Can anyone make sense of this to explain to a layperson?

[[cs...]]

And once our cells are damaged, there could be an immune response to those damaged cells.  Read fellow bb,  Hope4us's latest posts.  Docs found tons of autoantibodies attacking her brain and body causing further symptoms and damage.  Docs gave her immunoglobulin, but not sure how it worked out for her since she hasn't posted since last year.

 

Thanks BecksBlue.  I did read an interesting thread on Autoimmune encephalitis, here on BB around 4 months back.  I'm thinking that was the one.    She had very severe symptoms.  Praying for her.

[[Su...]]

Hi SufferingSixity

 

Congrats on halfway point.  It feels great, doesn't it. :)

 

Thanks for bumping.

 

Perhaps one of the admins can pin it in this Chewing the Fat along with the other articles so that it gets more visibility.  Also,perhaps re-title it as "Physiological Homeostasis and Benzodiazpahines: Tolerance, Withdrawal, and Recovery"

 

Spread the word about those orthosteric agonists and PAMs! to your fellow newbie BBs.

 

Knowledge is power, and unity is power!    Soon, we, as a group, can get these drugs reclassified to Schedule II in the U.S.  ......especially the shorter acting ones like lorazepam, xanax, and clonazepam.  They serve no medical therapeutic purpose outside of the hospital.  The only exceptions are for seizure disorders, and  for systemic genetic defects in the GABA system and neuromuscular diseases, etc.

 

ff rat I'm not trying to intentionally make it harder to get an Rx, but Schedule II will make the docs and naturopaths think twice about prescribing these drugs so indiscriminately for things like anxiety.  Publicity will help as well.  Opiates are already seeing a significant drop oe in the number of prescriptions.  I know this fosters illegal distribution of the drug, but reclassification of benzodiazaphines is a good start.  Nothing is perfect.

 

Best wishes.

 

Yes to the reclassification of these poisons!  I know that my GP has said that she is much less likely to prescribe them any longer and is trying to get all her patients to consider tapering.  (She's good she won't "make" anyone taper, she is pointing out that long term use is dangerous and she will help anyone taper in any way that she can).

Information is such power!  And the more I learn the more empowered I feel in the face of these challenges.  Thank you so much for your research and generosity in sharing.

[[cs...]]

Hi SufferingSixity

 

Congrats on halfway point.  It feels great, doesn't it. :)

 

Thanks for bumping.

 

Perhaps one of the admins can pin it in this Chewing the Fat along with the other articles so that it gets more visibility.  Also,perhaps re-title it as "Physiological Homeostasis and Benzodiazpahines: Tolerance, Withdrawal, and Recovery"

 

Spread the word about those orthosteric agonists and PAMs! to your fellow newbie BBs.

 

Knowledge is power, and unity is power!    Soon, we, as a group, can get these drugs reclassified to Schedule II in the U.S.  ......especially the shorter acting ones like lorazepam, xanax, and clonazepam.  They serve no medical therapeutic purpose outside of the hospital.  The only exceptions are for seizure disorders, and  for systemic genetic defects in the GABA system and neuromuscular diseases, etc.

 

ff rat I'm not trying to intentionally make it harder to get an Rx, but Schedule II will make the docs and naturopaths think twice about prescribing these drugs so indiscriminately for things like anxiety.  Publicity will help as well.  Opiates are already seeing a significant drop oe in the number of prescriptions.  I know this fosters illegal distribution of the drug, but reclassification of benzodiazaphines is a good start.  Nothing is perfect.

 

Best wishes.

 

Yes to the reclassification of these poisons!  I know that my GP has said that she is much less likely to prescribe them any longer and is trying to get all her patients to consider tapering.  (She's good she won't "make" anyone taper, she is pointing out that long term use is dangerous and she will help anyone taper in any way that she can).

Information is such power!  And the more I learn the more empowered I feel in the face of these challenges.  Thank you so much for your research and generosity in sharing.

 

I'm glad she or  you added the small amt of Valium to level off your serum levels.  I was crossed over from lorazepam to Librium.  No way I could cut directly from lorazepam, as I hit tolerance as well.

[[cs...]]

Hi, these are some quotes from this wonderful (but long) medical journal article on the allosteric stress response model.  In considering that benzodiazaphines are a stress to the status quo of the neuron, the excerpts below give us some context into how far the body goes to achieve homeostasis, even if it's a newly established homeostasis.  Downregulation, upregulation, alterations in gene expression of the GABA receptor, etc, begin to make sense when viewed from this model.  The brain as the control center is adjusting parameters to meet the demands of its new environment....in this case an overly suppressed CNS.

 

------

 

The example of high blood pressure is an example that they use throughout the article.  Eventually, when stressed consistently over a long period of time, the arteries undergo physiological changes to accommodate the high blood pressure.  Other physiological changes occur as well.

 

Blood pressure arousal analogy

In short, the system is responding to “anticipated demand” (Sterling, 2004, p. 24), as the aroused brain activates the sympathetic and hormonal systems. These increase cardiac output, blood volume, sodium appetite (and thus sodium intake), and vascular constriction to temporarily raise blood pressure. When arousal becomes chronic, the body adapts by thickening arteriolar smooth muscle and increasing the vascular wall-to-lumen ratio so that they are more effective in maintaining a higher blood pressure (Boulos & Rosenwasser, 2004; Sterling, 2004). For such individuals, even under conditions of maximum relaxation, blood pressure does not decrease to the previous low point. This is because blood pressure Is maintained by vascular resistance such that a higher blood pressure is needed to maintain the same blood flow (Boulos & Rosenwasser, 2004; Folkow & Neil, 1971; Lund-Johanson, 1984). The vascular system, under the direction of the aroused brain, has adjusted its parameters to meet the demands of the chronically stressful environment.

End quote

 

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2808193/#!po=10.4839

 

Quotes

 

Thus, when a physiological system is activated by a current stressor, it accommodates by adjusting its parameters within a range of functioning (allostatic accommodation). “Different circumstances demand different homeostatic set points” (Sapolsky, 1998, p. 7). These changes will have cascading effects in other systems, producing organism-wide accommodation to the environment. Thus, in response to a stressor, the organism is not struggling to get its homeostatic systems back into their initial balance. Instead, it is making wide-ranging physiological changes in order to find a new homeostasis that better fits the circumstances (McEwen, 1998). By identifying the brain as the central mediator of allostatic accommodation to a stressor, Sterling and Eyer’s (1988) theory of allostasis accounts for the effects of anticipatory arousal, appraisal, coping, learning, and memory on physiological regulation under adversity and subsequent effects on health.

 

Allosteric load

Notably, under conditions of repeated or chronic stress, this system-wide accommodation can combine with the physiological tendency for the body to create “fixed automatisms” (Sterling & Eyer, 1988, p. 641) and cause the lasting cardiovascular alterations associated with high blood pressure, as well as a range of other possible changes, such as alterations in the concentration and receptor densities of key hormones (e.g., Blanchard, McKittrick, & Blanchard, 2001; Yehuda, 1997) or irreversible activation and/or downregulation of the transcription of specific genes (e.g., Levine, 2001; Valentino & Van Bockstaele, 2004). Implicit in this analysis is the notion that allostatic accommodation over time also results in“wear and tear” in the very systems that are experiencing adaptation to meet the environmental challenge (McEwen, 1998).

