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

[Guest [Sk...]]

Thanks dm123 for all your efforts.

 

This withdrawal gets us looking at and often blaming many things including our needed medication  :'(

 

as you say

 

I think these types of drugs do benefit mankind, and we are lucky to have them. 

They prevent so many HBP related secondary diseases ,

including kidney failure itself, strokes, etc.

Sometimes HBP can be simply age related, and these drugs extend our lives.

 

Thanks for eliminating one less thing to blame.   

 

 

 

 

[[fr...]]

Dm,  Yes thanks for such a good explanation of the drugs action.  Explains why my Dr isn’t concerned with my numbers but he did tell me not to limit salt so that is contradicting controlling my HBP.  Guess I’ll stay on the med.  just wish I could exercise.  Thanks again.

[[cs...]]

Thanks dm123 for this simple explanation of why the sodium is low taking the ACE inhibitor and not to eat too much salt.  I have been wondering about this, sometimes I overdo the salt which in the future I will be more cognizant of "don't overdo."  In my case restraint is the key.

 

Thanks again.

 

Sweet pea

 

Hi sweet pea, regarding the salt intake, i would just maintain a normal diet.  I would not try to cut out all salt, as the serum Na is already borderline low.    I've been borderline low in Na, and from what my doctor stated, it's not dangerous (136).  If it drops way below, I would see your doctor and ask him or her if it's ok to add salt to the diet.

[[cs...]]

Dm,  Yes thanks for such a good explanation of the drugs action.  Explains why my Dr isn’t concerned with my numbers but he did tell me not to limit salt so that is contradicting controlling my HBP.  Guess I’ll stay on the med.  just wish I could exercise.  Thanks again.

 

Hi freeme, yes I would just keep a regular salt diet.  From what I understand most of the postings have borderline low salt at 136.  If you try to normalize your salt via diet, while in these BP meds, I think it will take a lot of salt

 

If you are borderline, I would not intentional limit salt.    You might go too low.

 

I think the tolerance for exercise will come with time.

 

As always, please consult with your MD if you do plan to alter your dietary Na intake.

He or she can monitor your serum electrolyte levels.

[[cs...]]

Thanks dm123 for all your efforts.

 

This withdrawal gets us looking at and often blaming many things including our needed medication  :'(

 

as you say

 

I think these types of drugs do benefit mankind, and we are lucky to have them. 

They prevent so many HBP related secondary diseases ,

including kidney failure itself, strokes, etc.

Sometimes HBP can be simply age related, and these drugs extend our lives.

 

Thanks for eliminating one less thing to blame.   

 

 

Hi skyblue, yes I do the same.  Sometimes increased anxiety, for example,  which is directly related to a Benzodiazaphine taper, can produce very strange symptoms.    I think this is one reason why Benzodiazaphine tolerance and withdrawal produces such a wide variety of symptoms across different people.  The Benzodiazaphine decompensates very basic physiological functions like stress resiliency (=anxiety), the sympathetic and parasympathetic nervous systems (=autonomic dysfunction), and the neurotransmitter systems (= muscle rigidity, depression, apathy). 

 

 

If we are off the drug and not experiencing PWS, it much easier to determine that it's not the Benzodiazaphine.  However, diagnosing PWS, in and of itself, can be very challenging.  That's where things get very confusing and muddled.....

[[cs...]]

Wow, I just noticed we cracked 10,000 views.    Hopefully the thread will get pinned soon.

[[Te...]]

Amazing work, dm!!!

[[Re...]]

Wow, I just noticed we cracked 10,000 views.    Hopefully the thread will get pinned soon.

 

Hooray and OUTSTANDING dm123.  So appreciate of all your work.!!!

[[Su...]]

Yes thank you for this thread!!  :high five:

SS

[[cs...]]

Hi kpin,

 

I hope you've found this tread and can begin going through it.

Hopefully we can get it pinned soon, so that it doesn't get "lost"'with the passage of time.

 

 

Here's my very limited research on marijuana.  As I mentioned in the other thread response to you, there are many others here on BBs who are expert on this very complex plant.  My research below is limited, as I didn't have time to delve in deep.  The Israeli researchers seem to be producing the most cutting edge research in this area.

 

I'm sure you can find more recent research from them using the links below as a starting point.  mIPSCs are affected by marijuana use.  This doesn't make it bad or good, but we need to be aware. I haven't looked at THC.  Most of the info below is relative to CBD and its various isoforms.  There are effects on the the GABAAR channel itself as well as presynaptic release of GABA

 

 

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

 

This was just published this year

 

Cbd

 

https://www.ncbi.nlm.nih.gov/pubmed/28249817

 

 

I think you've seen this one

 

 

https://www.projectcbd.org/science/cannabis-pharmacology/how-cbd-works

This section

 

CBD as an allosteric modulator

 

 

https://www.projectcbd.org/science/cannabis-pharmacology/how-cbd-works

 

And this

 

https://news.lift.co/discovery-cannabidiol-acts-gaba-neurons-explain-antiepileptic-properties/

 

This signaling to presynaptic CB1 and CB2 receptors to reduce GABA release is not good for us.

Quote

Endocannabinoids can modulate GABA activity too. When a neuron is under extreme inhibition due to GABA activity, it can synthesize 2-AG and anandamide and send them to the previous neuron whereupon they bind to CB1 and CB2 receptors, leading to a cascade of molecular reactions that ultimately reduces GABA release. Recently, it has been found that the endocannabinoids can also act directly on GABA receptors in a way that is very similar to how the abovementioned drugs work.

 

This finding could help explain how cannabidiol (CBD), which unlike its cousin THC is not able to activate neither CB1 or CB2 receptors, nevertheless exerts actions that strikingly resemble those of other GABA-mediated drugs. To explore this idea, Dr. Mary Chebib and other researchers from the University of Sydney conducted a highly technical investigation measuring the effects of CBD on human GABA receptors. Their report was recently published in the journal of Pharmacological Research.

End quote

 

By safe profile they mean toxicity.  it means nothing in terms of our recovery.

 

Quote

 

The results demonstrated that both cannabinoids are able to modulate electrical currents via changes in GABA receptor activity. This effect was more noticeable when lower concentrations of GABA were present, possibly due to a higher affinity for the neurotransmitter. In fact, the cannabinoids did not alter the responses to maximal GABA concentrations, a phenomenon that is also observed with benzodiazepines and which confers them a highly safe profile.

End quote

 

Quote

 

2-AG and CBD were still able to exert their effects on receptors that lacked the proteins over which benzodiazepines act, suggesting the existence of a different binding site. Comparison of different GABA receptor configurations revealed further differences between the two cannabinoids, with CBD having a higher binding selectivity than that of 2-AG. This latter aspect draws CBD closer to other GABA drugs that are able to reduce symptoms of anxiety without generating sedation or ataxia.

 

End quote

 

 

And this

 

https://www.ncbi.nlm.nih.gov/pubmed/21324315

 

Quote

 

Prolonged treatment with the cannabinamimetic WIN 55,212-2 (+WIN, 1 μM, 24 h) caused profound CB1 receptor downregulation accompanied by neuronal hyperexcitability. Furthermore, prolonged +WIN treatment resulted in increased GABA release as indicated by increased mIPSC frequency, a diminished GABAergic inhibition as indicated by reduction in mIPSC amplitude and a reduction in GABA(A) channel number. Additionally, surface staining for the GABA(A) β(2/3) receptor subunits was decreased, while no changes in staining for the presynaptic vesicular GABA transporter were observed, indicating that GABAergic terminals remained intact. These findings demonstrate that agonist-induced downregulation of the CB1 receptor in hippocampal cultures results in neuronal hyperexcitability that may be attributed, in part, to alterations in both presynaptic GABA release mechanisms and postsynaptic GABA(A) receptor function demonstrating a novel role for cannabinoid-dependent presynaptic control of neuronal transmission.

