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

[[cs...]]

Please see this post in another section.

 

 

http://www.benzobuddies.org/forum/index.php?topic=191985.0

 

The research is pointing to aberrant neuroplastic changes in the hippocampus from dysfunctional stress, GABAergic , and glutamatergic systems.    All three of these systems are profoundly affected by chronic benzodiazaphine use, and these neuroplastic changes in the hippocampus can possibly account for withdrawal symtoms.  As the reference above states, intrusive thoughts and anxiety are driven by GABAergic inhibitory interneurons in the hippocampus.    The hippocampus, being very plastic is one part of the brain that is particularly sensitive to dysfunction in those three areas I mentioned above.  Changes in the hippocampus have far reaching symptomatic affects, and the reference above illustrates one such affect, intrusive thoughts.

 

 

[[Te...]]

Oh, I didn't see that. Excellent article. Thank you, dm123!!

[[Be...]]

I have bad OCD now.  It's been getting worse since I got off the pills.  Wonder what part of my damaged brain is causing that?

[[cs...]]

I have bad OCD now.  It's been getting worse since I got off the pills.  Wonder what part of my damaged brain is causing that?

 

Hi,  I'm sure you know more about OCD than I do, but from Wikipedia it looks like a few areas of the brain are involved with OCD

 

It looks like the OFC, ACC and caudate nucleus are the main areas involved from the quote below.  I also know  that the nucleus accumbens can be involved.  Some of these areas are plastic and ammenable to change.

 

 

Quotes

 

The leading hypotheses propose the involvement of the orbitofrontal cortex, basal ganglia, and/or the limbic system, with discoveries being made in the fields of neuroanatomy, neurochemistry, neuroimmunology, neurogenetics, and neuroethology.

 

Data obtained from this research suggests that three brain areas are involved with OCD: the orbitofrontal cortex (OFC), the anterior cingulate cortex (ACC), and the head of the caudate nucleus.[1] Several studies have found that in patients with OCD, these areas: (1) are hyperactive at rest relative to healthy control; (2) become increasingly active with symptom provocation; and (3) no longer exhibit hyperactivity following successful treatment with SRI pharmacotherapy or cognitive-based therapy.[2] This understanding is frequently cited as evidence that abnormality in these neuroanatomical regions may cause OCD.

 

End quotes

 

 

I know I keep bringing up exercise as a general therapeutic modality during PWS, because it does favorably influence plasticity in the regions of the brain indicated below.  The changes include increased dendritic length, spine density, etc.

 

Note the major brain areas affected by exercise in bold below. Some of these are regions that affect OCD

 

Quote

 

Aerobic exercise promotes adult neurogenesis by increasing the production of neurotrophic factors (compounds that promote growth or survival of neurons), such as brain-derived neurotrophic factor (BDNF), insulin-like growth factor 1 (IGF-1), and vascular endothelial growth factor (VEGF).[46][47][48] Exercise-induced neurogenesis in the hippocampus is associated with measurable improvements in spatial memory.[49][50][51][52] Consistent aerobic exercise over a period of several months induces marked clinically significant improvements in executive function (i.e., the "cognitive control" of behavior) and increased gray matter volume in multiple brain regions, particularly those that give rise to cognitive control.[48][49][53][54] The brain structures that show the greatest improvements in gray matter volume in response to aerobic exercise are the prefrontal cortex and hippocampus;[48][49][50] moderate improvements are seen in the anterior cingulate cortex, parietal cortex, cerebellum, caudate nucleus, and nucleus accumbens.[48][49][50] Higher physical fitness scores (measured by VO2 max) are associated with better executive function, faster processing speed, and greater volume of the hippocampus, caudate nucleus, and nucleus accumbens.[49]

 

End quote

 

 

 

 

Do you mind me asking what your OCD symtoms are?

[[li...]]

dm123,

 

You've written a lot in this thread. And I do know you also wrote a document, but I believe the contents aren't the same (based on my recollection).

 

Wouldn't it make sense to put it all in one post ? Or perhaps attach a document ? (I guess the staff could help you with that) That makes everything much more readable.

[[cs...]]

dm123,

 

You've written a lot in this thread. And I do know you also wrote a document, but I believe the contents aren't the same (based on my recollection).

 

Wouldn't it make sense to put it all in one post ? Or perhaps attach a document ? (I guess the staff could help you with that) That makes everything much more readable.

 

Hi liberty, 

 

thanks for your interest and hope all is well.  Unfortunately, I/we can't just post my books.

Wikipedia and a lot of other references are ok, so I can continue to use those on this thread

This is the best that we can do.

 

Hope this makes sense.

 

 

[[Be...]]

dm, my OCD is ritual type stuff, but sometimes I count the strokes of brushing my teeth.  I need to do certain things each day like, check my water meter outside twice a day; make sure my atomic clock sets at 2am; wipe the gas-powered door hinge with a paper towel each day since it leaks a bit of oil and I probably don't need to; wipe out the bathtub after my shower and if I don't, I get anxiety; lie on my back and roll back two times after dinner and if I don't do it, I get anxiety.  My mind is a mess.  I can't do aerobic exercising because I can barely walk anymore or stand up.  I'm 56 years old.  I'm really sick.  My brain and CNS are on fire.  I walk to the mailbox up the street sometimes up to five times a day to check for the mail.  I must get my mail everyday.  After I do laundry, I check a plumbing fitting to see if it leaked and that was replaced years ago, but I still check it.  I check my toilet line fitting each day to see if it leaks, since it's just got electrical tape on it.  Everytime it rains, I check about 10 places in here for roof leaks including both sheds since I've had bad roof here in the past.  If anything leaks, I get the ladder out and get on the roof and caulk it, which is how I probably hurt my hip and leg.  I have no man here to help me.  I can't stop myself from doing it.  I did read about the frontal lobes being involved.  Also doc thinks I might have had a stroke and it might the one that affects the frontal lobes, etc.  My forehead feels like a block of concrete. 

[[cs...]]

 

 

Hi all,

I'm going to post a series that introduces us to neural circuits.  Then introduction is below.  I hope this gives the readers some insight into why they feel the way they do from a neuro-physiological perspective.

 

Be well and prosper...

 

 

"When man chose to mess with the GABAa receptor he opened up a Pandora's box.  This is a box that can be hard to close, but nonetheless we must persist....".  dm123

 

 

~ And down the rabbit hole we go….. 

From Lewis Carroll’s “Alice’s Adventures in Wonderland”

https://en.m.wikipedia.org/wiki/Alice's_Adventures_in_Wonderland

 

 

 

Introduction to Interneurons, neural physiology, and basic neural circuits focusing on the motor cortex circuit, the DA mesolimbic pathway and the hippocampus

 

Introduction

 

Why present neural circuits ?  The reason for this series of modules are the following:

 

A. They help us appreciate how important GABAergic signaling is for proper brain function. We will see that proper GABAergic signaling is essential for neural circuits to relay signals properly throughout the brain.

 

B. The basic understanding of brain neural architecture will help us understand why we feel the way we do when taking benzodiazaphines chronically, when tapering off of them, and when hitting tolerance or withdrawal.