 

Rutter has referred to the effects of prior stressors as the “long-term carry-forward of the sequelae of stress and adversity” (Rutter, 1994, p. 373) and argued that they must be accounted for in any formulation of the stress process. In allostasis, the new balance of system parameters that follows stressor exposure comes at a physiological cost that McEwen and Stellar (1993) have called allostatic load. This cost can occur through the adoption of Sterling and Eyer’s “fixed automatisms” (1988. p. 641), i.e., those small and large physiological changes that do not revert to the way they were when the challenge has passed. Such changes may be helpful in the short term (as with the increases in blood pressure discussed above) but may have negative long-term consequences for the organism (e.g., increased wear-and-tear on the heart). This cost can also come through damage due to overproduction of the neurochemicals involved in the stress response, some of which are toxic. For example, persistent high concentrations of cortisol can cause damage to regions of the hippocampus (e.g., Bremner et al., 1995; Gurvits et al., 1996; Sapolsky, 1984; Sapolsky et al., 1986; Uno, Tarara, Else, Suleman, & Sapolsky, 1989) and inhibit neurogenesis in this region (Gould, McEwen, Tanapat, Galea, & Fuchs, 1997), both of which potentially interfere with cognition and future adaptation to stressors. Allostatic load can also occur through exhaustion of stress response systems, as can occur in the immune system. This can result in compromised immunocompetence, which is related to higher levels of infection and vulnerability to cancer (Cohen, Tyrrell, & Smith, 1991; Sapolsky, 1998; Sapolsky & Donnelly, 1985). Increased load can also come through the inability to activate a particular stress response system, in which case other stress responses over-respond (McEwen, 1998).

 

 

The concepts of allostasis and allostatic load allow for dynamic change in the adaptive capacity of the organism and they highlight individual differences in ability to withstand stressors (which can be related to Antonovsky’s [1974] early concept of “homeostatic flexibility”). By defining this accumulating cost of physiological adaptation and outlining some of the biomarkers by which it might be identified, McEwen and Stellar (1993) provided a conceptual framework to explain the accumulated effects of prior experience on physical and mental health (e.g., Boulos & Rosenwasser, 2004; Heim et al, 2000; Levine, 2001; Mason, 1971, 1975a; Resnick, Yehuda, Pitman, & Foy, 1995).

 

[[Be...]]

I was diagnosed with Paroxsymal Tachycardia and Thrombophilia and even Lupus a few years ago. I really think my entire cardiovascular system is messed up.  I've had head pressure for over 4 years now.  I have too much stress on me all the time. 

[[cs...]]

Hi BecksBlue, were these all after you stopped benzodiazaphines.  I assume so, in looking at your signature. 

[[Be...]]

Hi BecksBlue, were these all after you stopped benzodiazaphines.  I assume so, in looking at your signature.

 

When I was in tolerance and interdose w/d after being on the pills for 3 years, I went to the docs complaining of dizziness and bad anxiety.  He sent me to a neurologist where my ANA, anti-nuclear antibody, screening test, was positive.  Then I went to a Rheumatologist and she ran more tests and then diagnosed me with Lupus.  Then I took all my med. records to see a Hematologist and he diagnosed me with Thrombophilia.  Then two years off of the pills I went to a family doc and he told me to stand up and then he checked my heart and diagnosed me with Paroxsymal Tachycardia.  I know it's from the pills.  I never had any of these problems before getting off the pills.  I worked a very physically demanding job and had to use my mind too alot.  I'm brain and nerve damaged for sure.   

[[Su...]]

Hi SufferingSixity

 

Congrats on halfway point.  It feels great, doesn't it. :)

 

Thanks for bumping.

 

Perhaps one of the admins can pin it in this Chewing the Fat along with the other articles so that it gets more visibility.  Also,perhaps re-title it as "Physiological Homeostasis and Benzodiazpahines: Tolerance, Withdrawal, and Recovery"

 

Spread the word about those orthosteric agonists and PAMs! to your fellow newbie BBs.

 

Knowledge is power, and unity is power!    Soon, we, as a group, can get these drugs reclassified to Schedule II in the U.S.  ......especially the shorter acting ones like lorazepam, xanax, and clonazepam.  They serve no medical therapeutic purpose outside of the hospital.  The only exceptions are for seizure disorders, and  for systemic genetic defects in the GABA system and neuromuscular diseases, etc.

 

ff rat I'm not trying to intentionally make it harder to get an Rx, but Schedule II will make the docs and naturopaths think twice about prescribing these drugs so indiscriminately for things like anxiety.  Publicity will help as well.  Opiates are already seeing a significant drop oe in the number of prescriptions.  I know this fosters illegal distribution of the drug, but reclassification of benzodiazaphines is a good start.  Nothing is perfect.

 

Best wishes.

 

Yes to the reclassification of these poisons!  I know that my GP has said that she is much less likely to prescribe them any longer and is trying to get all her patients to consider tapering.  (She's good she won't "make" anyone taper, she is pointing out that long term use is dangerous and she will help anyone taper in any way that she can).

Information is such power!  And the more I learn the more empowered I feel in the face of these challenges.  Thank you so much for your research and generosity in sharing.

 

I'm glad she or  you added the small amt of Valium to level off your serum levels.  I was crossed over from lorazepam to Librium.  No way I could cut directly from lorazepam, as I hit tolerance as well.

 

Yes my wise doctor added the bit of Valium which made the w/d tolerable.  I don't really know where I would be without that!  Too much Valium causes depressionn me! Yowza I went low so on 10 mg i wan afraid to try again, but then I stopped being able to function in the evenings....  at all!

[[cs...]]

Hi BecksBlue, were these all after you stopped benzodiazaphines.  I assume so, in looking at your signature.

 

When I was in tolerance and interdose w/d after being on the pills for 3 years, I went to the docs complaining of dizziness and bad anxiety.  He sent me to a neurologist where my ANA, anti-nuclear antibody, screening test, was positive.  Then I went to a Rheumatologist and she ran more tests and then diagnosed me with Lupus.  Then I took all my med. records to see a Hematologist and he diagnosed me with Thrombophilia.  Then two years off of the pills I went to a family doc and he told me to stand up and then he checked my heart and diagnosed me with Paroxsymal Tachycardia.  I know it's from the pills.  I never had any of these problems before getting off the pills.  I worked a very physically demanding job and had to use my mind too alot.  I'm brain and nerve damaged for sure. 

 

Hi BecksBlue, I think we all speak from experience when we say that the body has an amazing ability to heal, and even regenerate nerves.  Even more so, if it was due to benzodiazaphines.  I will keep this thread going as well.

 

Are you taking a blood thinner for the Thrombophilia

[[Be...]]

No blood thinner.  Doc told me to take a baby aspirin which I do at bedtime.  I'm very ill.  I'm even too sick to get back to the docs.  I'm in big trouble.  I've been very sick ever since I got off the pills.  More recently diagnosed with Memory Impairment and Amnesia.  Doc wanted me to get memory testing done and a brain MRI, but I don't have insurance to have it done.  Doc agrees with me that I might have had a stroke.  I'm at risk for it.

[[Su...]]

No blood thinner.  Doc told me to take a baby aspirin which I do at bedtime.  I'm very ill.  I'm even too sick to get back to the docs.  I'm in big trouble.  I've been very sick ever since I got off the pills.  More recently diagnosed with Memory Impairment and Amnesia.  Doc wanted me to get memory testing done and a brain MRI, but I don't have insurance to have it done.  Doc agrees with me that I might have had a stroke.  I'm at risk for it.

 

Very sorry to here that you are having such a rough time, and that insurance won't pay for testing.... Thinking of you and hoping that things ease at some point soon, or at some points during your days. 

[[cs...]]

No blood thinner.  Doc told me to take a baby aspirin which I do at bedtime.  I'm very ill.  I'm even too sick to get back to the docs.  I'm in big trouble.  I've been very sick ever since I got off the pills.  More recently diagnosed with Memory Impairment and Amnesia.  Doc wanted me to get memory testing done and a brain MRI, but I don't have insurance to have it done.  Doc agrees with me that I might have had a stroke.  I'm at risk for it.

Hi BecksBlue prayers out to you 

I'm posting ADDENDUM 5 today.  I hope it helps everyone understand what an action potential is.

 

[[cs...]]

Hi, this is ADDENDUM 5 in the series.  I'm hoping it all pasted correctly.  If someone knows how to directly import from a word doc, let me know.  2 images would not paste even when I tried to use the image tag

Also some additional formatting lost from the word doc paste.