 

End quote

 

 

http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0034129

 

Quote

 

Long-term CBD (50 mg/kg) also selectively increased GABAA receptor binding in the granular retrosplenial cortex in Nrg1 TM HET mice and reduced 5-HT2A binding in the substantia nigra in WT mice. Nrg1 appears necessary for CBD-induced anxiolysis since only WT mice developed decreased anxiety-related behaviour with repeated CBD treatment.

 

End quote

[[cs...]]

I'm posting this here as well, from the kpin marijuana thread because the Subunit affinity is a work in progress.  We are looking for GABAAR Subunit specific affinity bindings at the Subunit level of the receptor.  The chart below is for the GABAAR itself.    Librium is at the bottom (chlordiazepoxide)

 

----------

 

 

 

3. Regarding toerance.  Could you post the rat studies.  Looking back, i developed tolerance to lorazepam very very quickly, on the order of weeks.  But I so see your point.  I would need to see those rat studies, namely because the amount of Benzodiazaphine might have been a super physiological dose, and it might have been administered intravenously, etc...

 

https://www.ncbi.nlm.nih.gov/pubmed/8818332

 

Quote

Abstract

1. Chronic benzodiazepine treatment of rat cerebellar granule cells induced a transient down-regulation of the gamma-aminobutyric acidA (GABAA) receptor alpha 1 subunit protein, that was dose-dependent (1 nM-1 microM) and prevented by the benzodiazepine antagonist flumazenil (1 microM). After 2 days of treatment with 1 microM flunitrazepam the alpha 1 subunit protein was reduced by 41% compared to untreated cells, which returned to, and remained at, control cell levels from 4-12 days of treatment. Chronic flunitrazepam treatment did not significantly alter the GABAA receptor alpha 6 subunit protein over the 2-12 day period. 2. GABA treatment for 2 days down-regulates the alpha 1 subunit protein in a dose-dependent (10 microM-1 mM) manner that was prevented by the selective GABAA receptor antagonist bicuculline (10 microM). At 10 microM and 1 mM GABA the reduction in alpha 1 subunit expression compared to controls was 31% and 66%, respectively. 3. The flunitrazepam-induced decrease in alpha 1 subunit protein is independent of GABA, which suggests that it involves a mechanism distinct from the GABA-dependent action of benzodiazepines on GABAA receptor channel activity. 4. Simultaneous treatment with flunitrazepam and GABA did not produce an additive down-regulation of alpha 1 subunit protein, but produced an effect of the same magnitude as that of flunitrazepam alone. This down-regulation induced by the combination of flunitrazepam and GABA was inhibited by flumazenil (78%), but unaffected by bicuculline. 5. The flunitrazepam-induced down-regulation of alpha 1 subunit protein at 2 days was completely reversed by the protein kinase inhibitor staurosporine (0.3 microM). 6. This study has shown that both flunitrazepam and GABA treatment, via their respective binding sites, caused a reduction in the expression of the GABAA receptor alpha 1 subunit protein; an effect mediated through the same neurochemical mechanism. The results also imply that the benzodiazepine effect is independent of GABA, and that the benzodiazepine and GABA sites may not be equally coupled to the down-regulation process, with the benzodiazepine site being the more dominant. The biochemical mechanism underlying the benzodiazepine-mediated down-regulation of the alpha 1 subunit protein seems to involve the activity of staurosporine-sensitive protein kinases.

 

Can you tell me if this sentence from the above study has any significance?

 

The results also imply that the benzodiazepine effect is independent of GABA, and that the benzodiazepine and GABA sites may not be equally coupled to the down-regulation process, with the benzodiazepine site being the more dominant. The biochemical mechanism underlying the benzodiazepine-mediated down-regulation of the alpha 1 subunit protein seems to involve the activity of staurosporine-sensitive protein kinases.

 

 

Hi kpin

 

Thanks for the citation.  As I mentioned above it's very old, but they were on the right track.  They ultimately pointed to changes in phosphorylation ("protein kinases") which affect what is called receptor trafficking .  Receptor trafficking refers to how receptors are absorbed (endocytosis) and how they re-emerge at the neuron membrane surface (exocytosis) based on what is going on outside of the neuron.  If there is excessive potentiation of a receptor at particular subunits, the receptor tends to downregulate the population density of those receptors with those subunits and repopulate with GABAaRs with different subunits that are potentially less sensitive to the endogenous GABA neurotransmitter and/or the Benzodiazaphine.  Changes in phosphorylation are intracellular processes which are behind neuro-kindling, downregulation, etc.

 

The drug concentrations used are "normal".  For reference here are some affinities of various Benzodiazaphines for the GABAAR.  I'm working in trying to find a reliable source of affinities of the various Benzodiazaphines at the Subunit level, but this data is hard to find.

 

Here is the table for your reference.  You can see that the concentrations in the study were in nM to microM.  The GABA concentrations were much higher (up to mill-M range), but I don't know what a normal GABA concentration is.

 

(In this table you can see just how weak Librium is relative to the high potency Benzodiazaphines, Librium is at the bottom.  I will post this table on the Layman's thread as well)

triazolam 1.31 umol

alprazolam 1.38 umol

clonazepam 1.43 umol

flunitrazepam 1.60 umol

lorazepam 2.65 umol

loprazolam 2.90 umol

lormetazepam 3.58 umol

eszopiclone 4.24 umol

estazolam 4.73 umol

bromazepam 14.61 umol

quazepam 17.06 umol

zaleplon 19.65 umol

zopiclone 21.22 umol

nitrazepam 30.48 umol

diazepam 32.67 umol

medazepam 33.23 umol

nordazepam 33.25 umol

clorazepate 41.27 umol

prazepam 41.56 umol

flurazepam 47.08 umol

halazepam 51.03 umol

ketazolam 53.69 umol

clobazam 59.90 umol

zolpidem 59.90 umol

temazepam 63.90 umol

oxazepam 67.00 umol

chlordiazepoxide 75.00 umol

 

Keep in mind, this is the general affinity of the Benzodiazaphine for the GABAAR at the Benzodiazaphine binding site, and I don't have the information at the Subunit level.  We do know that the Benzodiazaphine binding site is at α and γ and GABA at α and β, but Benzodiazaphines also have affinity to β subunits as well.

 

I mention this because the α1  is common to both, hence the purpose of the study: to differentiate between the downregulation effects of Benzodiazaphines vs endogenous GABA . 

 

They do this via a Benzodiazaphine, GABA, a GABA antagonist, and a Benzodiazaphine antagonist.

 

The Benzodiazaphine incites a particular protein kinase intracellularly, that adversely affects the α1 Subunit (downregulates it) in a way that natural endogenous GABA does not.  They use antagonists to selectively block the effects of each to isolate what is causing this downregulation of the α1.

 

See also point 4 below

Quote

Simultaneous treatment with flunitrazepam and GABA did not produce an additive down-regulation of alpha 1 subunit protein, but produced an effect of the same magnitude as that of flunitrazepam alone. This down-regulation induced by the combination of flunitrazepam and GABA was inhibited by flumazenil (78%), but unaffected by bicuculline.

End quote

 

 

So GABA incites downregulation of α1 via a completely different process than that of the Benzodiazaphine. The Benzodiazaphine's intracellular effect on the neuron is unique and completely uncoupled from the effect that GABA has on the neuron.  Using the GABA antagonist, as indicated in the quote above does not reverse this effect because of the discrete process involved.