 

C. An understanding of the motor neural circuit will help us understand why our muscles are stiff and rigid during withdrawal, or why our muscles are twitching , or even why we feel we have jelly legs. Walking and standing is a very fundamental prefrontal motor cortex activity which is highly dependent on proper functioning GABA neurons and proper levels of dopamine (DA)

 

D. An understanding of the reward neural circuit and the DA mesolimbic pathway will help us understand why we are depressed or can’t experience pleasure during withdrawal, or even why we can’t calculate risk and make decisions based on that risk. Recently,  pleasure has been found to be much more complex than previously thought, and it involves more than just the mesolimbic pathway.  Nonetheless, understanding the importance of GABA in the mesolimbic pathway is fundamental to understanding more complex "emotions" like pleasure and depression, which involve other regions of the brain and other neurotransmitters as well  (not just serotonin).  Interestingly, chronic stress increases reward thresholds, which is thought to reflect a reward deficit (i.e., anhedonia), whereas drugs of abuse have the opposite effect.  Dysfunction in reward circuits is now being implicated in pain, pain responses and analgesia. Imaging studies in humans show that higher functional connectivity of the NAc with PFC predicts pain persistence in patients with chronic back pain. Furthermore, the degree of dopamine release in the NAc is associated with the  perceived effectiveness of a placebo relative to pain reduction. Pleasure and pain seem to be linked through this pathway, and this could explain why chronic pain and mood disorders are often comorbid conditions.

 

 

E. An understanding of hippocampal interneurons will help us understand  why we have cognitive difficulties, or no resilience against stressors, or why we can’t spatially navigate during withdrawal.  The hippocampus is one of the most densely populated GABA receptor and GABA interneuron regions of the brain.

 

F. We will recognize that proper dopamine and GABA function are essential to maintaining the physiological integrity of many different types of neural circuits.  GABA provides the brute force inhibitory constraint through interneurons and MSNs (see G below), and dopamine provides the fine tuning and the maintenance of stability, consistency and fluidity to the neural currents in the circuit.

 

G. A type of GABAergic hub neuron called a medium spiny neuron found in the striatum (and the greater basal ganglia) will help us understand how fundamentally important the neurotransmitters GABA and dopamine are for our neural physiology.  MSNs are medium sized neurons that have a high spine density (hence spiny) on their many dendrites.  As such, they can receive many different neurotransmitters from many different  local interneurons in the striatum, as well as from many different relay interneurons that project into the striatum from other brain regions. They are essentially hub neurons.  The fact that they ultimately release GABA from their axon terminals gives us an idea of how fundamentally important GABA is for proper neural function and circuitry.  We were designed with MSNs for a purpose, which I hope will become clear as we learn about the fundamentals about neural circuits….

[[Mo...]]

 

Thank you, if you can.

 

Very interesting Terry and dm123, thx.....following now.

[[cs...]]

Hi all, I hope and pray everyone is doing well and if not, that we all have hope.  I'm posting the first two modules of the series below.  You need not understand everything in the figures at this time.  These first two modules are merely a prelude to acquaint the reader with some basic terminology and microcircuits in a few areas of the brain. By the end of this series we will be able to analyze these microcircuits in excruciating detail.

 

I hope that one day a clinical physician (i.e., a prescribing MD) stumbles upon this thread, and realizes the full implications of prescribing a benzodiazaphine to his or her patients. It should not be considered a simple and light decision without consequence.  I hope the medical community comes to realize the full complexity and vulnerability of the cellular neurophysiology that they are tinkering with, when they prescribe this blunt and crude little tool in their toolkit.  When one fully realizes the complexity of our neurophysiology, prescribing benzodiazaphines is truly like letting a child perform an overhaul on your car engine.  They are all too eager to do it, but have no idea what the are doing, and the consequences, as we all know, can be quite dire. I say this with full confidence and conviction.. 

 

A pervasive theme throughout all of the modules in this series is that inhibitory signaling is pervasive throughout our nervous system and that it is absolutely and unequivocally necessary for properly functioning neural circuits....so important that without it we could not even perform the most basic of involuntary and voluntary functions. I honestly did not intend for this theme to materialize, but the research guided me right to it. Impairment of this system (benzodiazaphines are a sure way to do it) presents a patient with, what appears to the archaic medical establishment,a constellation of mysterious illnesses....illnesses that physicians might term somatic (anxiety) .  The physician is all to eager to tinker with this interesting set of symptoms once again, thus perpetuating the vicious cycle.  This is a cycle that is inherent in the very foundations of our current medical system: treating the symptom rather than taking the time to find out the root cause of the issue.  Nonetheless, even after all of this abuse, we can and do recover! This, perhaps, is the most miraculous and amazing aspect of our neurophysiology......

 

1. Module 1: First figure of the DA mesolimbic system.  Starting out simple….

 

 

Here is a figure of the mesolimbic DA(dopamine) system (link below). It’s a complicated feedback mechanism involving GABA, Glutamate and DA.

 

For now, we don’t need to focus on the details.  Just realize that it involves several different regions of the brain and involves interneurons, and DA, Glutamate and GABA projections from their respective neurons.  Projections refers to the terminal aspect of the neuron, and the neurotransmitters that are released from it.  For example, throughout these modules we will see that the DA neurons on the VTA are affected by GABA interneurons as inhibitory inputs in the VTA DA neurons , and that these same DA neurons project  to several different areas of the brain, the NAc for example, to release the neurotransmitter DA. 

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4020178/figure/F3/?report=objectonly

 

Source

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4020178/

 

Trends Neurosci. Author manuscript; available in PMC 2014 May 14.

Published in final edited form as:

Trends Neurosci. 2011 Apr; 34(4): 188–197.

Published online 2011 Feb 25. doi:  10.1016/j.tins.2011.01.004

Hooked on benzodiazepines: GABAAreceptor subtypes and addiction

Kelly R. Tan, Uwe Rudolph, and Christian Lüscher

 

 

Here are some basic observations:

 

First, in this figure note the dopamine projections from the VTA to the NAc. That’s the important thing to note.  Also note that the GABA interneurons provide local feedback in the VTA (to dopamine neurons).  Also note that the NAc provides inhibitory projections (GABA) to the VTA.

 

 

Quote(with slight modifications that I made to make it read easier)

 

The reward system originates in the VTA, which is composed of two major cell types, the DA neurons and the GABA neurons.

 

1. From the VTA, The DA neurons (blue) project to the ventral striatum, the NAc, the PFC and the hippocampus.

 

2. The VTA receives inhibitory GABA projections (red) back from the NAc and from the pedunculopontine nucleus (PPT) and

 

3. The VTA receives excitatory Glutamate projections (green) from the PFC, the PPT, the amygdala, the lateral hypothalamus (LH), the laterodorsal tegmental nucleus (LDTg) and the bed nucleus of the stria terminalis (BNST),

 

4. The VTA  receives local inhibitory feedback from the GABA interneurons in the VTA itself.

End quote

 

2. Module 2: second figure of the DA mesolimbic system. Added layer of complexity….

Here is another figure that is similar

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3867253/

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3867253/figure/F1/?report=objectonly

 

Source

FromThe brain reward circuitry in mood disorders

• Scott J. Russo

• & Eric J. Nestler

Nature Reviews Neuroscience14,609–625(2013)doi:10.1038/nrn3381

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3867253/

 

Note the legend, in this figure.  The dot represents the source of the interneuron projection (i.e. Analogous to post synaptic membrane and receptors), and the arrow

  ---< or the flat ----|

 

represents the destination of the projection where the neurotransmitters are actually released (terminal aspect of the axons).