 

ADDENDUM 5: The Action Potential PART I

 

~”Ignorance is Bliss”

 

~”A man walks up to the bartender, and the bartender says to him,    ‘How come every time I see ya, ur never smilin’. ‘,  to which the man intelligently replied, ‘If you knew everything that I knew, you wouldn’t be smilin’ either.’  “

 

~”Knowledge is Power”

 

 

Key objective: Understanding action potentials and their dynamics in depth, and understanding  why glutamate and GABA ion channels and their stability dynamics are so critical to homeostatic neuronal function .  The material in  ADDENDUM 4 will help one understand the concepts presented in this ADDENDUM.

 

Quote

Ion pumps influence the action potential only by establishing the relative ratio of intracellular and extracellular ion concentrations. The action potential involves mainly the opening and closing of ion channels not ion pumps. If the ion pumps are turned off by removing their energy source, or by adding an inhibitor such as ouabain, the axon can still fire hundreds of thousands of action potentials before their amplitudes begin to decay significantly.[8] In particular, ion pumps play no significant role in the repolarization (i.e., making more negative and decaying) of the membrane after an action potential.[3]

End quote

 

 

 

 

-1. Preface:  Establishing the importance of ligand and voltage gated sodium ion channels

 

  As the paragraph above states, ion pumps are very weak voltage ion membrane modulators relative to ion channels, and are really not used much in the creation of an action potential.

 

As the quote states, ion pumps have little to do with repolarization as well (this is the fall or decay in voltage potential as the action potentials are firing off) .  Ion channels are are used for this as well.  Repolarization involves the fall in voltage potential after it has been charged up (depolarized).  Depolarization is the charging up phase and is governed by an a initiation of  initial stimuli (glutamate sodium channels + GABA chloride channels), and a ramping up phase (governed by voltage gated sodium channels).  An action potential is fired off.  Repolarization occurs when potassium efflux  ion channels kick in at the peak of the action potential, and the voltage potential dramatically drops.  At this point,  the action potiential is in a hyperpolarized state which is usually negative.  It’s an overly “corrected” negative voltage that is corrected back to the resting potential via ion pumps.  See links below

 

https://en.m.wikipedia.org/wiki/Depolarization

 

https://en.m.wikipedia.org/wiki/Hyperpolarization_(biology)

 

https://en.m.wikipedia.org/wiki/Action_potential

 

 

 

Since the ion channels are the main way by which the membrane potential is  depolarized(making more positive) , our focus relative to  benzodiazaphine affects should be in this area, because  benzodiazaphines overly hyperpolarize (make more negative) the membrane potoential.  If the GABAa receptors have not downregulated significantly (and this is a big assumption), this will make it more difficult to achieve threshold potoential during benzodiazaphine use, and thus more difficult to achieve action potential when glutamate activates the sodium ion ligand channels. (This will all make sense much better by the end of this paper).  The end result is an overly suppressed nerve that is not generating current down its axon very frequently, or as frequently as it would have without the benzodiazaphine.

 

 

 

 

-2. The stimulus or catalyst

 

In terms of this simplified model there are basically 2 stimuli that are affecting the membrane potential of the post synaptic neuron.  The first one is the glutamate receptor ligand based ion channel that influxes Na+ ions into the post synaptic neuron to move the potential towards the threshold potential(i.e., depolarize it or make it less negative or more positive).  The second one is the GABAa receptor ligand based ion channel that influxes Cl- ions into the post synaptic neuron as well.  These ions act as an inhibitory force on the Na+ influx, thus making it “harder” for the glutamate ion to get the voltage potential to threshold.

 

Why is the stimuli important?  Because the net result of the stimuli are what either causes the threshold potential to be reached or not.  If threshold is not reached, the voltage gated sodium channels in the post synaptic neuron will not open (much more on this later), and there will be no depolarization of the membrane potential, and no nerve or impulse (action potential)sent down the axon.  In other words, the neuron will be effectively “dead” for now.

 

 

From the quote above and the preceding  information, we already know that the ion pumps or transporters are really only effective for restoring the membrane potential back to its resting potiential, after it has been hyperpolarized  (it’s really negative after firing many action potentials, and needs to be brought back up to resting potiential.).  They are used in tons of other areas, but are not relevant to this discussion topic.

 

 

 

-3. The action potential: More detail on what is actually going on in the post synaptic membrane

 

 

 

Depolarization

 

Depolarization is mainly performed by  an voltage gated Na+ ion channel.  Depolarizing means switching of the voltage potential, in this case from a negative resting potential, to a positive voltage potential.

It’s a feedback mechanism called Hodgkin cycle, with a stimulus, say a net result of GABA and glutamate channels (see above) pushing Na+ and Cl-  into the post synaptic neuron membrane. Without these stimuli there would never be an action potential(see below).  This is why the dynamics of the stimui are so critical to the function of the neuron as a whole(and to our well being).

 

Once the voltage potential rises to the threshold potential via the stimui (-70 mV is resting potential, so once it gets to ~ -55mV,  the threshold potential) , the action potential starts.  The voltage gated sodium ion channels in the post synaptic neuron begin to open.  These voltages are not random, but based on the physiological electrochemical dynamics of the ions that affect the channels and their gating dynamics of the channels.

As the voltage potential increases (becomes more positive or here,in the early stages, less negative) more and more sodium channels open, and more Na+ goes into the post synaptic neuron. This is why the Hodgkin cycle is a feedback mechanism.  As more and more sodium channels are opened, more Na+ flows into the post synaptic membrane raising the voltage potiential in an upward slope.  More sodium gated channels open, as the voltage potential becomes more positive.  Voltage gated ion channels respond to positive potentials, and more gates are opened as the membrane becomes more positive.  They are either fully open, or fully closed.  There is no intermediate state.

 

Failed attempts

 

There can be failed attempts to reach threshold.  If threshold is not reached the neuron will not fire as there is no action potential.  This threshold is typically 15 mV above resting potential so at about -70+15 or -55 mV.  This stresses how important the stimuli (i.e., GABA and glutamate receptors and channels) are to this process, and why benzodiazaphines are so physiologically disruptive.They inherently instigate more failed attempts and prompt a homeostatic response from the body to compensate.

 

Quote

The inward flow of sodium ions increases the concentration of positively charged cations in the cell and causes depolarization, where the potential of the cell is higher than the cell's resting potential. The sodium channels close at the peak of the action potential, while potassium continues to leave the cell. The efflux of potassium ions decreases the membrane potential or hyperpolarizes the cell. For small voltage increases from rest, the potassium current exceeds the sodium current and the voltage returns to its normal resting value, typically −70 mV.[4][5][6] However, if the voltage increases past a critical threshold, typically 15 mV higher than the resting value, the sodium current dominates. This results in a runaway condition whereby the positive feedback from the sodium current activates even more sodium channels. Thus, the cell fires, producing an action potential.[4][7][8][note 1] The frequency at which cellular action potentials are produced is known as its firing rate.

End quote

 

 

 

More than just the Hodgkin cycle ….you can skip this section if too technical (optional)

 

 

The Hodgkin cycle and dynamics are very complicated.  Some very selected quotes reveal just how complex.  See the source references for more information.  Electrical engineers will like this section.  The circuit representation is in the second link.

 

https://en.m.wikipedia.org/wiki/Action_potential

https://en.m.wikipedia.org/wiki/Hodgkin%E2%80%93Huxley_model

There is a nice graphic in the second link last figure showing a Hodgkin action potential live in action.  The Hodgkin action potential  does not perfectly model a real life action potential due to the shortcomings below, and has been augmented by the newer model mentioned below, that I I incorporates things like entropy, and more accurately modeling ion proteins which don’t exactly behave like their electrical counterparts.

https://en.m.wikipedia.org/wiki/Action_potential_pulse

 

 

 

In this reference, the channels are the sodium and potassium ion channels.  These create and regulate the dynamics of the action potential curve.