 

In real life, if GABA concentrations rose to a level that started downregulating α1, the neurons acting as a collective neural circuit would homeostatically adjust, and the presynaptic release of GABA would be throttled down, to alleviate the α1 downreguation.  Injecting GABA directly into the extracelluar compartment does not happen in real life, but it did serve a purpose in this study. (Brain blood barrier even blocks GABA supllements from hitting the brain)

 

When we ingest Benzodiazaphines, it is a completely different story.  Natural homeostatic plasticity is completely messed up, and the neural circuits will not be able to adjust after a certain point, as the α1 slowly and continually downregulates further and further.  These kinases that are involved in the aberrant phosphorylation of the receptor are not natural.  Eventually , the neural circuit can no longer accommodate and we enter a symptomatic tolerance.  This can take weeks, months or even years.    I haven't presented the material on homeostatic plasticity and neural circuits yet, in the Layman's thread.   

 

You are correct.  The process of downregulation can occur very rapidly, but the neural circuit can accommodate quite a bit of stress (Benzodiazaphine) before physiological function deteriorates and tolerance symptoms emerge.

 

I hope this helps.  The takeaway is that Benzodiazaphines are unique in their detrimental effects on the receptor configuration, as opposed to naturally occurring endogenous GABA

 

 

 

 

[[li...]]

dm123,

 

Do you have a source for that table ?

 

I'm suprised by the ration alprazolam:clonazepam. Supposedly, clonazepam is twice as potent.

[[cs...]]

dm123,

 

Do you have a source for that table ?

 

I'm suprised by the ration alprazolam:clonazepam. Supposedly, clonazepam is twice as potent.

 

Yes liberty, unfortunately its bluelight, so take it with that i mind.  I don't pull information from there but I wanted to get a ballpark figure of the magnitude of the molar affinities, to respond to kpin's citation.  (It just so happens that the dosages used in that study were about on the average)

 

 

The blue light poster said he/she got it from a paper copy, i assume from a pharmacology book.

 

From what I understand, many tables list xanax and clonazepam at the same conversion levels to Valium indicating similar potency.  I do see other tables with the 2x potent you indicate, but not very often.  Perhaps this is because their pharmacokinetics are so different?

 

As we discussed on PMs, there's a general lack of information on affinity bindings of the various Benzodiazaphines to the GABAAR.    Getting affinities at the level of subunits might even be more elusive.  I don't think we will find this information outside of a pharmacology reference book on Benzodiazaphines, or perhaps in a Benzodiazaphine chemistry reference guide.  I don't know where we can find such books.

[[cs...]]

Hi all, I hope everyone is doing ok.  I'm posting PART I of module 4 of the Neural Circuits paper.  To see where this Neural circuts overlay fits into the overall model, see the summary on page 40 of this thread.

 

This module 4 is very academic, but it's necessary to understand basic brain Neuro-anatomy, moving forward.  You needn't understand all the details of this module, but the flow of circuitry from the higher brain levels (cortical and striatal)to the lower levels like the thalamus and brain stem are the key takeaways. 

 

PART II, module 4 will be posted in a week or two. It's all ready to go, but I don't want to overwhelm with too massive of a data dump.  I'm not sure how many parts I will break this module into.  Perhaps 3 or 4. 

 

The modules following module 4 will make a lot of sense once the basic neural flow through the brain is understood.

One last thing, our main objectives for this Neural circuts paper are:

 

1. To see how it overlays in the higher model presented on page 40 (model summary)

 

2. To understand more about neural circuit dynamics, once we understand neural circuits.

 

3. To understand  the intricacies of one type of neural circuit dynamics called homeostatic plasticity, and to understand why this is pertinent to the Benzodiazaphine wd model presented on page 40.  Neurons don't live in isolation. They are a part of a neural circuit, and thrive relative to the synaptic connections that they make with neighboring neurons.  Furthermore, neurons in a given neural circuit homeostatically adjust receptor conductances and synaptic strengths when the circuit is faced with a perturbation (i.e., a stressor), to maintain physiological function of the circuit .  When the circuit is compromised beyond its ability to homeostatically adjust to severe perturbations, it can crash, at which time physiological function deteriorates and manifests itself in the form of outward symptoms.  Crashes are fully  recoverable provided the perturbation is removed.

 

Be well and prosper.  Prayers out to all.

 

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

4. Module 4 (PART I):  Introduction to brain architecture and brain neuroanatomy, microcircuits, and a brief introduction to some neural brain circuits   

 

 

 

 

(4.1)Introduction

 

The brain is far too complex to introduce it completely in this module.  Instead, we will only focus on the regions of the brain that will be relevant for the brain circuits that we will be presented later in this series….This is a challenging module, particularly some of the quoted material from Wikipedia.  One does not have to understand everything in the quoted material to proceed to the next module.  I will provide commentary on most of the quoted material that will hopefully clarify and delineate the relevant material for the modules that follow.

 

Note: the term microcircuit is used in the literature to refer to a segment of a complete circuit.  It’s a relative and subjective term.  Some of the literature uses this term to refer to very very specific neural regions of the brain at the level of the actual neuron, whereas other literature is a bit more liberal in its use, referring to a small segment of a complete functional neural circuit.

 

This reference below gives us some insight into some various types of neural circuits.  Scroll down to the figure entitled “MicroNetwork Motifs”.  These are symbolic motifs used to represent specific types of microcircuits.

 

Some examples of microcircuits are

https://canvas.brown.edu/courses/851434/pages/neural-circuits

 

 

Quote

Feedforward excitation.  Allows one neuron to relay information to its neighbor.  Long chains of these can be used to propagate information through the nervous system.

 

Feedforward inhibition.  A presynaptic cell excites an inhibitory interneuron (an interneuron is a neuron interposed between two neurons) and that inhibitory interneuron then inhibits the next follower cell.  This is a way of shutting down or limiting excitation in a downstream neuron in a neural circuit.

 

Convergence/Divergence.  One postsynaptic cell receives convergent input from a number of different presynaptic cells and any individual neuron can make divergent connections to many different postsynaptic cells.  Divergence allows one neuron to communicate with many other neurons in a network.  Convergence allows a neuron to receive input from many neurons in a network.

 

Lateral inhibition.  A presynaptic cell excites inhibitory interneurons and they inhibit neighboring cells in the network.  As described in detail later in the Chapter, this type of circuit can be used in sensory systems to provide edge enhancement.

 

Feedback/recurrent inhibition.  In Panel E1, a presynaptic cell connects to a postsynaptic cell, and the postsynaptic cell in turn connects to an interneuron, which then inhibits the presynaptic cell.  This circuit can limit excitation in a pathway.  Some initial excitation would be shut off after the red interneuron becomes active.  In Panel E2, each neuron in the closed chain inhibits the neuron to which it is connected.  This circuit would appear to do nothing, but, as will be seen later in the Chapter, it can lead to the generation of complex patterns of spike activity.

 

Feedback/recurrent excitation.  In Panel F1, a presynaptic neuron excites a postsynaptic neuron and that postsynaptic neuron excites the presynaptic neuron.  This type of circuit can serve a switch-like function because once the presynaptic cell is activated that activation could be perpetuated.  Activation of the presynaptic neuron could switch this network on and it could stay on.  Panel F2 shows variants of feedback excitation in which a presynaptic neuron excites a postsynaptic neuron that can feedback to excite itself (a, an autapse) or other neurons which ultimately feedback (b) to itself.