 

 

  For example, a GABAergic interneuron (blue) looks like (dot)-------|.    Referring to the figure cited above, one can see in the VTA , for example, that the dopaminergic interneuron receives GABA neurotransmitters (inhibitory control) from GABAergic interneurons (blue) that originate in the VTA itself, and from GABAergic interneurons that originate in the RMTg and NAc.(as well as the PPT as noted in the first figure above).  The dopaminergic interneuron in the VTA also receives glutamate neurotransmitters (excitatory stimulus) from glutamatergic interneurons (red) that originate in the LTDg and LH (lateral hypothalamus ), and other areas as noted in the first figure above like the PPT and PFC.

 

One can also see that the dopaminergic interneuron projections (green) from the VTA are numerous, as the VTA is kind of a control center for DA release to various parts of brain. Thus the VTA plays a part in drug addiction Physiology. The VTA DA interneuron projections (green) are to the mPFC, the hipp (hippocampus), and the NAc.  The hippocampus is a highly plastic region of the brain.

 

The NAc’s involvement in receiving DA from the VTA dopaminergic interneurons sets in motion a more widespread involvement of other brain regions in addiction Physiology relative to DA release.

 

  Note that relative to neurotransmitters, interneurons can have an opposite effect on  the primary neuron to which they project to, as opposed to the neurotransmitters acting directly on the primary neuron.  For example, for GABAergic interneurons, when these interneurons are hit with GABA, they hyperpolarize and are less likely to release their GABA to the primary neuron that they project to.  Thus the primary neuron will be more likely to depolarize (excite).  If the same neurotransmitter, GABA, acts directly on the primary neuron, it will of course hyperpolarize the primary neuron (inhibit it, not excite it).  We will explore this more thoroughly in a much later module, in the context of the hippocampus and GABAergic interneurons.

 

For more detail from the second figure above, there is textual description below the figure in the link I posted.  It’s worth reading….

 

 

No need to be concerned about all the fancy terms for different regions of the brain.  We will explore all these regions and much more, in a later module.

 

 

 

Quote

 

A simplified schematic of the major dopaminergic, glutamatergic and GABAergic connections to and from the ventral tegmental area (VTA) and nucleus accumbens (NAc) in the rodent brain.

 

The primary reward circuit includes dopaminergic projections from the VTA to the NAc, which release dopamine in response to reward-related stimuli (and in some cases, aversion-related stimuli).

There are also GABAergic projections from the NAc to the VTA; projections through the direct pathway (mediated by D1-type medium spiny neurons (MSNs)) directly innervate the VTA, whereas projections through the indirect pathway (mediated by D2-type MSNs) innervate the VTA via intervening GABAergic neurons in the ventral pallidum (not shown). The NAc also contains numerous types of interneurons (Fig. 2).

 

The NAc receives dense innervation from glutamatergic monosynaptic circuits from the medial prefrontal cortex (mPFC), hippocampus (Hipp) and amygdala (Amy), as well as other regions.

 

The VTA receives such inputs from the lateral dorsal tegmentum (LDTg), lateral habenula (LHb) and lateral hypothalamus (LH), as well as both GABAergic and glutamatergic connections from the extended amygdala (not shown). These various glutamatergic inputs control aspects of reward-related perception and memory.

 

The dashed lines indicate internal inhibitory projections  ( dm123: i.e., local; these are blue dashed lines in the VTA and NAC).

 

The glutamatergic circuit from the LH to the VTA is also mediated by orexin (not shown). Greater details of these monosynaptic circuits for NAc and VTA are shown in Fig. 2. RTMg, rostromedial tegmentum.

 

End quote

 

 

 

In module 3 we will ramp things up quite a bit and introduce a very important type of neuron called a medium spiny neuron or MSN for short....It's found at very high densities in a very important region of the brain called the stiatum.

 

[[cs...]]

Hi all, please see below for module 3, an introduction to an important neuron called an MSN.  We will introduce brain anatomy in module 4, following this, and in module 5 we will do a differential brain  circuit analysis between the two types of MSNs, which will be introduced below.

MSN axons project and release GABA.

 

 

Be well and prosper ....

 

 

Module 3: Brief Introduction to MSNs

 

 

 

See this third figure in the link below (relative to this series of modules; it is figure 2 in the source document).

 

 

 

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3867253/figure/F2/?report=objectonly

 

 

We are going to dissect this figure in detail in a later module.  Right now, we are going to focus on the top part “a” of the figure, detailing the local microcircuitry in an area of the brain called the NAc or nucleus accumbens, an important part of the of the striatum region of the brain.  The striatum region of the brain makes up what are called input nuclei to the basal ganglia (the striatum is part of the basal ganglia).  The basal ganglia is a large region of the brain that includes many subregions. It’s kind of a large relay station for routing information to another very important region of the brain called the thalamus.    This  precise routing will be explored in great detail in a later module as we explore brain neural circuitry for motor movement and for risk and reward behavior.  For now we want to look at the NAc in the figure because it includes a very very important type of GABAergic neuronal cell called medium spiny neurons, or MSNs.  The MSN in the figure is right in the center of  the figure in part “a”  , Nucleus Accumbens, of the figure.  The inputs into the MSN include local interneurons as well as relay neurons from other regions of the brain like the BLA (lateral amygdala), VTA, mPFC(prefrontal cortex), and the hippocampus.  These relay neurons are mostly glutamatergic (excitatory) as noted by the + at the end of their respective axon terminals.

 

  The VTA interneuron is not glutamatergic, but dopaminergic.  Note the +/- sign.  As will be explained, there are two types of MSNs, direct MSNs or dMSNs, which have D1 type dopamine receptors, and indirect MSNs , or iMSNs, which have  D2 receptors.  As will be explained, D1 and D2 receptors have opposite effects on intracellular processes (dopamine receptors are GPCRs or G protein coupled receptors), when DA locks onto these receptors.  Thus the dopamine interneuron input into the MSN can be either excitatory or inhibitory.

 

  Relative to the final destination of the data flow to the thalamus and then to the cerebral cortex,  the type of  MSN (direct (D1 receptors) or indirect (D2 receptors)) is critically important.  We will explore this dichotomy in later modules, but to understand why, we have to first understand the neural circuitry in the relevant regions of the brain.  Direct and indirect MSNs provide inputs to different circuit routes through the brain, and assuming an aggregate excitatory input into the MSN neural cell body, the dMSN will excitethe thalamus and cerebral cortex, whereas the iMSN will have a net inhibitory effect on the thalamus and cerebral cortex. This is very important because the 95% of the striatum neurons are MSNs, and 40% of these MSNs have both D1 and D2 receptors on their spines.  This makes circuit analysis in real life somewhat more complicated, but we will have to make some assumptions to simplify the MSN distribution, so that we can properly determine the neural output of the circuit to the thalamus.