 

Quote

In physiology, an action potential occurs when the membrane potential of a specific axon location rapidly rises and falls:[1] this depolarisation then causes adjacent locations to similarly depolarise. In the Hodgkin–Huxley (HH) model of Alan Lloyd Hodgkin and Andrew Fielding Huxley, speed of transmission of an action potential was undefined and it was assumed that adjacent areas became depolarised due to released ion interference with neighbouring channels. Measurements of ion diffusion and radii have since shown this to not be possible. Moreover, contradictory measurements of entropy changes and timing disputed the HH as acting alone. More recent work has shown that the HH action potential is not a single entity but is a Coupled Synchronised Oscillating Lipid Pulse (Action potential pulse) powered by entropy from the HH ion exchanges.[2]

End quote

 

HH model basics

 

Quote

 

The typical Hodgkin–Huxley model treats each component of an excitable cell as an electrical element (as shown in the figure). The lipid bilayer is represented as a capacitance (Cm). Voltage-gated ion channels are represented by electrical conductances (gn, where n is the specific ion channel) that depend on both voltage and time. Leak channels are represented by linear conductances (gL). The electrochemical gradients driving the flow of ions are represented by voltage sources (En) whose voltages are determined by the ratio of the intra- and extracellular concentrations of the ionic species of interest. Finally, ion pumps are represented by current sources (Ip).[clarification needed] The membrane potential is denoted by Vm.

 

End quote

 

 

 

The Action Potential Pulse: Coupled synchronized Oscillating Lipid Pulse powered by entropy from HH ion exchanges

 

This illustrates the shortcomings of electrical circuits and cable theory in modeling membrane biophysics, and truly how wonderfully designed our bodies are.

 

 

 

Quote

 

An action potential pulse is a mathematically and experimentally correct Synchronized Oscillating Lipid Pulse[1] coupled with an Action Potential. This is a continuation of Hodgkin Huxley's work in 1952 with the inclusion of accurately modelling ion channel proteins, including their dynamics and speed of activation.[2]

The action potential pulse is a model of the speed an action potential that is dynamically dependant upon the position and number of ion channels, and the shape and make up of the axon. The action potential pulse model takes into account entropy and the conduction speed of the action potential along an axon. It is an addition to the Hodgkin Huxley model.

Investigation into the membranes of axons have shown that the spaces in between the channels are sufficiently large, such that cable theory cannot apply to them, because it depends upon the capacitance potential of a membrane to be transferred almost instantly to other areas of the membrane surface. In electrical circuits this can happen because of the special properties of electrons, which are negatively charged, whereas in membrane biophysics potential is defined by positively charged ions instead. These ions are usually Na1+ or Ca2+, which move slowly by diffusion and have limited ionic radii in which they can affect adjacent ion channels. It is mathematically impossible for these positive ions to move from one channel to the next, in the time required by the action potential flow model, due to instigated depolarization. Furthermore entropy measurements have long demonstrated that an action potential's flow starts with a large increase in entropy followed by a steadily decreasing state, which does not match the Hodgkin Huxley theory. In addition a soliton pulse is known to flow at the same rate and follow the action potential. From measurements of the speed of an action potential, hyperpolarizationmust have a further component of which the 'soliton' mechanical pulse is the only candidate.[citation needed]

The resulting action potential pulse therefore is a synchronized, coupled pulse with the entropy from depolarization at one channel providing sufficient entropy for a pulse to travel to sequential channels and mechanically open them.

This mechanism explains the speed of transmission through both myelinated and unmyelinated axons.

This is a timed pulse, that combines the entropy from ion transport with the efficiency of a flowing pulse.

The action potential pulse model has many advantages over the simpler Hodgkin Huxley version including evidence, efficiency, timing entropy measurements, and the explanation of nerve impulse flow through myelinated axons.

Myelinated axons

This model replaces saltatory conduction, which was a historical theory that relied upon cable theory to explain conduction, and was an attempt at a model that has no basis is either physiology or membrane biophysics.

In myelinated axons the myelin acts as a mechanical transducer preserving the entropy of the pulse and insulating against mechanical loss. In this model the nodes of Ranvier (where ion channels are highly concentrated) concentrate the ion channels providing maximum entropy to instigate a pulse that travels from node to node along the axon with the entropy being preserved by the shape and dynamics of the myelin sheath.

End quote

 

Summary so far….

 

 

There are some nice diagrams in the following links along with summaries of the preceding

 

 

https://en.m.wikipedia.org/wiki/Action_potential

 

 

https://upload.wikimedia.org/wikipedia/commons/4/4a/Action_potential.svg

 

Quote

Approximate plot of a typical action potential shows its various phases as the action potential passes a point on a cell membrane. The membrane potential starts out at -70 mV at time zero. A stimulus is applied at time = 1 ms, which raises the membrane potential above -55 mV (the threshold potential). After the stimulus is applied, the membrane potential rapidly rises to a peak potential of +40 mV at time = 2 ms. Just as quickly, the potential then drops and overshoots to -90 mV at time = 3 ms, and finally the resting potential of -70 mV is reestablished at time = 5 ms.

End quote

 

https://en.m.wikipedia.org/wiki/Depolarization

 

https://en.m.wikipedia.org/wiki/Hyperpolarization_(biology)

 

https://en.m.wikipedia.org/wiki/File:Action_Potential.gif

 

 

This is the rising of the action potential in the graphs, and when it crosses over from negative mV to positive, the membrane has been depolarized.  The action potential will rise to its  peak (+40 mV).(the curve is roughly modeled by differential equations in the HH model mentioned above). At this peak of +40 mV, the potassium ion channels in the membrane, which are efflux  ion channels, start to pump out K+ ions in an attempt to balance the inside potential with the extracellular potential..  This is the start of the repolarization process.  Note all channels up to this point  in the discussion are ion channels.  There are no ion pumps involved yet.

 

Quote to summarize

As a nerve impulse (action potential)travels down the axon, there is a change in polarity across the membrane. The Na+ and K+ gated ion channels open and close in response to a signal from another neuron. At the beginning of action potential, the Na+ gates open and Na+ moves into the axon. This is depolarization. Repolarization occurs when the K+ gates open and K+ moves outside the axon. This creates a change in polarity between the outside of the cell and the inside. The impulse continuously travels down the axon in one direction only, through the axon terminal and to other neurons.

End quote

 

 

Repolarization 

 

This occurs when the voltage gets to +40 mV and the potassium ion channels start to open, in a sense catching up with the depolarizing from the  sodium channels.  It’s  going with the gradient as an ion channel, and as such acting as an efflux ion channel sending out K+ ions in an effort to decrease all of that positive potential built up in the post synaptic neuron during depolarization.

Note no ATP or ion pumps are used yet, only ion channels.(see ADDENDUM 4)

 

 

Quote

After a cell has been depolarized, it undergoes one final change in internal change. Following depolarization, the voltage gated sodium ion channels that had been open while the cell was undergoing depolarization close again. The increased positive charge within the cell now causes the potassium channels to open. Potassium ions (K+) begin to move down the electrochemical gradient (in favor of the concentration gradient and the newly established electrical gradient). As potassium moves out of the cell the potential within the cell plummets and approaches its resting potential once more. The sodium potassium pump  works continuously throughout this process

End quote

 

Hyperpolarization and Restoration to resting potential after hyperpolarization.

 

 

At this point the interior of the post synaptic neuron has been overcorrected to between -75mV and -90 mV.  A small correction is needed to get the interior voltage potential back up to -70 mV, the resting potential .  This is where  ATP ion pumps come in.  They move ions much more slowly  when compared to ion channels.  In this case they pump negative ions out of the membrane using ATP as a source of mitochondrial energy. See below for the process in detail .  The ion pump is only used at the end to correct the overly negative hyperpolarization by the potassium ion channels. It corrects the potential to resting state of -70mV.

