destabilized, with the third to fall shortly thereafter. We know from the sections above that the dysfunction in the GABAergic system leads to aberrant Hippocampal neurogenesis (see alcohol study). The stress system (pillar number 3) rapidly becomes dysfunctional because: 1. The dysfunction in the GABAergic system (GABAergic based CRH modulation directly affects the HPA),(Note: CRH in turn can decrease benzodiazaphine binding, making GABAa receptor inhibitory signaling less efficient. Extreme stress raises CRH; see also point 2 , below) 2. Sustained elevated cortisol levels during cold turkey withdrawal itself, which further contributes to aberrant (reduced rate of) Hippocampal neurogenesis,(…and stress induced elevated CRH levels reduce inhibitory signaling efficiency, see point 1, above ) 3. Sustained elevated cortisol levels contribute to dysfunctional LTP and LTD (Neuroplasticity )in the hippocampus (see RTP2 and Neurogenesis PART 1 papers posted earlier). This is primarily due to the differential effects that glucocorticoids have on the inhibitory post synaptic current frequencies and amplitudes which affect VGCCs and group I metabotropic glutamate receptors. It’s also due to glucocorticoid effects directly on VGCCs and NMDARs. 4. Aberrant neurogenesis and hyperexcitability in the hippocampus rapidly causes a deterioration in stress resiliency and symptomatic anxiety at even very low stress levels. Once neurogenesis becomes aberrant and stress resiliency breaks down, the feedback cycle ensues and perpetuates the issue, according to the model dynamics. In the case of cold turkey, the model predicts a much much higher probability and greater severity of PWS because all three pillars are completely destabilized. Nonetheless, although slow and difficult , recovery is still possible. 5.Resiliency of the model, and why we need to layer in Neural Circuit dynamics We have discussed stress resiliency as it applies to the model, the hippocampus and the HPA, but what about the resiliency of the model itself?!! A biological model is only useful if it is able to dynamically account for real life challenges across a wide variety of individuals. If system x is affected by y, does the model correctly predict what happens to the individual biological entity in term of physiological function? That’s the key. It should be flexible enough to account for differences in responses to a given perturbation between individuals, and ideally should be applicable to all individuals in a population. Here, the population is current and former chronic users of benzodiazaphines. We will learn much more about what constitutes “physiological function” in terms of neurophysiology in the neural circuits paper. We will also see how homeostatic plasticity in the neural circuit accounts for how various individuals respond to the same perturbation or stress. Homeostatic plasticity accounts for why we all have consistent physiological function when stressed (up to a point), why we all crash uniquely, and perhaps why all of our recoveries are so very unique…..This aspect of the model is necessary to understand the differences and similarities between individuals when their nervous system encounters a perturbation or stress such as benzodiazaphines. This aspect of the model is absolutely required to model real life biological entities because neurons do not live in isolation in the real world. Neuromodulators act in concert with feedback mechanisms to insure that physiological function is maintained. Homeostatic plasticity takes over to maintain physiological function, but it can only accommodate stress to a certain point ……Benzodiazaphines inflict one of the most potent stressors to neural circuits, because inhibitory signaling forms the backbone of all types of neural circuits, and the output of neural circuits are what determine our physiological function. We will see just how critical inhibitory signaling is, in the context of neural circuit output in the Neural Circuits paper. We must continue to challenge the model with our unique withdrawals and recoveries. In challenging the model, it with ultimately become a better and more robust model…… ~Finito~ Link to comment Share on other sites More sharing options...
[Su...] Posted March 3, 2018 Share Posted March 3, 2018 fantastic.... It always is good to see the science behind what we are doing: a sxs based slow taper to allow the body to recover. Although it is scary to consider the aftermath of all of this. Thanks for all your hard work in bringing this to us! SS Link to comment Share on other sites More sharing options...
[Re...] Posted March 4, 2018 Share Posted March 4, 2018 Fantastic work. Your contribution, dm123, has had a huge impact on my understanding. Through this process, my awareness of what is happening has been akin to observing an image in a highly fractured mirror. There is a sense of what the image looks like but the cracks distort it so much as to make a full appreciation impossible. Your contribution has helped eliminate so many of those distorting cracks and vastly improved my sense of the complex interactions occurring in our bodies. Perseverance, faultandfracture and others have helped me too and it is just this type of community of knowledge that may see us through to, perhaps, an approach that brings the healing we all hope for. -RST Link to comment Share on other sites More sharing options...
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