 

In this respect, one can think of dopamine (DA) as being a neurotransmitter that “smooths” things out, for example, allows for fluid continuous voluntary movements, and nonrigid muscle tone.  When dopamine levels become dysfunctional, one can end up with jerky movements, twitching, tics, or in the case of too little dopamine, extreme muscle rigidity and stiffness, and hypokinesia. Understanding neural circuits helps us understand our symptoms in real life!  At the same time we understand where important neurotransmitters like DA and GABA fit in to provide normal neural physiological function.

 

Another more intuitive way to think of dopamine is the following

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3812767/#!po=16.3793

 

Quote

 

Dopaminergic circuits are important for the action of the basal ganglia, which normally exert a constant inhibitory influence on the motor systems (dm123: as we will see in detail, this is a constant tonic inhibitory current, in the absence of any input signal into the basal ganglia). This prevents the motor systems from becoming active at inappropriate times. (dm123: i.e., dopamine provides us with truly voluntary movement control) When a decision is made to perform a particular action, inhibition of the required motor system is reduced, thereby releasing it for activation. Dopamine acts to facilitate this release of (dm123:tonic) inhibition, and thus the net effect of dopamine depletion (dm123: for example , diseases like Parkinson’s disease) is to produce hypokinesia.

 

End quote

 

 

Source

FromThe brain reward circuitry in mood disorders

• Scott J. Russo

• & Eric J. Nestler

Nature Reviews Neuroscience14,609–625(2013)doi:10.1038/nrn3381

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3867253/

 

 

Here is a link to the figure again

 

 

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3867253/figure/F2/?report=objectonly

 

 

 

 

Introduction to MSNs (medium spiny neurons); center neuron in the figure part “a”,  NAc, cited above

 

 

MSNs are a very significant type of GABAergic neuron, and for our purposes, they are noted in the figure above,  part a, of the NAc.  I’m introducing them here, because they are a GABAergic inhibitory neuronal cell that is pervasive throughout the regions of the brain indicated below (95% of the striatum neurons are MSNs) and are intimately involved in what are called neural circuits.  The thalamus is involved in the circuitry .  The dorsal and ventral striatal MSNs are of particular interest as the former is involved in motor movement initiation and control, and the later (ventral) is involved in motivation, reward, reinforcement and aversion.  There is some overlap in this function between the two, but that is beyond the scope of this post.  I’m also just focusing on these two areas, to limit the scope of this post.  However, one must realize that for all of our various psychological and physical functions, there are many many other circuits and pathways involved.

 

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

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

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

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

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

 

 

Note the MSNs’ location.  They are located in the NAc (part of the ventral striatum), amongst many other areas of the brain like the thalamus. The basal ganglia, which we will examine in detail, is also densely populated with MSNs. Whenever we see MSNs we can note that GABA is playing a critical role in maintaining a “healthy” neural circuit through the brain by properly modulating the action potentials along the circuit.

 

D1 type MSNs are direct, whereas D2 type MSNs are indirect.

Note that MSNs are not interneurons, but spiny projection neurons, a special type of GABAergic inhibitory neuronal cell that have many inputs from local and relay interneurons.

Referring back to the figure above , part a NAc, one can see that MSNs are like hubs, with many dendrites and many incoming connections from various types of interneurons.  We will explore the types of interneurons that connect to the NAc MSNs in great detail in a later module.  As noted above, depending on the type of interneuron and the neurotransmitter that is released, the input can be either excitatory or inhibitory as noted by the little +/- signs in the figure.  MSNs ultimately project out to other regions of the brain, and if the overall membrane potential in the MSN is high enough and action potential will fire and it will release GABA out of its many axon terminal vesicles.  The fact that benzodiazaphines affect the GABAa receptors so profoundly implicates their potential to cause dysfunction relative to the GABA that the MSNs are releasing  into the synapse, in effect making the job of the MSN and the entire neural network much more difficult as these neurons try to maintain homeostasis .

 

For our purposes and examples, the MSNs in the striatum will mostly project into the areas of the brain called the internal globus palladis (for direct MSNs) and the external globus palladis (for indirect MSNs).  These different circuit paths are what gives rise to their differential effects on the ultimate destination of the data to the ventrolateral thalamus (VTh) and then to the cerebral cortex (frontal lobe).  Some MSNs (40% of those in the striatum) have both D1 (direct) and D2 (indirect) receptors on their dendrite spines, complicating the neural circuit output.

 

 

Quote

Medium spiny neurons (MSNs), also known as spiny projection neurons, are a special type of GABAergic inhibitory cell representing 95% of neurons within the human striatum, a basal ganglia structure.[1]

Medium spiny neurons have two primary phenotypes (characteristic types): D1-type MSNs of the direct pathway and D2-type MSNs of the indirect pathway.[1][2][3] Most striatal MSNs contain only D1-type or D2-type dopamine receptors, but a subpopulation of MSNs exhibit both phenotypes.[1][2][3]

End quote

 

 

[[cs...]]

This is not a part of the neural circuit paper, but I just wanted to post this as a friendly warning in regards to exogenous corticosteroids, mineralocorticoids, and Neurosteroids during benzodiazaphine taper and recovery.  Both endogenous and exogenous steroids have far reaching effects on the GABAergic system.  I've pulled several quotes from this research paper.

 

It's also very telling on the importance of stress itself in tolerance, withdrawal and recovery

 

There's an earlier post with a complete and thorough description of all of the Neurosteroids, and how they modulate the GABAa receptor.  This poor receptor seems to be the target of so many endogenous and exogenous compounds.

 

Refer to the link below for all source references.  Most are free online in full text....

-----------------

 

https://www.frontiersin.org/articles/10.3389/fncel.2012.00004/full

 

Quote 1

 

Acute and chronic stress has been shown to alter the expression of both GAD and GABA (Yoneda et al., 1983; Otero Losada, 1988; Maroulakou and Stylianopoulou, 1991; Acosta et al., 1993; Bowers et al., 1998) [for review see Cullinan et al. (2008)]. Increased GAD65 and GAD67 expression have been demonstrated following stress in brain regions associated with the regulation of the HPA axis, including the anterior hypothalamic area, dorsomedial nucleus, medial preoptic area, suprachiasmatic nucleus, anterior BST, perifornical nucleus, and peri-PVN region [bowers et al., 1998; for review see Cullinan et al. (2008)]

 

End quote

 

 

Quote 2

Despite the upregulation of enzymes responsible for GABA synthesis, the frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) has been shown to be decreased following stress (Verkuyl et al., 2004). Similarly, a high dose of exogenous corticosterone has been shown to decrease mIPSC frequency (Verkuyl et al., 2005) and adrenalectomy increases miniature inhibitory postsynaptic currents (mIPSC) frequency (Verkuyl and Joels, 2003) and the number of GABAergic synapses on CRH neurons (Miklos and Kovacs, 2002).