 

 

Quote

 

Hyperpolarization is often caused by efflux of K+ (a cation) through K+ channels, or influx of Cl– (an anion) through Cl–channels. On the other hand, influx of cations, e.g. Na+ through Na+ channels or Ca2+ through Ca2+ channels, inhibits hyperpolarization. If a cell has Na+ or Ca2+ currents at rest, then inhibition of those currents will also result in a hyperpolarization. This voltage-gated ion channel response is how the hyperpolarization state is achieved.

 

In neurons, the cell enters a state of hyperpolarization immediately following the generation of an action potential. While hyperpolarized, the neuron is in a refractory period that lasts roughly 2 milliseconds, during which the neuron is unable to generate subsequent action potentials. Sodium-potassium ATPases (Ion pumps) redistribute K+ and Na+ ions until the membrane potential is back to its resting potential of around

–70 millivolts, at which point the neuron is once again ready to transmit another action potential.

End quote

 

Quote

 

The process of repolarization causes an overshoot in the potential of the cell. Potassium ions continue to move out of the axon so much so that the resting potential is exceeded and the new cell potential becomes more negative than the resting potential. The resting potential is ultimately re-established by the closing of all voltage-gated ion channels and the activity of the sodium potassium ion pump.[5]

End quote

 

 

One note I want to make.  Human physiology often overcorrects initially, in its attempt to establish homeostasis, in this case get back to the resting potiential.  I personally  think that this plays a large and critical part in neuro-kindling or simply kindling.

 

 

CONTINUED ON NEXT POST (part 2)

[[cs...]]

ADDENDUM 5: The Action Potential (PART II)

 

-4. More on Voltage gated Sodium channels and a summary of timing

 

 

Note the entire process occurs on the order of milliseconds.  Thus  a neuron can fire many times per second .  Also note that the voltages are not random but due to the electrophysiological characteristics of the ions.  Nature expresses itself through physics.  This section gives us a good feel for the magnitudes of time we are talking about (very short).

 

 

https://en.m.wikipedia.org/wiki/Hyperpolarization_(biology)

See the diagram below or posted here

 

https://en.m.wikipedia.org/wiki/File:Apshoot.jpg

 

Quote

Voltage gated ion channels respond to changes in the membrane potential. Voltage gated potassium, chloride and sodium channels are key component for generating the action potential as well as hyper-polarization. These channels work by selecting an ion based on electrostatic attraction or repulsion allowing the ion to bind to the channel.[2] This releases the water molecule attached to the channel and the ion is passed through the pore. Voltage gated sodium channels open in response to a stimulus and close again. This means the channel either is open or not, there is no part way open. Sometimes the channel closes but is able to be reopened right away,known as channel gating, or it can be closed without being able to be reopened right away, known as channel inactivation.

At resting potential, both the voltage gated sodium and potassium channels are closed but as the cell membrane becomes depolarized the voltage gated sodium channels begin to open up and the neuron begins to depolarize, creating a current feedback loop known as the Hodgkin cycle.[2] However, potassium ions naturally move out of the cell and if the original depolarization event (a stimulus like a glutamate Na+ ligand based ion channel) was not significant enough then the neuron does not generate an action potential. If all the sodium channels are open( threshold reached to start the Hodgkin cycle), however, then the neuron becomes ten times more permeable to sodium than potassium, quickly depolarizing the cell to a peak of +40 mV.[2] At this level the sodium channels begin to close and voltage gated potassium channels begin to open. This combination of closed sodium channels and open potassium channels leads to the neuron re-polarizing and becoming negative again. The neuron continues to re-polarize until the cell reaches ~ –75 mV,[2] which is the equilibrium potential of potassium ions. This is the point at which the neuron is hyperpolarized, between –70 mV and –75 mV. After hyperpolarization the potassium channels close and the natural permeability of the neuron to sodium and potassium(ion pumps) allows the neuron to return to its resting potential of –70 mV.

 

 

During the refractory period, which is after hyper-polarization but before the neuron has returned to its resting potential the neuron is capable of triggering an action potential due to the sodium channels ability to be opened, however, because the neuron is more negative it becomes more difficult to reach the action potential threshold.  (So ion pumps aren’t involved in action potentials at all)

 

 

1. During the afterhyperpolarization period after an action potential, the membrane potential is more negative than when the cell is at the resting potential. In the figure to the right, this undershoot occurs at approximately 3 to 4 milliseconds (ms) on the time scale. The afterhyperpolarization is the time when the membrane potential is hyperpolarized relative to the resting potential.

2. During the rising phase of an action potential, the membrane potential changes from negative to positive, a depolarization. In the figure, the rising phase is from approximately 1 to 2 ms on the graph. During the rising phase, once the membrane potential becomes positive, the membrane potential continues to depolarize (overshoot) until the peak of the action potential is reached at about +40 millivolts (mV). After the peak of the action potential, a hyperpolarization repolarizes the membrane potential to its resting value, first by making it less positive, until 0 mV is reached, and then by continuing to make it more negative. This repolarization occurs in the figure from approximately 2 to 3 ms on the time scale.

End quote

 

<<<<< I could not paste the image in here using the img tag button. Not sure how to do this>>>>

 

 

 

 

Hodgkin-Huxley voltage gated sodium channels-  more detail, feedback loops, etc.

 

 

Quote

 

 

Voltage-gated ion channels are capable of producing action potentials because they can give rise to positive feedback loops: The membrane potential controls the state of the ion channels, but the state of the ion channels controls the membrane potential. Thus, in some situations, a rise in the membrane potential can cause ion channels to open, thereby causing a further rise in the membrane potential. An action potential occurs when this positive feedback cycle proceeds explosively. The time and amplitude trajectory of the action potential are determined by the biophysical properties of the voltage-gated ion channels that produce it. Several types of channels that are capable of producing the positive feedback necessary to generate an action potential exist. Voltage-gated sodium channels are responsible for the fast action potentials involved in nerve conduction. Slower action potentials in muscle cells and some types of neurons are generated by voltage-gated calcium channels. Each of these types comes in multiple variants, with different voltage sensitivity and different temporal dynamics.

The most intensively studied type of voltage-dependent ion channels comprises the sodium channels involved in fast nerve conduction. These are sometimes known as Hodgkin-Huxley sodium channels because they were first characterized by Alan Hodgkin and Andrew Huxley in their Nobel Prize-winning studies of the biophysics of the action potential, but can more conveniently be referred to as NaV channels. (The "V" stands for "voltage".) An NaV channel has three possible states, known as deactivated, activated, and inactivated. The channel is permeable only to sodium ions when it is in the activated state. When the membrane potential is low, the channel spends most of its time in the deactivated (closed) state. If the membrane potential is raised above a certain level, the channel showsy increased probability of transitioning to the activated (open) state. The higher the membrane potential the greater the probability of activation. Once a channel has activated, it will eventually transition to the inactivated (closed) state. It tends then to stay inactivated for some time, but, if the membrane potential becomes low again, the channel will eventually transition back to the deactivated state. During an action potential, most channels of this type go through a cycle deactivated→activated→inactivated→deactivated. This is only the population average behavior, however — an individual channel can in principle make any transition at any time. However, the likelihood of a channel's transitioning from the inactivated state directly to the activated state is very low: A channel in the inactivatedstate is refractory until it has transitioned back to the deactivated state.

End quote

 

 

 

 

-5. More on the Action potential generation and action potential rates

 

https://en.m.wikipedia.org/wiki/Action_potential

https://upload.wikimedia.org/wikipedia/commons/4/4a/Action_potential.svg

 

Quote

Action potentials are generated by special types of voltage-gated ion channels embedded in a cell's plasma membrane. These channels are shut when the membrane potential is near the (negative) resting potential of the cell, but they rapidly begin to open if the membrane increases to a precisely defined threshold voltage, depolarising the transmembrane potential. When the channels open they allow an inward flow of sodium ions, which changes the electrochemical gradient, which in turn produces a further rise in the membrane potential. This then causes more channels to open, producing a greater electric current across the cell membrane, and so on. The process proceeds explosively until all of the available ion channels are open, resulting in a large upswing in the membrane potential. The rapid influx of sodium ions causes the polarity of the plasma membrane to reverse, and the ion channels then rapidly inactivate. As the sodium channels close, sodium ions can no longer enter the neuron, and then they are actively transported back out of the plasma membrane. Potassium channels are then activated, and there is an outward current of potassium ions, returning the electrochemical gradient to the resting state. After an action potential has occurred, there is a transient negative shift, called the afterhyperpolarization.