Source: Neuroscience Online, UT Health

 

End quote

 

 

 

  In a much later module, we will explore the local microcircuitry of the NAc and VTA, and in this module we will introduce some circuitry in the striatal region of the brain, called the frontostriatal circuit.  The later (frontostriatal circuit) is a much larger segment of a specific brain region circuit, and hence the term “circuit” rather than “microcircuit” is used….

 

 

 

 

 

 

 

(4.2)Basic brain architecture: the striatum (input nuclei of the basal ganglia)

 

To get a better idea of where these MSNs reside and what regions of the brain we are focusing on, let’s first take a look at the striatum region. The striatum consists of the putamen (Put), claudate nucleus (CN), and the nucleus accumbens (NAc) and olfactory tubercle.

 

  The dorsal part of the striatum consists of the CN and Put, whereas the ventral striatum consists of the NAc and olfactory tubercle.  It’s interesting to note that the dorsal aspect MSNs are primarily associated with initiating and controlling motor movements , whereas the ventral aspect MSNs  are associated with reward, motivation, aversion and reinforcement via the VTA and other brain structures. Dopamine (DA) plays a critical role in both motor control and risk/reward.

 

 

As we will see, the striatum is part of a larger group of nuclei in the brain called the basal ganglia. This group of nuclei encompasses other brain regions that output to a part of the brain called the thalamus, which is critical  for sensory and motor signal relay to the (prefrontal) cerebral cortex.

 

 

Quote

In primates, the striatum is divided into ventral and dorsal subdivisions, based upon function and connections. The ventral striatum consists of the nucleus accumbens and the olfactory tubercle. The dorsal striatum consists of the caudate nucleus and the putamen. A white matter, nerve tract (the internal capsule) in the dorsal part separates the caudate nucleus and the putamen.[4] Anatomically, the term striatum describes the striped (striated) appearance of the grey-and-white matter that composes said structure of the brain.[7]

End quote

 

 

Quote

The ventral striatum, and the nucleus accumbens in particular, primarily mediates reward cognition, reinforcement, and motivational salience, whereas the dorsal striatum primarily mediates cognition involving motor function, certain executive functions (e.g., inhibitory control), and stimulus-response learning;[2][3][4][29] there is a small degree of overlap, as the dorsal striatum is also a component of the reward system that, along with the nucleus accumbens core, mediates the encoding of new motor programs associated with future reward acquisition (e.g., the conditioned motor response to a reward cue).[3][29]

End quote

 

 

Most of the cell types in the striatum are MSNs, but there are other neuronal types present as well including cholinergic interneurons (designated as ChAT in the figure part “a”), PV interneurons (see the figure), and somatostatin, calretinin, and calbindin interneurons (see figure).

 

 

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

 

 

  These interneurons supply excitatory input into the MSN.  In addition, as noted earlier, there are relay interneurons from other parts of the brain that provide input (mostly excitatory glutamatergic, except for the DA interneuron from the VTA).  These relay interneurons are not part of the striatum cellular space, but project into it, thus they are not included in the listing below.

 

 

Quote

Types of cells in the striatum include:

 

 Medium spiny neurons, which are the principal neurons of the striatum.[2] They are GABAergic and, thus, are classified as inhibitory neurons. Medium spiny projection neurons comprise 95% of the total neuronal population of the human striatum.[2]Medium spiny neurons have two primary phenotypes (i.e., characteristic types): D1-typeMSNs of the direct pathway and D2-type MSNs of the indirect pathway.[2][4][12] A subpopulation of MSNs contain both D1-type and D2-type receptors, with approximately 40% of striatal MSNs expressing both DRD1 and DRD2 mRNA.[2][4][12]

 

 Cholinergic interneurons release acetylcholine, which has a variety of important effects in the striatum. In humans, other primates, and rodents, these interneurons respond to salient environmental stimuli with stereotyped responses that are temporally aligned with the responses of dopaminergic neurons of the substantia nigra.[13][14] The large aspiny cholinergic interneurons themselves are affected by dopamine through dopamine receptors D5.[15]

 

 There are many types of GABAergic interneurons.[16] The best known are parvalbumin expressing interneurons, also known as fast-spiking interneurons, which participate in powerful feedforward inhibition of principal neurons.[17] Also, there are GABAergic interneurons that express tyrosine hydroxylase,[18] somatostatin, nitric oxide synthase and neuropeptide-y. Recently, two types of neuropeptide-y expressing GABAergic interneurons have been described in detail,[19] one of which translates synchronous activity of cholinergic interneurons into inhibition of principal neurons.[20] These neurons of the striatum are not distributed evenly.[16]

End quote

 

 

 

 

 

(4.2.1)Brief introduction to some circuitry (striatal)

 

Here is a simplified diagram of the striatal-thalamus motor circuit pathway.  We will examine this much more closely in a later module.  Below is a brief introduction to some of the circuits and pathways originating from the striatum.  We will focus on a few of these in detail in a later module.

 

https://en.m.wikipedia.org/wiki/File:Basalganglien.png

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

 

 

Quote

Frontostriatal circuits are neural pathways that connect frontal lobe regions with the basal ganglia (striatum) that mediate motor, cognitive, and behavioural functions within the brain.[1] They receive inputs from dopaminergic, serotonergic, noradrenergic, and cholinergic cell groups that modulate information processing.[2] Frontostriatal circuits are part of the executive functions. Executive functions includes following: selection and perception of important information, manipulation of information in working memory, planning and organization, behavioral control, adaptation to changes, and decision making.[3] These circuits are involved in neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease as well as neuropsychiatric disorders including schizophrenia, depression, obsessive compulsive disorder (OCD), and attention-deficit hyperactivity disorder (ADHD).[3][4]

 

There are five defined frontostriatal circuits: motor and oculomotor circuits originating in the frontal eye fields are involved in motor functions; while dorsolateral prefrontal, orbital frontal, and anterior cingulate circuits are involved in executive functions, social behavior and motivational states.[2]

 

These five circuits share same anatomical structures. These circuits originate in prefrontal cortex and project to the striatum followed by globus pallidusand substantia nigra and finally to the thalamus.[2]

 

There are also feedback loops from thalamus back to prefrontal cortex completing the closed loop circuits. Also, there are open connections to these circuits integrating information from other areas of the brain.[2]

 

The role of frontostriatal circuits is not well understood. Two of the common theories are action selection and reinforcement learning. The action selection hypothesis suggest that frontalcortex generates possible actions and the striatum selects one of these actions by inhibiting the execution of other actions while allowing the selected action execution.[5] Whereas, the reinforcement learning hypothesis suggest that prediction errors are used to update future reward expectations for selected actions and this guides the selection of actions based on reward expectations.[6]

 

The ventromedial prefrontal cortex and its connections to ventral striatum and amygdala are important in affective-emotional processing. They are responsible for elaboration of the plan of actions responsible for goal-directed behavior.[7]

In the eye movement circuitry, prefrontal cortex and anterior cingulate cortex provide the cognitive control of attention and eye movements, while striatum and brainstem initiate the eye movements. Reduced recruitment of prefrontal cortex while relatively intact brainstem functions during task performance contributes to deficits in the voluntary control of saccades in individual with autism.[8]

End quote

 

 

 

 

(4.2.2)inputs (striatal)

 

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

 

Quote

The largest connection is from the cortex, in terms of cell axons. Many parts of the neocortex innervate the dorsal striatum. The cortical pyramidal neurons projecting to the striatum are located in layers II-VI, with the most dense projections come from layer V.[25] They end mainly on the dendritic spines of the spiny neurons. They are glutamatergic, exciting striatal neurons.