End quote

 

 

Quote 3

Further, demonstrating presynaptic changes in GABAergic inhibition following stress, the expression of receptors for stress-derived steroid hormones (MRs and GRs) have been identified on GABAergic interneurons in the peri-PVN region and stress hormones have been shown to increase the burst firing of these neurons (Shin et al., 2011). These findings are in contrast with the decreased frequency of both mIPSCs and sIPSCs following stress (Verkuyl et al., 2004) and may represent a compensatory change to restore inhibition in this region following stress.

End quote

 

 

 

Effects of stress on GABAaR expression

 

 

Quote 5

 

In addition to potential changes in presynaptic GABAergic release suggested by changes in GAD expression and GABA levels, there is also abundant evidence of postsynaptic changes in GABAAR subunit expression associated with stress.

 

 

One thing is for certain, the changes in binding to GABAARs following stress is extremely variable and results differ according to gender, paradigm used, and laboratory where the experiments were conducted. These results leave little certainty regarding changes in radio-labeled ligand binding to GABAARs following stress. Pharmacological changes more consistently point to alterations in GABAAR expression following stress. For example, stress and adrenalectomy have both been shown to alter benzodiazepine binding (Majewska et al., 1985; De Souza et al., 1986; Goeders et al., 1986; Miller et al., 1987, 1988; Weizman et al., 1990; Smith et al., 1992). However complex, these data suggest that there are changes in GABAAR expression associated with stress.

 

 

Studies investigating changes in GABAAR subunit expression following stress have demonstrated specific changes in GABAAR subtypes. There are brain region-specific alterations in GABAAR subunit expression following stress, including decreased GABAAR β1 and β2 subunit expression in the PVN following stress, with no change in GABAAR α1, α3, γ1, or γ2 expression (Verkuyl et al., 2004). Consistent with a role of extrasynaptic GABAARs in the regulation of the HPA axis, a significant increase in GABAAR α5 subunit expression and a decrease in GABAAR δ subunit expression have been demonstrated in the PVN following stress (Verkuyl et al., 2004). In the hippocampus, GABAAR β1 and β2 subunit expression is increased (Cullinan and Wolfe, 2000) and GABAAR γ2 subunit expression is decreased (Maguire and Mody, 2007). Increased expression of the predominantly extrasynaptic GABAAR δ subunit was demonstrated in the hippocampus following stress (Maguire and Mody, 2007) [for review see Belelli et al. (2009); Maguire and Mody (2009)] and these changes can by mimicked by treatment with THDOC (Maguire and Mody, 2007). Although the exact mechanisms underlying alterations in GABAAR subunit expression associated with stress are not fully understood, it is thought that these changes are mediated by the actions of stress hormones and/or stress-derived neurosteroids.

 

 

 

Both steroid hormones and neurosteroids are elevated in response to acute stress (Majewska et al., 1985; Purdy et al., 1991; Barbaccia et al., 1996a, b). Acute stress induces an elevation in circulating levels of THDOC from 1–5 nM to 15–30 nM (Reddy and Rogawski, 2002) [for review see Reddy (2003)]. Stress can increase neurosteroid levels to concentrations which can act directly on GABAARs to both potentiate the effects of GABA (Purdy et al., 1991; Barbaccia et al., 1996b) as well as alter GABAAR subunit expression (Maguire and Mody, 2007). Neurosteroids can potentiate the tonic component of GABAergic inhibition via action on GABAAR δ subunit-containing receptors at low concentrations (Stell et al., 2003), can potentiate the phasic component of GABAergic inhibition at higher concentrations, and at very high concentrations have even been shown to directly gate the receptor [for review see Lambert et al. (2009)]. In addition to the potentiation of GABAergic transmission by neurosteroids, steroid hormones themselves can alter synaptic GABAergic transmission (Maggio and Segal, 2009). Corticosterone alters the frequency of spontaneous sIPSCs in the hippocampus via actions on MRs (Maggio and Segal, 2009) and increases the amplitude of sIPSCs via actions on GRs (Maggio and Segal, 2009).

 

End quote

 

 

 

How stress alters GABAaR expression, one possible mechanism via Neurosteroidgenesis

 

Quote

 

Neurosteroidogenesis has been demonstrated to be essential for steroid hormone-linked alterations in GABAAR subunit expression (Maguire and Mody, 2007). These alterations in GABAAR subunit expression following stress are likely mediated by neurosteroid-mediated effects on GABAAR phosphorylation (Brussaard and Koksma, 2003), which controls GABAAR expression [for review see Kittler and Moss (2003)]. These data demonstrate the complex actions of both steroid hormones and neurosteroids on GABAARs via direct modulation or by altering receptor expression.

 

End quote

 

 

[[Re...]]

Yeah, but haven't you found a cure for us yet!!!!  JAJAJAJAJAJAJA (I laugh in Spanish)  :laugh:

 

-RST

 

[[cs...]]

Yeah, but haven't you found a cure for us yet!!!!  JAJAJAJAJAJAJA (I laugh in Spanish)  :laugh:

 

-RST

Hi RST

EDIT: fixed numerous typos

 

 

I wanted to post about that  as well. 

 

  When we find out why or how something occurs, it doesn't mean it will provide us with therapeutics, but It will help us work towards that goal.  The problem is that we are all looking for that one magic pill.    We all know that the crude pharmaceuticals don't agree with our complex physiology.    If anything, all of the technical stuff on this thread should make this very clear.  A drug is antagonistic and blocks one receptor type off, and the homeostatic processes in the body push back, and you end up with a whole new set of problems., as the body re establishes balance....

 

Doctors are no better.  You break your arm.  We know how the body mends the bone, but there's no pill that we can take to speed up the healing.  The doctor can set the arm in a cast, but it's the body that mends the bone.

 

Knowing the hows and whys also helps us avoid things that make it worse.  PAMs, Neurosteroids, corticosteroids, mineralocorticoids.  If you are kindled, switch to a longer acting benzodiazaphine.  Don't mix classical benzodiazaphines with z-drugs.  I wish someone had told me about these things years ago....

 

I know it sounds trite, but Anything that helps foster the body's natural healing processes helps a great deal.  I'm going through this withdrawal process myself.  For example, exercise, stress reduction, and all the difficult things that we don't want to do, and things that we doubt can really help...,.Who wants to overhaul their life, take a less stressful job that pays much less, and who wants to exercise when we can barely move.?  I know what that  burning feels like.  I have it too.  If I don't exercise , it's much much worse.

 

I know it's nearly impossible to reduce stress to the levels that would really speed up healing, especially in today's society.  Reality.  Bills have to be paid. 

 

You know about the latest in cancer research.  It's therapeutics geared toward mobilizing the body's own immune system against cancer cells.....  There's no cure for cancer, and no pharmaceuticals that really work.  They just buy you time.

 

The answer lies in our own body, what we do with it, and how we perceive the stressors in our lives, and how we think. .  If we understand the physiology behind the problem, we can then find ways to better mobilize the body's own resources to re-establish  balance. That's the cure.  This thread is about lifting the veil of mystery behind what is making us so sick (why and how).  If a curative protocol comes out of all of this, that's great. 

 

 

 

[[Re...]]

Yeah, but haven't you found a cure for us yet!!!!  JAJAJAJAJAJAJA (I laugh in Spanish)  :laugh:

 

-RST

Hi RST

EDIT: fixed numerous typos

 

 

I wanted to post about that  as well. 