 

 

Each excitable patch of membrane has two important levels of membrane potential: the resting potential, which is the value the membrane potential maintains as long as nothing perturbs the cell, and a higher value called the threshold potential. At the axon hillock of a typical neuron, the resting potential is around –70 millivolts (mV) and the threshold potential is around –55 mV. Synaptic inputs(like glutamate ion channels or GABA ion channels, serving as a stimulus) to a neuron cause the membrane to depolarize or hyperpolarize; that is, they cause the membrane potential to rise or fall. Action potentials are triggered when enough depolarization accumulates to bring the membrane potential up to threshold. When an action potential is triggered, the membrane potential abruptly shoots upward and then equally abruptly shoots back downward, often ending below the resting level, where it remains for some period of time. The shape of the action potential is stereotyped; that is, the rise and fall usually have approximately the same amplitude and time course for all action potentials in a given cell. (Exceptions are discussed later in the article). In most neurons, the entire process takes place in about a thousandth of a second. Many types of neurons emit action potentials constantly at rates of up to 10–100 per second; some types, however, are much quieter, and may go for minutes or longer without emitting any action potentials.

 

End quote

 

A question would be if the brain and central nervous system uses these typical firing rates and the failed attempts in section 3 (shown graphically in the graph of section 4) as a feedback mechanism to modulate GABA and glutamate receptors.  If a nerve is “underperforming” and overly suppressed, does the CNS zero in on this and take action through some sort of signaling protein(s)? This is a possible area of additional research.  Most of the theories for benzodiazaphine upregulation of glutamate receptors and downregulation of the GABAa receptors are cellular feedback models and gene regulatory models (LTP), wherein the brain is not the explicitly the master controller (like with the HPA axis and stress).

 

 

 

-6. The big picture: Instigating stimulus, axons,  neurotransmitters, etc.

 

 

 

 

Anatomy of a neuron.  Pers’s paper (Layman’s guide to neurons) goes into this in a more presentable fashion.

 

See https://en.m.wikipedia.org/wiki/Action_potential for a nice diagram

 

Quote

 

 

Neurons are electrically excitable cells composed, in general, of one or more dendrites, a single soma, a single axon and one or more axon terminals. Dendrites are cellular projections whose primary function is to receive synaptic signals. Their protrusions, or spines, are designed to capture the neurotransmitters released by the presynaptic neuron. They have a high concentration of ligand-gated ion channels. These spines have a thin neck connecting a bulbous protrusion to the dendrite. This ensures that changes occurring inside the spine are less likely to affect the neighboring spines. The dendritic spine can, with rare exception (see LTP), act as an independent unit. The dendrites extend from the soma, which houses the nucleus, and many of the "normal" eukaryotic organelles. Unlike the spines, the surface of the soma is populated by voltage activated ion channels. These channels help transmit the signals generated by the dendrites. Emerging out from the soma is the axon hillock. This region is characterized by having a very high concentration of voltage-activated sodium channels. In general, it is considered to be the spike initiation zone for action potentials.[14] Multiple signals generated at the spines, and transmitted by the soma all converge here. Immediately after the axon hillock is the axon. This is a thin tubular protrusion traveling away from the soma. The axon is insulated by a myelin sheath. Myelin is composed of either Schwann cells (in the peripheral nervous system) or oligodendrocytes (in the central nervous system), both of which are types of glial cells. Although glial cells are not involved with the transmission of electrical signals, they communicate and provide important biochemical support to neurons.[15] To be specific, myelin wraps multiple times around the axonal segment, forming a thick fatty layer that prevents ions from entering or escaping the axon. This insulation prevents significant signal decay as well as ensuring faster signal speed. This insulation, however, has the restriction that no channels can be present on the surface of the axon. There are, therefore, regularly spaced patches of membrane, which have no insulation. These nodes of Ranvier can be considered to be "mini axon hillocks", as their purpose is to boost the signal in order to prevent significant signal decay. At the furthest end, the axon loses its insulation and begins to branch into several axon terminals. These presynaptic terminals, or synaptic boutons, are a specialized area within the axon of the presynaptic cell that contains neurotransmitters enclosed in small membrane-bound spheres called synaptic vesicles.

 

End quote

 

Quote

 

Neurons

Depolarization is essential to the functions of many cells in the human body, which is exemplified by the transmission of stimuli both within a neuron and between two neurons. The reception of stimuli, neural integration of that stimuli, and the neuron's response to stimuli all rely upon the ability of neurons to utilize depolarization to transmit stimuli either within a neuron or between neurons.

Response to stimulus

Stimuli to neurons can be a physical, electrical, chemical stimulus, which can either inhibit or excite the neuron being stimulated. An inhibitory stimulus is transmitted to the dendrite of a neuron, causing hyperpolarization of the neuron. The hyperpolarization following an inhibitory stimulus causes a further decrease in voltage within the neuron below the resting potential. By hyperpolarizing a neuron, an inhibitory stimulus results in a greater negative charge that must be overcome for depolarization to occur. (Ex GABA).  Excitation stimuli, (glutamate) on the other hand, increases the voltage in the neuron, which leads to a neuron that is easier to depolarize than the same neuron in the resting state. Regardless of excitatory or inhibitory, the stimuli travel down the dendrites of a neuron to the cell body for integration.

 

 

Integration of stimuli

 

 

<<<<<<image would not paste>>>>>

Here is a link to it

 

https://en.m.wikipedia.org/wiki/File:1224_Post_Synaptic_Potential_Summation.jpg

 

Once the stimuli have reached the cell body, the nerve must integrate the various stimuli (like the original video) before the nerve can respond. The stimuli that have traveled down the dendrites converge at the axon hillock, where they are summed to determine the neuronal response. If the sum of the stimuli reaches a certain voltage, known as the threshold potential, depolarization continues from the axon hillock down the axon.

 

Response

The surge of depolarization traveling from the axon hillock to the axon terminal is known as an action potential. Action potentials reach the axon terminal, where the action potential triggers the release of neurotransmitters from the neuron.(the end of the terminal axon where the next presynaptic neuron is)

 

The neurotransmitters that are released from the axon (terminal) continue on to stimulate other cells such as other neurons or muscle cells. After an action potential travels down the axon of a neuron, the resting membrane potential of the axon must be restored before another action potential can travel the axon. This is known as the recovery period of the neuron, during which the neuron cannot transmit another action potential.

 

End quote

 

On to the next presynaptic neuron….

In general, action potentials that reach the synaptic knobs (axon terminal)cause a neurotransmitter to be released into the synaptic cleft.[z]Neurotransmitters are small molecules that may open ion channels in the postsynaptic cell; most axons have the same neurotransmitter at all of their termini.

 

The arrival of the action potential opens (Calcium) voltage-sensitive calcium channels in the presynaptic membrane (like in the beginning of the video); the influx of calcium causes vesicles filled with neurotransmitter to migrate to the cell's surface and release their contents into the synaptic cleft.[aa] 

 

End quote

 

This corresponds to the beginning of the video, in the first post of this thread.

 

 

These neurotransmitters, like glutamate and GABA, go on to lock into the next postsynaptic neuron (in the dendrites) in the chain via GABA and glutamate ligand based ion channels, to start the process all over again in the next neuron, create an action potential down the axon, etc……

 

 

[[Be...]]