The ventral striatum receives direct input from multiple regions in the cerebral cortexand limbic structures such as the amygdala, thalamus, and hippocampus, as well as the entorhinal cortex and the inferior temporal gyrus.[26] Its primary input is to the basal gangliasystem.

 

Additionally, the mesolimbic pathway projects from the ventral tegmental area to the nucleus accumbens of the ventral striatum.[27]

 

Another well-known afferent is the nigrostriatal connection arising from the neurons of the substantia nigra pars compacta. While cortical axons synapse mainly on spine heads of spiny neurons, nigral axons synapse mainly on spine shafts. In primates, the thalamostriatal afferent comes from the central median-parafascicular complex of the thalamus (see primate basal ganglia system). This afferent is glutamatergic. The participation of truly intralaminar neurons is much more limited. The striatum also receives afferents from other elements of the basal ganglia such as the subthalamic nucleus(glutamatergic) or the external globus pallidus (GABAergic).

End quote

 

 

 

 

 

(4.2.3)outputs or targets (striatal)

 

Quote

The primary outputs of the ventral striatum project to the ventral pallidum, then the medial dorsal nucleus of the thalamus, which is part of the frontostriatal circuit. Additionally, the ventral striatum projects to the globus pallidus, and substantia nigra pars reticulata. Some of its other outputs include projections to the extended amygdala, lateral hypothalamus, and pedunculopontine nucleus.[28]

 

Striatal outputs from both the dorsal and ventral components are primarily composed of medium spiny neurons (MSNs), a type of projection neuron, which have two primary phenotypes: "indirect" MSNs that express D2-type receptors and "direct" MSNs that express D1-type receptors.[2][4]

 

The basal ganglia core is made up of the striatum along with the regions to which it projects directly, via the striato-pallidonigral bundle. The striato-pallidonigral bundle is a very dense bundle of sparsely myelinated axons, giving a whitish appearance. This projection comprises successively the

 

 

external globus pallidus (GPe),

the internal globus pallidus (GPi),

the pars compacta of the substantia nigra(SNc),

and the pars reticulata of substantia nigra (SNr).

 

 

The neurons of this projection are inhibited by GABAergic synapses from the dorsal striatum.(dm123: i.e., MSNs in the striatum )

 

Among these targets, the GPe does not send axons outside the system.

 

Others send axons to the superior colliculus. Two others comprise the output to the thalamus, forming two separate channels: one through the internal segment of the globus pallidus to the ventral oralis nuclei of the thalamus and from there to the cortical supplementary motor area and another through the substantia nigra to the ventral anterior nuclei of the thalamus and from there to the frontal cortex and the oculomotor cortex.

End quote

 

 

 

 

 

 

(4.2.4)function of striatum(dorsal and ventral)

 

Quote

The ventral striatum, and the nucleus accumbens in particular, primarily mediates reward cognition, reinforcement, and motivational salience, ….

 

whereas the dorsal striatum primarily mediates cognition involving motor function, certain executive functions (e.g., inhibitory control), and stimulus-response learning;[2][3][4][29] there is a small degree of overlap, as the dorsal striatum is also a component of the reward system that, along with the nucleus accumbens core, mediates the encoding of new motor programs associated with future reward acquisition (e.g., the conditioned motor response to a reward cue).[3][29]

End quote

 

 

 

 

 

 

 

 

(4.3)Basic brain architecture: the basal ganglia

 

 

 

The basal ganglia nuclei are depicted in figure in this link

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

https://en.m.wikipedia.org/wiki/File:Basal_Ganglia_and_Related_Structures.svg

https://en.m.wikipedia.org/wiki/File:Constudoverbrain_-_2.png

 

In its simplest form the basal ganglia should be thought of as kind of a big relay station that involved in completing neural circuits (which will be explained in a later module), and also receiving inputs from a number of different brain regions, assimilating the signals, and then outputting the signal to the thalamus.  The thalamus then relays the signals to the cerebral cortex (frontal lobe) for further processing. 

 

 

The cortical, thalamic, and nigral regions of the brain send information to the input nuclei of the basal ganglia.

 

 

The input nuclei consist of the dorsal and ventral aspects of the striatum discussed above. 

Thus the basal ganglia is THE relay station for risk, reward, motor movement, as discussed in the context of the striatum above. 

 

 

Once the information is received it’s then passed to the intrinsic nuclei of the basal ganglia.  The intrinsic nuclei are listed below, and are not critical insofar as this discussion is concerned, but nonetheless are functionally important.  They can be thought of as a sub relay station bridging the input and output nuclei of the basal ganglia.

 

 

The output nuclei consist of the globus pallidus (GPi) and the substantia nigra pars reticulata (SNr).  These nuclei are important in that they output the information from the basal ganglia system to the thalamus, which is another major hub for sensory and motor control.  The thalamus projects mainly back into the cerebral cortex frontal lobe (in this discussion; however it has other projections as well) to complete the CNS brain portion of the neural circuit.

Given what we have learned in the first 2 modules, it’s no great surprise that the input nuclei of the basal ganglia require dopamine to perform the proper relaying of the signal information into the basal ganglia.  Dopamine can provide either excitatory or inhibitory signaling to MSNs located in the ventral striatum (NAc ) and the dorsal striatum MSNs, as noted earlier.  The dopamine comes from the VTA DA interneurons as detailed in the figures in the earlier modules.  This explains why dopamine dysfunction is associated with movement disorders.  The circuit will become sporadic if DA release is insufficient, kind of like an electrical wire that’s ready to break.  Wiggling it around makes the current inconsistent, and the light will start to flicker….DA is like a stabilizer for the current (data) flowing through the basal ganglia.

 

 

The output nuclei can provide either excitatory or inhibitory signals to the thalamus, depending on what neural control is required, and what type of MSN the dopamine is hitting.  In general, as we will see, direct MSNs provide the cerebral cortex with motor movement signaling (if data is passing through the dorsal striatum), or reward signaling (if data is passing through the ventral striatum, i.e. The NAc), and indirect MSNs provide the cerebral cortex with prevention of motor movement (dorsal), or aversion signaling (ventral). 

 

The circuits for direct and indirect are a bit different causing the different output behavior in the signaling to the cerebral cortex. The indirect route has a few additional stops prior to getting to the output nuclei of the basal ganglia en route to the thalamus.  The risk aversion, ventral striatum routing also passes through a region of the brain called the ventral pallidum, whereas the motor circuit does not.

 

 

 

Quote

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3543080/

 

The term basal ganglia in the strictest sense refers to nuclei embedded deep in the brain hemispheres (striatum or caudate-putamen and globus pallidus), whereas related nuclei consist of structures located in the diencephalon (subthalamic nucleus), mesencephalon (substantia nigra), and pons (pedunculopontine nucleus).

 

 

…..

 

 

The basal ganglia and related nuclei can be broadly categorized as (1) input nuclei, (2) output nuclei, and (3) intrinsic nuclei.

Input nuclei are those structures receiving incoming information from different sources, mainly cortical, thalamic, and nigral in origin. The caudate nucleus (CN), the putamen (Put), and the accumbens nucleus (Acb) (dm123: this is the NAc)are all considered input nuclei.

 

The output nuclei are those structures that send basal ganglia information to the thalamus and consist of the internal segment of the globus pallidus (GPi) and the substantia nigra pars reticulata (SNr).

 

Finally, intrinsic nuclei such as the external segment of the globus pallidus (GPe), the STN and the substantia nigra pars compacta (SNc) are located between the input and output nuclei in the relay of information.

 

Cortical and thalamic efferent information enters the striatum (CN, Put, and Acb) to be processed further within the basal ganglia system.