 

  When we find out why or how something occurs, it doesn't mean it will provide us with therapeutics, but It will help us work towards that goal.  The problem is that we are all looking for that one magic pill.    We all know that the crude pharmaceuticals don't agree with our complex physiology.    If anything, all of the technical stuff on this thread should make this very clear.  A drug is antagonistic and blocks one receptor type off, and the homeostatic processes in the body push back, and you end up with a whole new set of problems., as the body re establishes balance....

 

Doctors are no better.  You break your arm.  We know how the body mends the bone, but there's no pill that we can take to speed up the healing.  The doctor can set the arm in a cast, but it's the body that mends the bone.

 

Knowing the hows and whys also helps us avoid things that make it worse.  PAMs, Neurosteroids, corticosteroids, mineralocorticoids.  If you are kindled, switch to a longer acting benzodiazaphine.  Don't mix classical benzodiazaphines with z-drugs.  I wish someone had told me about these things years ago....

 

I know it sounds trite, but Anything that helps foster the body's natural healing processes helps a great deal.  I'm going through this withdrawal process myself.  For example, exercise, stress reduction, and all the difficult things that we don't want to do, and things that we doubt can really help...,.Who wants to overhaul their life, take a less stressful job that pays much less, and who wants to exercise when we can barely move.?  I know what that  burning feels like.  I have it too.  If I don't exercise , it's much much worse.

 

I know it's nearly impossible to reduce stress to the levels that would really speed up healing, especially in today's society.  Reality.  Bills have to be paid. 

 

You know about the latest in cancer research.  It's therapeutics geared toward mobilizing the body's own immune system against cancer cells.....  There's no cure for cancer, and no pharmaceuticals that really work.  They just buy you time.

 

The answer lies in our own body, what we do with it, and how we perceive the stressors in our lives, and how we think. .  If we understand the physiology behind the problem, we can then find ways to better mobilize the body's own resources to re-establish  balance. That's the cure.  This thread is about lifting the veil of mystery behind what is making us so sick (why and how).  If a curative protocol comes out of all of this, that's great.

 

I absolutely agree and so appreciate your contribution.  This thread has helped me greatly.  Understanding is a critical part of acceptance and moving toward healing.  I don't know how others deal with some of the symptoms.  It's been a long miserable ride for me so far and I'm not even finished my gabapentin taper.  Going from Lorazepam to valium to gabapentin has been terrible for my CNS. 

 

As an incredibly short time user when I stopped and went into WD, I was faced with making critical decisions in an information vacuum with strong time constraints by my benzo-ignorant physician.  Knowing what I know now, I'd have tried to manage everything quite differently.  Your contribution (and others here) is important in helping us understand what is happening and to appreciate the factors that seem to lead to healing.  In this way we'll be able to avoid unnecessary polydrugging, wasting money and energy chasing shams and get to the finish line more quickly. 

 

Again, thank you so much.  The burning though.... that's my undoing.  It's so utterly agonizing for me and the only thing that's caused me to updose.  The painful lesson: I realized I'd been cutting too quickly as I'd been watching the mg's instead of percentages.  Then, got a little exercise because I thought I could given how low I'd gotten.....  BAD MISTAKE.  Some of us can get aerobic exercise in this, others can't.  I can't.  Between the two led, to was a catastrophic spike in symptoms....  Yeah, there's so much at play here it's just hard to know what to do sometimes.  Painful lessons that I hope others can avoid.  To your point, tapering slowly is usually better than quickly unless you are a very short term user.

 

-RST

[[li...]]

At a minumum, understanding these things ('model') will teach us what to avoid, and what might speed up healing. Maybe even some medical intervention, but not 'chemcial warfare against the body'. And if only doctors learned this and would understand ...

[[Re...]]

At a minumum, understanding these things ('model') will teach us what to avoid, and what might speed up healing. Maybe even some medical intervention, but not 'chemcial warfare against the body'. And if only doctors learned this and would understand ...

 

So true.  Well said. 

 

-RST

[[cs...]]

Yeah, but haven't you found a cure for us yet!!!!  JAJAJAJAJAJAJA (I laugh in Spanish)  :laugh:

 

-RST

Hi RST

EDIT: fixed numerous typos

 

 

I wanted to post about that  as well. 

 

  When we find out why or how something occurs, it doesn't mean it will provide us with therapeutics, but It will help us work towards that goal.  The problem is that we are all looking for that one magic pill.    We all know that the crude pharmaceuticals don't agree with our complex physiology.    If anything, all of the technical stuff on this thread should make this very clear.  A drug is antagonistic and blocks one receptor type off, and the homeostatic processes in the body push back, and you end up with a whole new set of problems., as the body re establishes balance....

 

Doctors are no better.  You break your arm.  We know how the body mends the bone, but there's no pill that we can take to speed up the healing.  The doctor can set the arm in a cast, but it's the body that mends the bone.

 

Knowing the hows and whys also helps us avoid things that make it worse.  PAMs, Neurosteroids, corticosteroids, mineralocorticoids.  If you are kindled, switch to a longer acting benzodiazaphine.  Don't mix classical benzodiazaphines with z-drugs.  I wish someone had told me about these things years ago....

 

I know it sounds trite, but Anything that helps foster the body's natural healing processes helps a great deal.  I'm going through this withdrawal process myself.  For example, exercise, stress reduction, and all the difficult things that we don't want to do, and things that we doubt can really help...,.Who wants to overhaul their life, take a less stressful job that pays much less, and who wants to exercise when we can barely move.?  I know what that  burning feels like.  I have it too.  If I don't exercise , it's much much worse.

 

I know it's nearly impossible to reduce stress to the levels that would really speed up healing, especially in today's society.  Reality.  Bills have to be paid. 

 

You know about the latest in cancer research.  It's therapeutics geared toward mobilizing the body's own immune system against cancer cells.....  There's no cure for cancer, and no pharmaceuticals that really work.  They just buy you time.

 

The answer lies in our own body, what we do with it, and how we perceive the stressors in our lives, and how we think. .  If we understand the physiology behind the problem, we can then find ways to better mobilize the body's own resources to re-establish  balance. That's the cure.  This thread is about lifting the veil of mystery behind what is making us so sick (why and how).  If a curative protocol comes out of all of this, that's great.

 

I absolutely agree and so appreciate your contribution.  This thread has helped me greatly.  Understanding is a critical part of acceptance and moving toward healing.  I don't know how others deal with some of the symptoms.  It's been a long miserable ride for me so far and I'm not even finished my gabapentin taper.  Going from Lorazepam to valium to gabapentin has been terrible for my CNS. 

 

As an incredibly short time user when I stopped and went into WD, I was faced with making critical decisions in an information vacuum with strong time constraints by my benzo-ignorant physician.  Knowing what I know now, I'd have tried to manage everything quite differently.  Your contribution (and others here) is important in helping us understand what is happening and to appreciate the factors that seem to lead to healing.  In this way we'll be able to avoid unnecessary polydrugging, wasting money and energy chasing shams and get to the finish line more quickly. 