A fellow lady bb on here had docs take her blood and checked her for antibodies and autoantibodies.  They found a high titer of the voltage gated calcium channel autoantibodies in her blood.  I believe these channels were damaged from the benzo's and her body had illicited an immune response to them.  Please read Hope4us's latest posts to see what the docs found.  Here's a link to her posts:

 

http://www.benzobuddies.org/forum/index.php?action=profile;area=showposts;u=3767

 

Tons of autoantibodies and antibodies that were attacking her brain and body causing all her symptoms.  Abnormal SPECT scan too.  It's not just dysregulated action potentials, or whatever they're called, causing symptoms or LTP.  I couldn't understand all the technical stuff posted here because I have dementia now, but do have a degree as a Med Lab Tech and learned about antigen/antibody complexes.  Autoantibodies to damaged cells and other structures of the body also may be what's causing so much pain and suffering for so many, IMO, from what I've read.  When someone gets a physical injury they have an immune response and it hurts.  That's what is happening with this benzo damage, and why it hurts so much, I think.

[[cs...]]

Hi BecksBlue, yes strangely enough I had read a lot of her posts prior to you bringing it up.  Autoimmune encephalitis has so many different manifestations.  I hope she is getting the help that she needs. 

 

I agree it's not just about the action potential that is the problem.  Many of our issues do stem from Glutamate system upregulation, which is what I am focused on now, in terms of research.  LTP is very interesting in this respect, and the latest findings in this area are very far reaching. However, the LTP as it occurs to benzodiazaphine use requres a massive chloride depletion in the neuron, and this only occurs typically with abrupt withdrawal.  However , there are aspects of LTP like retrograde  signaling that might be applicable to those of us who have suffered through interdose withdrawal.  I'm trying to figure out the common link.

 

My original issue was also immune related prior to getting on benzos, and I also have Hashimotos.  As you know, that in and of itself predisposes one to other immune and autoimmune related dysfunction.

 

I know there are a lot of people in pain out there.  I still think that if one learns about the foundational science behind how benzodiazaphines destroy our bodies, it helps us in the future understand much more complex, yet related physiological processes like LTP, autoimmune dysfunction, etc., and it helps us put the pieces of the puzzle together.

 

In regards to Glutamate, it does cause massive oxidative damage, and excitotoxicity to neural cells.  I'm sure there are links to immune dysregulation, and I do recall an article on certain inflammatory cytokine elevations correlated to Glutamate toxicity. 

 

Things will get better.

[[cs...]]

Hi BecksBlue

 

Here is the article I alluded to above

 

https://academic.oup.com/alcalc/article/44/2/128/184655/Biochemical-and-Neurotransmitter-Changes?view=long&pmid=19155229

 

There is a very long section on Glutamate.

 

Quote

Figure 2

 

The release of glutamate into the synaptic cleft will stimulate AMPA receptors inducing sodium (Na+) fluxes and NMDA receptors stimulating calcium fluxes Ca2+. Such calcium fluxes will bind to calcium-binding proteins including calmodulin to activate nitric oxide synthase to enhance nitric oxide, NO, production. Calcium fluxes will also stimulate phospholipases to generate reactive oxygen species, ROS.

End quote

 

 

Quote

 

Excessive glutamate release is a major cause of neuronal cell death, possibly involving two pathways. Firstly, excitotoxicity that occurs through the activation of glutamatergic receptors (Choi, 1988; Michaels & Rothman, 1990), causing Ca2+ ion influx, with NMDA-mediated generation of nitric oxide (NO), mitochondrial depolarization, Na+ influx leading to an unsustainable increase in ATP demand, microtubule depolymerization, mitochondrial collapse and dendritic beading (reviewed by Greenwood et al.,2007) (Fig. 2). Secondly, oxidative glutamate toxicity, that is mediated via a series of disturbances to the redox homeostasis of the cell (Murphy et al., 1989; Choi, 1992).

....

 

 

 

CNS immunity

 

Glial cells play an important function in the brain, nurturing neurons and facilitating neuronal activity. Four different types of glial cells exist, e.g. oligodendrocytes, ependymal cells, astrocytes and microglia. Microglial cells are closely related to monocytes and macrophages (Stoll and Jander, 1999) and play a pivotal role in CNS immunity. Glial cells, including astrocytes, are essential for the regulation of released glutamate and its conversion to glutamine through the enzyme glutamine synthetase. Activated microglia secretes neurotoxic inflammatory cytokines and mediators such as tumour necrosis factor (TNFα), and NO, which may initiate or amplify the neuroinflammatory responses

......

 

In the Glutamate section we know that excessive Glutamate clearly generates NO

 

Among the many inflammatory mediators produced by activated phagocytic cells, i.e. macrophages and microglia, NO production has been widely regarded as representative of inflammatory activation. Microglia-derived NO will exert direct toxicity towards neurons (Liu et al.,2002).

 

 

......

In figure 8 it's clear that there are differences in chronic vs binge drinkers, bingers having a much higher level of nitrate release extracelluarly.  Extracellular is key here

 

Fig 8

Release of nitrite into the extracellular fluid after incubation of alveolar macrophages isolated from binge drinking rats (EtOH) or chronically alcoholized rats, after incubation with stimulants, either lipopolysaccharide (LPS) alone or together with interferon gamma (INFγ).

 

.....

 

In our previous studies, alveolar macrophages (which are the functional equivalent of brain microglia) isolated from various animal models of alcohol toxicity, i.e. chronic alcohol intoxication (Zhang et al., 1998) and ‘binge drinking’ model (Ward et al.,2008), showed variable responses in LPS-induced NO release (Fig. 8.  ).

 

........

 

As can be clearly observed, the LPS-stimulated NO release from the chronically alcoholized macrophages was significantly reduced by comparison to controls. In contrast, binge drinking significantly increased LPS-stimulated NO release both at the end of the binge-drinking regime and after 28 days of no further treatment.

 

........

 

End quote

 

And it's clear that the immune system plays a critical role in the release of glutamate (and NO)from these microglia cells

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1949347/

 

 

Once the immune system is hyperactive it leads to a very destructive cascade on the neurons because we know that Glutamate induces more NO release from the above original link

The microglia also release NO directly in response to pro inflammatory cytokines. 

 

In fact in a recent kindling study

 

It does look like LPS and a pro inflammatory cytokine produces an increase in extracellular Glutamate and accelerated kindling, and Glutamate induces the release of NO which is destructive to neurons.

 

http://www.jni-journal.com/article/S0165-5728(16)30174-6/abstract

 

Quote

In our study, we used rapid electrical hippocampal kindling and in vivo microdialysis methods to assess the involvement of inflammatory mediators: lipopolysaccharide (LPS) and proinflammatory interleukin-1β (IL-1β) in mechanisms of epileptogenesis. We observed, that both, LPS and IL-1β, administered into stimulated hippocampus, accelerated kindling process. LPS also increased the expression of IL-1β in stimulated hippocampus in kindled rats. In vivo acute LPS perfusion, via a microdialysis cannula implanted into the naïve rat's hippocampus, produced an increase in extracellular glutamate release. We suppose, that particularly IL-1β action and increased glutamate concentration may significantly contribute to LPS effects on kindling development.

End quote

 

[[Be...]]

dm, I've been diagnosed with Memory Impairment and Amnesia by the doc and can't understand complicated stuff anymore, so can't read all the information you're posting.  I have early onset Dementia.  I'm in big trouble.  I did read a mice research study years ago when my brain functioning was better that said that after long-term use of benzo's and then withdrawal, the mice CREATED new glutamate receptors, by as much as 50%.  It's not just upregulating these receptors.  Once the new ones are made, it's bad news.  How do you get rid of them? Then they looked at the mice brains under a microscope and found all the new glutamate receptors.  They had the mice do the open arms test and the mice didn't want to explore their surroundings anymore and just sort of huddled in a corner because their brains were damaged.  I think that's what happened to me.  Too many glutamate receptors and damaged GABA receptors.  That imbalance is very bad.  No wonder I'm so sick all the time and can never calm down.  Plus, I have too much external stress on me all the time and it makes me very stressed out.  I live alone and have been isolated here by myself for years with no outside contact except the guy who gets me my food and people on this forum.  I'm dying a slow miserable death.  I've been getting worse as the months go by.  I have the mental functioning of a young person now.  I've lost my ability to cope and deal with my life now.   