 

The output nuclei (GPi and SNr) project mainly to the thalamus (ventral nuclei; dm123: commonly referred to as the ventrolateral thalamus or VTh), which, in turn, project back to the cerebral cortex (mainly frontal lobe; dm123: which includes prefrontal motor cortex).

 

The appropriate functioning of the basal ganglia system requires dopamine to be released at the input nuclei. Dopamine dysfunction is associated with several basal ganglia movement disorders such as the parkinsonian syndrome (i.e., Parkinson’s disease), dystonia, chorea, and tics. All major basal ganglia components are illustrated in Figure 1.

 

End quote

 

 

 

NEXT UP (Parts 2,3,4) : globus palladis, substantia nigra pars reticulata, then the thalamus (big section), and then the cerebral cortices......

[[Re...]]

Fascinating, dm123.  Now, try to get some rest!!!

 

Dopamine is particularly interesting to me in all this given it's 'dual-function' in excitatory / inhibitory processes.  As someone who has had restless leg syndrome since my early 20's, I am curious about how the effect of low/high dopamine may also be influencing my current gabapentin dependence at 49mg TID (total daily dose of 147mg) and difficulty with tapering/tolerance. 

 

RLS is associated with dysfunction in the basal ganglia........ 

 

Thanks for all your work, dm123.

 

All the best,

 

-RST

[[li...]]

dm123,

 

Good work. Rather complicated, but I suppose it is a good foundation.

[[cs...]]

Fascinating, dm123.  Now, try to get some rest!!!

 

Dopamine is particularly interesting to me in all this given it's 'dual-function' in excitatory / inhibitory processes.  As someone who has had restless leg syndrome since my early 20's, I am curious about how the effect of low/high dopamine may also be influencing my current gabapentin dependence at 49mg TID (total daily dose of 147mg) and difficulty with tapering/tolerance. 

 

RLS is associated with dysfunction in the basal ganglia........ 

 

Thanks for all your work, dm123.

 

All the best,

 

-RST

 

Hi RST,

 

I'm glad you brought up dopamine because it plays a big part in striatal motor circuits.  The MSNs that were introduced  in earlier modules are indirect MSNs or direct MSNs and are differentiated by the type of dopamine receptors that are on the cell membrane surface of the MSN (D1 vs D2 receptors).  As we will see, these different types of MSNs balance each other out to produce voluntary and smooth muscle motor movement and prevent unwanted jerkey movmemenf.  Dopamine and GABA are the key neurotransmitters involved in a properly functioning motor circuit.(acetylcholine plays a big role at the end, of course,  at the neuromuscular junction)

 

RLS is truly a syndrome in every sense of the word.  We seem to have a lot in common.  I was misdiagnosed with idiopathic RLS (most RLS is idiopathic as you know). I had compressed lateral femoral cutaneous nerves.  I can tell you more about this if you need more info on it, over PM.  Given that you were/are an athelete like me, I'm wondering if you compressed it at some point.  Lateral femoral nerve compression will manifest as nerve pain deep in the anterior hip tissue and muscular tissue and as burning along the anterior and side of the legs (not below the knee, only the thigh).  I don't know how far down your legs your burning goes,

 

It doesn't suprise me that dopamine is involved in a RLS and it's counterpart PLMD(periodic limb movement disorder) because DA plays such a huge role in regulating smooth controlled motor movement, and at the same time prevents unwanted jerky muscle movements and twitching.  Benzodiazaphines affect many different neurotransmitter levels, and so it's no wonder why we burn, twitch and feel restless during wd.  Benzodiazaphine kindling greatly exasperated my nerve pain and akathisia by orders of magnitude.  Once the kindling was under control the akathisia faded quite a bit.  So all these systems affect one another, and Benzodiazaphines throw a big wrench into the delicate balanced between these neurotransmitter levels.

 

Also, as you know iron homeostasis might play a role in RLS, and I've read reports that Benzodiazaphines can affect iron homeostasis.  All related.

 

I think akathisia (I hate that word) is also related, in part, to dysregulated dopamine homeostasis.  I haven't had a chance to research this in depth, but we know that most of the psychoactive pharmaceuticals either directly or indirectly affect dopamine homeostasis.

 

Be well,

 

Dm123

[[cs...]]

dm123,

 

Good work. Rather complicated, but I suppose it is a good foundation.

 

Hi Liberty,

 

Thanks.  I was reticent to post the neural circuts paper on this thread, because it's by far the most difficult model component of the three.  This module (4) is a necessary labor, kind of like going to school.  Nothing in module 5 will make sense without becoming familiar with the basic neuronal projection flow from one region of the brain to the other.  And neural circuit dynamics will bring it up a notch further.  We will see just how pervasive and important GABA and inhibitory signaling is to all neural circuits, both voluntary and involuntary circuts alike.

 

For others, a summary of the model is on page 40.  The two other components to the model, action potential dynamics and adult neurogenesis, have been presented methodically in several preceding papers (throughout pages 1-40)

 

I suppose collectively, this is the full ugly truth of what's really causing our tolerance , wd, and PWS symptoms.  I wish it were much simpler, but syndromes like PWS are very complex by their very nature.  To model it appropriately is kind of messy. ;(

 

Best,

Dm123

[[Pl...]]

Dm123,

    Do benzodiazepines effect dopamine levels in the same way as say an antipsychotic would effect dopamine in causing tardive dyskenesia?

 

I understand that it’s the gaba imbalance effecting the dopamine with benzos

 

Can one recover from td due to the benzo?

 

Or does it not really matter how the dopamine was effected? Either way the damage is done?

 

Is that what plays a part in dystonia?

 

I have an inherent cns issue with dopamine due to genetic testing (but not an issue whatsoever before benzos; just some sort of sensitivity) and since I’ve taken benzos this is where I got hit severely

 

Thank you

[[li...]]

Re: the few posts above: I don't think it's just about dopamine, more like dopamine/acetylcholine. And clonazepam has such an intense effect of the motor cortex, and I can take it only once a day ...

 

I may have mentioned it previously somewhere (post/PM), I think there is a link between dopamine/acetylcholine and HPA axis issues/hormonal isses.

[[Pl...]]

Re: the few posts above: I don't think it's just about dopamine, more like dopamine/acetylcholine. And clonazepam has such an intense effect of the motor cortex, and I can take it only once a day ...

 

I may have mentioned it previously somewhere (post/PM), I think there is a link between dopamine/acetylcholine and HPA axis issues/hormonal isses.

 

Thank you Liberty

 

Yes;;; I also have severe muscle contractions/tremors which I think is related to the acetylcholine

My other concern is psychomotor slowness and agitation and severe muscle weakness;;; I think these are effects from the drugs them selves though

 

I see people now and then diagnosed with ms after taking benzos and someone stated that benzos degrade the myelin sheath?

 

Is there any conclusive research that states this with certainty?

I have heard of drug induced Parkinson’s with meds..... maybe ms and als too;;; I don’t know?

 

I don’t think motor neurons repair themselves :'(

[[cs...]]

Dm123,

    Do benzodiazepines effect dopamine levels in the same way as say an antipsychotic would effect dopamine in causing tardive dyskenesia?

 

I understand that it’s the gaba imbalance effecting the dopamine with benzos

 

Can one recover from td due to the benzo?

 

Or does it not really matter how the dopamine was effected? Either way the damage is done?

 

Is that what plays a part in dystonia?

 

I have an inherent cns issue with dopamine due to genetic testing (but not an issue whatsoever before benzos; just some sort of sensitivity) and since I’ve taken benzos this is where I got hit severely

 

Thank you

 

Hi Pleasebehere,

 

I know we've discussed this before on PM.  I will try to provide more information below.  The short answer is that I don't think the dyskinesia due to Benzodiazaphines is td.  I think it's recoverable.  However, I am not a medical doctor and this is just an opinion based on the scientific literature below.  It is not diagnostic.