 

Again, thank you so much.  The burning though.... that's my undoing.  It's so utterly agonizing for me and the only thing that's caused me to updose.  The painful lesson: I realized I'd been cutting too quickly as I'd been watching the mg's instead of percentages.  Then, got a little exercise because I thought I could given how low I'd gotten.....  BAD MISTAKE.  Some of us can get aerobic exercise in this, others can't.  I can't.  Between the two led, to was a catastrophic spike in symptoms....  Yeah, there's so much at play here it's just hard to know what to do sometimes.  Painful lessons that I hope others can avoid.  To your point, tapering slowly is usually better than quickly unless you are a very short term user.

 

-RST

 

Hi RST,

 

Yes, I know.  I'm not a doctor of medicine, but I know that the burining is incomprehensible by those who don't have it.  The gabapentin does a lot to quiet down the voltage gated channels in the neuron.  The ionotropic glutamate receptors (NMDARs and AMPARs) might have homeostatically senstized or unregulated in response .  (?).  Neuropathic pain is the hallmark symptom of hyperexcitability.  The good thing is that we know what instigated your particular pain, and that you will heal.   Our neural physiology was beautifully designed for damage control....

 

The neural circuit material will get quite  challenging, but even if you pick up on half of it, it will help you at least understand why you are feeling the way you do. Inhibitory signaling is the most critical function to healthy neural circuits that rely on what is called phasic output. Phasic output is alternating firing of APs from the neurons in a neural circuit.  This manifests itself in very basic physiological functions like respiratory breathing, walking, and gut motility, and many many other functions.

 

  Neurons in the biological entity don't exist in isolation.  The model has to include the physiology of the neuron when it's put in the context of a network or circuit of neurons.  It's the output of the neural circuit that determines real life physiological function.  Some of the modules, for example on brain anatomy, might seem dull and overwhelming; it's  necessary to understand this foundational material in order to understand neural circuit dynamics. That's the goal. 

 

What happens when the neural circuit gets hit with a perturbation?  A perturbation, much like a stressor, is a term that is used when the circuit undergoes "stress" that

-alters the synaptic strengths between the neurons,

-affects the conductances that determine the membrane potentials in the neuronal membranes,

-affects enzymatic and neuromodulator processes, etc.

 

...Perturbations are analogous to the metabolic HPA stress that we are all familiar with, except perturbation is a term applied to a disruptor or stress to neural circuit homeostasis.

 

In learning about neural circuit dynamics under "stress" we will find out why each of us has very unique withdrawal, tolerance and recovery responses,  even though we all start out with similar physiological neural function.

 

 

Can benzodiazaphines be considered a perturbation in this context?.  I think so.  I think the principles of neural circuit dynamics can be applied to the benzodiazaphine model.

 

I know a lot of these posts seem overly technical and know-it-all, but I'm the first one to state that I am truly humbled by the complexities, intricacies, and dynamics of cellular neurophysiology....

[[Su...]]

I have a question about kindling that I though might be best posted here.

If someone is kindled, meaning they came off benzos in the past, and have sensitized their nervous systems, does that last forever?

 

Or does the kindling itself heal?

 

I'm pretty sure I have been kindled from being on and off a number of benzos over the years, or decades -- although the xanax remained a constant during that time.  There was some addition of zopiclone, sublinox (and some dalmane but that was over a decade ago)

I'm curious about this for all of us.

 

Anyone have any info or insight into this?

Thanks for your input.

Happy New Year all Benzo Warriors!

SS

[[cs...]]

I have a question about kindling that I though might be best posted here.

If someone is kindled, meaning they came off benzos in the past, and have sensitized their nervous systems, does that last forever?

 

Or does the kindling itself heal?

 

I'm pretty sure I have been kindled from being on and off a number of benzos over the years, or decades -- although the xanax remained a constant during that time.  There was some addition of zopiclone, sublinox (and some dalmane but that was over a decade ago)

I'm curious about this for all of us.

 

Anyone have any info or insight into this?

Thanks for your input.

Happy New Year all Benzo Warriors!

SS

 

 

Hi SS, happy new year. I know you’ve been waiting for this for a long time….

 

i do hope others with more knowledge on kindling  chime in as well…….

 

 

 

This is a high level of what I’ve found.  Like everything with the nervous system it can get very complicated, especially when considering how effective benzodiazaphines are at completely crippling and destabilizing inhibitory GABAergic signaling….

 

 

 

Neuro-Kindling

We know that alterations in phosphorylation are involved in the kindling process.  I’ve got lots of  material on this.  Let’s just focus on one aspect.  Let’s remove the entire glutamatergic side of kindling (it’s a big part of it, but let’s simplify) and look at what kindling does to the GABAergic system.  The study below (at the bottom) is one such study.  Note that there a lots of studies in this area of altered phosphorylation in alcohol kindling studies and epileptogenesis studies(where they induce seizure development via seizures to study the pathology of epilepsy development), so it’s very evident that altered phosphorylation accounts for at least some of the effects of all types  kindling.

 

Note: We do have to be careful of extrapolating directly from some of the alcohol studies, especially relative to the glutamatergic aspect of kindling, because alcohol in and if itself is a neurotoxic substance.  The amount of alcohol itself can produce differential glutamatergic effects from those seen  in benzodiazaphine studies , due to the neurotoxic aspect of alcohol. Alcohol at high levels can have an excitotoxic effect on neurons and result in neuronal destruction…..The substance itself (alcohol) has direct effects in NMDA sensitization.

 

I haven’t presented any of this because kinases, and phosphorylation haven’t  been presented yet, nor all the aspects of GABAergic tonic inhibition.  Epileptogenesis, for example , involves aberrant tonic inhibitory signaling amongst other things, and tonic inhibition happens to be an important part of kindling. Tonic inhibition is playing a part in the kindling process because at its extreme, kindling reduces seizure threshold. 

 

The homeostatic glutamatergic side of kindling  is probably the part you’ve heard  about already, and the part of kindling that is a bit abstract.  We know that neural circuits react homeostatically to perturbations, via altered conductances densities (i.e., altered conductances of the various ionotropic receptor channels on neurons). This homeostatic circuit response is most likely at play on the glutamatergic side of things when we become kindled.  Neuronal excitability and the rates of (glutamatergic) channel expression may be altered in response to kindling  in an attempt to maintain physiological functional output of the circuit..  Circuits react homeostatically to perturbations via altered channel conductance expression , to maintain the activity (i.e., APs fired off from the neuronal soma down the axons) of the various neurons in the circuit.  It’s the nervous system's way of attempting to maintain physiological function in the face of adversity (stress or perturbations ).  We have not discussed this yet in the neural circuits material.

 

 

There’s also  an old saying that “seizures beget seizures”, meaning the more seizures you have leads to an increase in seizure susceptibility.  There’s at least one reason for this(in certain types of epilepsy):

 

Kindling of repeated seizures produces changes in phosphorylation, resulting in a decrease in synaptic receptor populations with beta3 subunits in status epilepticus (SE), and changes in GABAa subunit distribution (synaptic  vs. extra synaptic) as in temporal lobe epilepsy (TLE).