[[Sc...]]

These drugs don't unbalance just gaba they unbalance all other receptors that have a natural balance. benzos are not selective to just gaba.

[[Ca...]]

Following, and thanks..

[[Te...]]

Thanks so much for your extensive research, dm123!!!  :thumbsup:

[[li...]]

dm123,

 

I'm pleased to see you're making a real contribution. It has been a long time since anyone has done that. The last person to do that was Perseverance if I recall correctly. She left, who could blame her ?

 

'If the GABAa receptors have not downregulated significantly (and this is a big assumption), this will make it more difficult to achieve threshold potoential during benzodiazaphine use, and thus more difficult to achieve action potential when glutamate activates the sodium ion ligand channels.' I do know that clonazepam supposedly has a major effect on sodium channels/sodium conductance. Up till now, I had not been able to find out the mechanism by which this takes place.

I still don't, but I know that clonazepam affects glutamate decarboxyalse. It's a complicated drug for sure.

[[cs...]]

dm123,

 

I'm pleased to see you're making a real contribution. It has been a long time since anyone has done that. The last person to do that was Perseverance if I recall correctly. She left, who could blame her ?

 

'If the GABAa receptors have not downregulated significantly (and this is a big assumption), this will make it more difficult to achieve threshold potoential during benzodiazaphine use, and thus more difficult to achieve action potential when glutamate activates the sodium ion ligand channels.' I do know that clonazepam suppsoedly has a major effect on sodium channels/sodiam conductance. Up till now, I had not been able to find out the mechanism by which this takes place.

I still don't, but I know that clonazepam affects glutamate decarboxyalse. It's a complicated drug for sure.

 

Hi liberty, yes I've read all Pers's wonderful work several times.  I'm committed to get some answers just because I want to figure out what happened to me as well.  I know it's the Benzo, and the feeling of hyoerexcitability that occurred at my worst point was something clearly distinct from benzodiazaphine withdrawal.  I've got some theories on he backburner now, but they still need a lot of work.    I find the references to the immune system fascinating because the more i research the immune systems potential to kick Glutamate into high gear and start producing NO (nitrous oxide in massive amounts, it's a free radical scavenger) the more i see the similar  ugly Glutamate side of benzos.    LTP is a great theory for describing the Glutamate potentiation, but when it comes to benzos it requires a massive chloride depleted state of the neurons.  This only occurs after tolerance of the GABAa receptors and wih abrupt and continued withdrawal, i.e. Cold turkey.  We need a concise model for why we see Glutamate upregulation in interdose withdrawal (my case) , and with interdose tolerance withdrawal.    I know the model involves kindling, but the classical kindling model does not involve benzodiazaphines at all.  Thus, if researches can kindle a rat brain through inducing seizures alone, it must be related to the rapid repeated depolarization, and subsequent repolarization, done over and over again. 

 

Im currently researching the area of epileptogenesis, which might help us understand what those physiological  changes actually are to cause this upregulation in the Glutamate system.  Is it sensitized receptors, increase in extracellular Glutamate , GABAa desensitization, or some, or all?

 

https://en.m.wikipedia.org/wiki/Epileptogenesis

Epileptogenesis

Quote

In epilepsy, the resistance of excitatory neurons to fire during this period is decreased.[2] This may occur due to changes in ion channels or inhibitory neurons not functioning properly.[2] This then results in a specific area from which seizures may develop, known as a "seizure focus".[2] Another mechanism of epilepsy may be the up-regulation of excitatory circuits or down-regulation of inhibitory circuits following an injury to the brain.[2][3] These secondary epilepsies occur through processes known as epileptogenesis.[2][3] Failure of the blood–brain barrier may also be a causal mechanism as it would allow substances in the blood to enter the brain.[60]

End quote

In the classical kindling model it appears that the seizures are due to an upregulated Glutamate system and/or a downregulated inhibitory system, but we still don’t have an mechanism as to how the glutamate systems are upregulated, or, if the inhibitory systems are downregulated without benzodiazaphines involved, how this occurs.

 

 

Regarding the quote in bold above, the Glutamate ion channels invariably will be hit, because there is always Glutamate extracellularly.  Without we would die.  So I was referring to, when those ion channels do get a hit of glutamate (and they will), the receptor is massively oversensitized because the neuron needs to achieve homeostatic balance.  If the potential has been overly suppressed and is overly suppressed, i.e. Hyperpolarized, the neuron will try to counter it with a compensatory response.

 

The kindling model is great, but it still does not tell us beyond homeostasis as to how the Glutamate system is unregulated.  My thinking is toward extracellular Glutamate increase, but the pieces of the puzzle are not all there yet.

 

One last thing about the classical kindling model

 

I am not fully convinced that it is entirely due to kindling, but it may have involved environmental cues as the rats were repeated seizure induced in a particular way.  This might account for the long term effects seen in the seizure threshold of the rats once they were kindled, via environmental cues and L-LTP model.

 

[[cs...]]

dm, I've been diagnosed with Memory Impairment and Amnesia by the doc and can't understand complicated stuff anymore, so can't read all the information you're posting.  I have early onset Dementia.  I'm in big trouble.  I did read a mice research study years ago when my brain functioning was better that said that after long-term use of benzo's and then withdrawal, the mice CREATED new glutamate receptors, by as much as 50%.  It's not just upregulating these receptors.  Once the new ones are made, it's bad news.  How do you get rid of them? Then they looked at the mice brains under a microscope and found all the new glutamate receptors.  They had the mice do the open arms test and the mice didn't want to explore their surroundings anymore and just sort of huddled in a corner because their brains were damaged.  I think that's what happened to me.  Too many glutamate receptors and damaged GABA receptors.  That imbalance is very bad.  No wonder I'm so sick all the time and can never calm down.  Plus, I have too much external stress on me all the time and it makes me very stressed out.  I live alone and have been isolated here by myself for years with no outside contact except the guy who gets me my food and people on this forum.  I'm dying a slow miserable death.  I've been getting worse as the months go by.  I have the mental functioning of a young person now.  I've lost my ability to cope and deal with my life now. 

 

Hi BecksBlue, could you try to find that reference if you can.  ?  I would be interested.....The changes in the Glutamate system that you mention, would not surprise me as the GABAa receptors go through similar but opposite changes, meaning the actually decrease in number and become conformationally less sensitive.  See below from Pers' paper.  But we know that these are homeostatic changes in response to the exogenous Benzo.  With Glutamate system, it's far more complex, partly homeostatic, partly changes in gene expression, etc......The rats in the study not exploring and huddled reminds me of agoraphobia in human beings and we see this in kindled Benzo users, so the Glutamate system has to be one of the instigators.  I call it hyperexcitability.

 

GABAa receptor changes

 

1) Changes in subunit composition of the GABAA receptor through gene expression to reduce sensitivity to BZs.  (1, 2, 18)

 

2) Phosphorylation, in which a phosphate may be added or removed to the GABAA receptor to either turn it on or off respectively (GABAA receptors are phosphorylated by various protein kinases and dephosphorylated by phosphatases). (2) 

 

3) Down-regulation of GABAA receptors, in which GABAA receptors are absorbed back into the neuron through endocytosis, thereby reducing their number at the synapse. (3)

 

[[li...]]

dm123, I don't know if this is helpful or just confusing since it doesn't focus on glutame and I can remove this post if you like.

 

There is much more than glutamate or gaba ... (not even talking about clonazepam!)

 

https://www.ncbi.nlm.nih.gov/pubmed/1358120

Cholinergic mechanisms in physical dependence on barbiturates, ethanol and benzodiazepines.

 

And more generic, the part of GABAA receptors likely isn't that interesting: https://www.hindawi.com/journals/aps/2012/416864/