 

 

 

Please note: i’m not a medical doctor but can present what goes on from a scientific viewpoint.

 

 

 

 

Benzodiaphines can disinhibit dopamine interneurons.

 

See the figure in this article

 

https://www.drugabuse.gov/news-events/nida-notes/2012/04/well-known-mechanism-underlies-benzodiazepines-addictive-properties

 

https://d14rmgtrwzf5a.cloudfront.net/sites/default/files/images/colorbox/benzodiazepines.gif

 

 

This means that they can increase inhibition in GABA interneurons that release GABA (this means less GABA is released at the terminal of the GABA interneuron) into the synaptic cleft between the GABA interneurons and the dopamine interneurons.  Since less GABA is released at the synaptic cleft between the GABA interneuron and the dopamine interneuron, the dopamine neuron is said to be disinhibited.  A disinhibited dopamine interneuron is much more prone to depolarization meaning it’s membrane is predisposed to being excited, i.e. Positive membrane potential .  This makes the dopamine interneuron much more apt to release dopamine from its axon terminal via the increased probability that the action potential is fired off…...  An increase in dopamine release could be the basis for any addictive properties of Benzodiazaphines, if there are any.  In theory excessive dopamine release could affect dopamine receptor sensitivity to dopamine, but this would mean that any activity or drug that affects dopamine levels, could cause alterations in  dopamine receptor sensitivity.  Even this is true, it’s very likely that such changes in sensitivity are reversible. Otherwise we would all be predisposed to severe dopamine receptor sensitivity dysfunction.    I don’t see how this is possible (i.e., so I don’t see how Benzodiazaphines could directly cause permanent dopamine receptor sensitivity.  Perhaps chronic repeated use could lead to long term alternations in dopamine receptor sensitivity, but it’s still hard to see these as permanent changes once the Benzodiazaphine is stopped and neurotransmitter levels normalization ). 

 

In Benzodiazaphine tolerance or wd, it is easy to see that the dopamine interneurons could be excessively inhibited, just the opposite as above, leading to lower dopamine levels.

 

I’ve read many articles stating that Benzodiazaphines do just the opposite as above relative to dopamine levels, so the data is very  inconsistent.

 

I think dystonia and td via antipsychotics are due to these types of drugs being either  a direct antagonist  or agonist on various dopamine receptors .

 

  I’m not an expert in these types of drugs.  The D2 receptor seems to be one of the likely candidates for the hypersensitivity to dopamine that results from these types of drugs, and the receptor that’s most often related with td and dystonia . It’s easy to see how antagonists of the receptor would make it eventually hypersensitive to dopamine, as the drug is continued over long periods of time..  Then when the drug is removed one would be left with an overly sensitive dopamine receptor.  But in this case  the drug is binding directly to the dopamine receptor.  As you know an endogenous dopamine neurotransmitter locking into the dopamine receptor (the Benzodiazaphine scenario) vs. an antipsychotic drug binding directly to it are two very different things.

 

In the motor circuits module (5)  we will see that indirect MSNs in the dorsal striatum are populated with D2 receptors at their membrane cell surface, and these indirect MSNs form the  start of a neural circuit that eventually reaches the thalamus, and provides inhibitory motor control.  But MSNs are like hub neurons and they collect inputs from many different neurotransmitters like GABA and acetylcholine and glutamate .  Not just dopamine.  See this figure (this is an MSN in the ventral striatum, but you get the idea)

 

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

 

 

Direct MSNs in the dorsal striatum, on the other hand,  are populated with D1 receptors at their cell surface, and  these direct MSNs form the start of a neural circuit that eventually reaches the thalamus to  provide  excitatory motor signaling.  Both of these types of MSNs make up a very large part of the neurons in the striatum, and are very critical for motor control.  The MSNs have GABAergic projections, meaning they release GABA out of their terminal projections to adjacent brain regions.  So in module 5 we will see how all this works in detail, but it’s easy to see how all these neurotransmitters (ACh, DA, GABA and glutamate ) effect motor control because the hub MSNs have receptors for all of these neurotransmitters, and the hub MSNs make a “decision” based on all inputs , not just DA..  The indirect and direct MSN motor paths occur at the same time in real life, and there is a delicate balance between the two to provide smooth voluntary muscle control.  When there’s too much activation and/or too little inhibitory motor control there can be involuntary jerky motor movement.  Most likely antipsychotics create such an imbalance via very very resultant sensitized or desensitized D1 and/or D2 receptors on the MSNs.  (And in other neurons in other areas of the brain)

 

  Benzodiazaphines, in causing dysfunctional GABAAR conductance  could cause issues with motor control via problems in downregulated GABAaRs that are insensitive to GABA.  Remember, the MSNs primarily release GABA out of their terminals when they are excited, so if the adjoining brain region’s GABAaRs are dysfunctional this could disrupt the motor circuit balance , even if the dopamine receptors and dopamine sensitivity is normal.  So possibly a somewhat similar symptomatic problem caused by an entirely different mechanism.

 

I don’t know if the genetic predisposition that you have for dopamine sensitivity would be directly affected by Benzodiazaphines, because of how Benzodiazaphines affect dopamine neurotransmitter levels.  Nonetheless, they don’t bind to the dopamine receptor.  Perhaps indirectly the excess dopamine from the Benzodiazaphine could temporarily desensitize the dopamine receptors , or perhaps during Benzodiazaphine withdrawal the lower dopamine levels sensitized the dopamine receptors, but it doesn’t seem possible to be a permanent change , otherwise many people on Benzodiazaphines and going through Benzodiazaphine wd would end up with permanently dysregulated dopamine receptors.  I don’t know if your genetic polymorphism or issue could have been exasperated by Benzodiazaphines in this way.   

 

 

 

 

Regarding dystonias:

 

The only direct linkage of GABAergic neuronal function and some types of dystonia that I see is in dysfunction in the sodium-potassium pump which controls the activity mode of very important GABAergic neurons called Purkinje neurons.  Wikipedia has a lot of great information on this, which you probably already know about.  The ATP1A3 gene Mutation in the Na-K pumps is one such mutation that can cause dysfunction in these pumps, causing dystonia.

It’s important to note that these Na-K pumps are ATP pumps and are important in many areas of cellular neurophysiology.  They are critical in re establishing membrane resting potentials, etc.

 

 

Also, I don’t see how a Benzodiazaphine would cause such dysfunction, because it appears to be genetic in origin.  Benzodiazaphines mangle our GABAaRs, and they don’t cause genetic mutations in ATP pumps.

 

 

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

 

 

Quote

Researchers suspect it is caused by a pathology of the central nervous system, likely originating in those parts of the brain concerned with motor function—such as the basal ganglia and the GABA (gamma-aminobutyric acid) producing Purkinje neurons. The precise cause of primary dystonia is unknown. In many cases it may involve some genetic predisposition towards the disorder combined with environmental conditions

…….