 

 

In his way, seizure threshold is progressively lowered, and the nervous system becomes more hyperexcitable, the more seizures that occur……Thus, kindling could be self-perpetuating in this respect, but I don’t know if we can extrapolate this to benzodiazaphine kindling.  I’ve been kindled by benzodiazaphines and crossing over to a longer acting benzodiazaphine and the continual tapering from that has helped greatly, but I find I’m still susceptible to hyperexcitability when presented with extremely stressful situations.  Thus, the healing process is most likely very slow…..

 

 

Anyways, here is a good study(one of many) that tells us what happens during kindling from the GABAergic side..  They were able to revert the aberrant phasic aspect of the kindling with a generic PKC antagonist , but to revert  the tonic aspect (extrasynaptic ) they had to resort to a broad spectrum PKC antagonist.  By revert I mean restore the GABAaRs sensitivity to the Neurosteroid THDOC.  . This might indicate why some aspects of kindling linger on for months in some of the studies I’ve read: tonic inhibitory signaling remains stubbornly aberrant.

 

For now you can think of phosphorylation simply as an intracellular cascade of processes that affect GABAa receptor trafficking, i.e. The expression of receptors with certain subunits present.  Kindling basically alters receptor Subunit expression in GABAa receptors via increased or decreased  endocytosis and exocytosis of specific Subunit containing receptors.  In this way it can  alter cluster subunit expression (both synaptic (phasic) and extrasynaptic (tonic)) as well.  The end result can be reduced (with kindling ) or enhanced tonic and/or phasic inhibitory receptor sensitivity …

 

 

I hope this helps a bit

 

https://www.researchgate.net/publication/49699906_Kindling_alters_neurosteroid-induced_modulation_of_phasic_and_tonic_GABAA_receptor-mediated_currents_Role_of_phosphorylation

 

Kindling alters neurosteroid-induced modulation of phasic and tonic GABAA receptor-mediated currents: Role of phosphorylation

• December 2010

• Journal of Neurochemistry 116(6):1043-56

• DOI

• 10.1111/j.1471-4159.2010.07156.x

• Source

• PubMed

 

Note THDOC was presented earlier in this thread as a potent Neurosteroid and allosteric modulator of the GABAa receptor. See the extensive post in this thread on Neurosteroids and steroids.

 

Quote

Abstract

J. Neurochem. (2011) 116, 1043–1056. We have previously shown that after kindling (a model of temporal lobe epilepsy), the neuroactive steroid tetrahydrodeoxycorticosterone (THDOC) was unable to augment GABA type A receptor (GABAA)-mediated synaptic currents occurring on pyramidal cells of the piriform cortex.

 

Phosphorylation of GABAA receptors has been shown previously to alter the activity of THDOC, so we tested the hypothesis that kindling induces changes in the phosphorylation of GABAA receptors and this accounts for the loss in efficacy.

 

To assay whether GABAA receptors are more phosphorylated after kindling, we examined the phosphorylation state of the β3 subunit and found that it was increased. Incubation of brain slices with the protein kinase C activator phorbol 12-myristate 13-acetate (PMA) (100 nM) also increased phosphorylation in the same assay.

 

In patch clamp, recordings from non-kindled rat brain slices PMA also reduced the activity of THDOC in a manner that was identical to what is observed after kindling.

 

We also found that the tonic current was no longer augmented by THODC after kindling and PMA treatment.

 

The protein kinase C (PKC) antagonist bisindolylmaleimide I blocked the effects PMA on the synaptic but not the tonic currents.

 

However, the broad spectrum PKC antagonist staurosporine blocked the effects of PMA on the tonic currents, implying that different PKC isoforms phosphorylate GABAA receptors responsible for phasic and tonic currents.

 

The phosphatase activator Li+palmitate restored the ‘normal’ activity of THDOC on synaptic currents in kindled brain slices but not the tonic currents.

 

These data demonstrate that kindling enhances the phosphorylation state of GABAA receptors expressed in pyramidal neurons reducing THDOC efficacy.

End quote

 

 

[[Su...]]

Thank you dm123!

In the end it doesn't matter does it?  we heal as we heal as we heal and it takes as long a it takes.. BUT it is good to know some of the science behind these things.  Somehow it eases the ruminative thinking that is so easy to get into at this juncture....

I remember my Mom giving me a Valium when my grandmother died when I was age 6  She didn't know any better, who knows what that set up in a young system.. Or perhaps that  started my system readying itself for this journey..

Again many thanks for the time and effort that you put into this thread....

:smitten:

SS

[[li...]]

SufferingSixtie,

 

'  we heal as we heal as we heal and it takes as long a it takes..' I wouldn't go as far as 'everyone heals, no matter what ...'

 

dm123, good post although obviously complicated.

 

I have a special place in my heart for those cholinergic neurons (animal studies, muscarinic receptors return to their previous state after abstinence convulsions, physical dependence being mediated via cholinergic neurons ...) http://onlinelibrary.wiley.com/doi/10.1002/syn.10064/abstract

'These findings suggest that the cholinergic system may contribute to the long-term structural and functional alterations that are characteristic of the kindled state. ' I know it's a lot of work ...

[Guest [me...]]

SufferingSixtie,

 

'  we heal as we heal as we heal and it takes as long a it takes..' I wouldn't go as far as 'everyone heals, no matter what ...'

 

dm123, good post although obviously complicated.

 

I have a special place in my heart for those cholinergic neurons

 

(animal studies, muscarinic receptors return to their previous state after abstinence convulsions, physical dependence being mediated via cholinergic neurons ...) http://onlinelibrary.wiley.com/doi/10.1002/syn.10064/abstract

'These findings suggest that the cholinergic system may contribute to the long-term structural and functional alterations that are characteristic of the kindled state. ' I know it's a lot of work ...

 

I too agree re the cholinergic neurons playing a major part in this process,

 

we are all very different to so take different paths to healing and it takes as long as it takes.

[[Su...]]

SufferingSixtie,

 

'  we heal as we heal as we heal and it takes as long a it takes..' I wouldn't go as far as 'everyone heals, no matter what ...'

 

dm123, good post although obviously complicated.

 

I have a special place in my heart for those cholinergic neurons (animal studies, muscarinic receptors return to their previous state after abstinence convulsions, physical dependence being mediated via cholinergic neurons ...) http://onlinelibrary.wiley.com/doi/10.1002/syn.10064/abstract

'These findings suggest that the cholinergic system may contribute to the long-term structural and functional alterations that are characteristic of the kindled state. ' I know it's a lot of work ...

 

So are you saying that some of us won't heal Liberty? That's a scary thought.... Although I know that I have healed in the time I have been tapering.  As for being off them all together perhaps that is a different story.  But the length of time this is taking is so tiring...

Not complaining here simply stating the obvious.

Any advice as to how to help those cholinergic systems?  Is there anything that has worked for you?  Just wondering...

SS

[[li...]]

SufferingSixtie,

 

'So are you saying that some of us won't heal Liberty?' Some ? Some won't. Basically, I'm saying that the idea that everyone heals no matter what is nonsense.

 

' Any advice as to how to help those cholinergic systems?' That's complicated theory. I'd say avoid polydrugging when possible, and avoid unnecessary stress. Which does not mean 'do nothing at all'.