 

Misfunction of the sodium-potassium pump may be a factor in some dystonias. The Na+-K+ pump has been shown to control and set the intrinsic activity mode of cerebellar Purkinje neurons.[16] This suggests that the pump might not simply be a homeostatic, "housekeeping" molecule for ionic gradients; but could be a computational element in the cerebellum and the brain.[17] Indeed, an ouabain block of Na+-K+ pumps in the cerebellum of a live mouse results in it displaying ataxia and dystonia.[18] Ataxia is observed for lower ouabain concentrations, dystonia is observed at higher ouabain concentrations. A mutation in the Na+-K+ pump (ATP1A3 gene) can cause rapid onset dystonia parkinsonism.[19] The parkinsonism aspect of this disease may be attributable to malfunctioning Na+-K+ pumps in the basal ganglia; the dystonia aspect may be attributable to malfunctioning Na+-K+ pumps in the cerebellum (that act to corrupt its input to the basal ganglia) possibly in Purkinje neurons.[16]

End quote

 

 

https://en.m.wikipedia.org/wiki/Na%2B/K%2B-ATPase

 

 

Quote

Alcohol inhibits sodium-potassium pumps in the cerebellum and this is likely how it corrupts cerebellar computation and body co-ordination.[14][15]The distribution of the Na+-K+ pump on myelinated axons, in human brain, was demonstrated to be along the internodal axolemma, and not within the nodal axolemma as previously thought.[16]

 

End quote

 

 

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

 

 

This is a drawing of a Purkinje neuron.  It’s the one in with the massive amounts of dentrite spines and its axon extends all the way down to the bottom right of this diagram. Their anatomical arrangement and the synapses that are made with their elaborate dendritic spines is very complex, as described in the wiki link above.  Their axons are very long and they send inhibitory projects into the deep cerebellar nuclei.  These projections release GABA as one of the main inhibitory signals.

 

https://commons.m.wikimedia.org/wiki/File:Gray706.png#mw-jump-to-license

 

 

Quote

Purkinje cells send inhibitory projections to the deep cerebellar nuclei, and constitute the sole output of all motor coordination in the cerebellar cortex.

End quote

 

And as was mentioned earlier

 

Quote

 

Findings have suggested that Purkinje cell dendrites release endocannabinoids that can transiently downregulate both excitatory and inhibitory synapses.[21] The intrinsic activity mode of Purkinje cells is set and controlled by the sodium-potassium pump.[22]  ……..Numerical modeling of experimental data suggests that, in vivo, the Na+-K+ pump produces long quiescent punctuations (>> 1 s) to Purkinje neuron firing; these may have a computational role.[26]Alcohol inhibits Na+-K+ pumps in the cerebellum and this is likely how it corrupts cerebellar computation and body co-ordination.[27][28]

End quote

 

 

 

 

 

In summary:

 

The only clear thing is that motor control can be dysfunctional via the GABAAR receptor being  dysregulated  by Benzodiazaphines. We do know that.  And we do know that it’s not permanent.  GABAaRs take a long time to resensitize and upregulate in their density populations.

 

Regarding dystonia, Benzodiazaphines don’t cause ATP pump genetic mutations, so I can’t see how they could cause clinical dystonia.

 

In a normal person, I don’t see how Benzodiazaphines could lead to td or dystonia, but transient motor dysfunction is possible given how GABA-dependent motor neural circuits are.  This would be through GABAaR dysfunction, which is not permanent..  I don’t know how severe this could get relative to antipsychotic induced motor dysfunction .  Also of note, all neural circuits depend on inhibitory signaling, not just motor circuits , explaining why Benzodiazaphine wd and tolerance has such a wide spectrum of various symptoms.

 

I don’t know if the  genetic dopamine sensitivity polymorphism that you have would come into play with just Benzodiazaphine use, because  only the GABAaRs have been directly affected.  The effect would have to be indirect,  via increased or decreased dopamine neurotransmitter levels.  However, these levels should normalize as the GABAaRs normalize, and in theory the issue would resolve, if this is the only mechanism behind the motor dysfunction.

 

I’m not sure if you are familiar with valbenazine, which acts presynaptically at the vesicular transport level (VMAT2) to very selectively reduce dopamine release at the terminal. Most of the other neurotransmitters don’t depend heavily on VMAT2, thus there’s not a lot of collateral on the other neurotransmitters like serotonin,etc.

 

Finally, most of the clinical citations on “dyskinesia and Benzodiazaphines” discuss it in the context of Benzodiazaphines as a therapeutic agent for neuroleptic induced dyskinesia.  I know that you already know this.  And we know that Benzodiazaphines, in general, are poor long term therapeutic agents.

 

I’m not a doctor, but I hope the above helps you understand that similar motor issues can be caused by entirely different and discrete  mechanisms, some of which can and do  resolve with time.  I believe the Benzodiazaphine induced mechanism does resolve with time.

 

 

 

 

 

 

Useful references on Na-K pumps and their effects on Purkinje neurons:

 

Note: given that these pumps control intrinsic firing of Purkinje neurons, this would ultimately disrupt normal GABA release from the terminals of these Purkinje neurons, this disrupting inhibitory motor control.

 

1. ^ Forrest MD, Wall MJ, Press DA, Feng J (December 2012). Cymbalyuk G, ed. "The Sodium-Potassium Pump Controls the Intrinsic Firing of the Cerebellar Purkinje Neuron". PLoS ONE. 7(12): e51169. doi:10.1371/journal.pone.0051169. PMC 3527461  . PMID 23284664.

 

 

2. ^ Forrest MD (December 2014). "The sodium-potassium pump is an information processing element in brain computation". Frontiers in Physiology. 5 (472). doi:10.3389/fphys.2014.00472.

 

 

3. ^ Cannon C (July 2004). "Paying the Price at the Pump: Dystonia from Mutations in a Na+/K+-ATPase". Neuron. 43 (2): 153–154. doi:10.1016/j.neuron.2004.07.002. PMID 15260948.

 

 

4. ^ Calderon DP, Fremont R, Kraenzlin F, Khodakhah K (March 2011). "The neural substrates of rapid-onset Dystonia-Parkinsonism". Nature Neuroscience. 14 (3): 357–65. doi:10.1038/nn.2753. PMC 3430603  . PMID 21297628.

 

 

 

 

[[cs...]]

Re: the few posts above: I don't think it's just about dopamine, more like dopamine/acetylcholine. And clonazepam has such an intense effect of the motor cortex, and I can take it only once a day ...

 

I may have mentioned it previously somewhere (post/PM), I think there is a link between dopamine/acetylcholine and HPA axis issues/hormonal isses.

 

Hi liberty,

 

Thanks for the feedback.  I agree,  There is another pillar to the model presented on page 40 of this thread an that is of GPCRs.  We've had many helpful exchanges over PMs on this pillar.  I haven't addressed it in the model yet because of the complexity of GPCRs, in general.  I don't know when or if I will be able to present all the material compiled on this complex area.  I can briefly explain how it ties into the page 40 model. 

They have been lumped in a term I call "other systems" which also includes neurotrophic factors, nitric oxide, neurosteroids , etc....  These all affect the 3 components listed below.

 

 

GPCRs and the Benzodiazaphine model

 

GPCR stands for G protein coupled receptors.  Many common neurotransmitter receptors fall into this category.  The science behind the coupling of GPCRs to their ionotropic counterparts is complex, and I won't delve into the details.  Most of the serotonin receptors are GPCRs, as are dopamine receptors and muscarinic acetylcholine receptors as well (mAChRs).  There are many other GPCRs, but we do know that some of the serotonin, dopamine and muscarinic receptors do in fact couple to the GABAAR.  In addition, as we've exchanged over PMs, these receptors can be excitatory and inhibitory relative to the membrane potential.  Hence, when Benzodiazaphines disrupt neurotransmitter homeostasis, our wd symptoms can be adversely affected.

 

Here is a high level of how they fit into the 3 main components of the model

1. Action potential dynamics.  GPCRs by their very nature and also by direct couplings to GABAaRs affect the membrane potential.  When Benzodiazaphines dysregulate these neurotransmitter levels this contributes to tolerance and wd symptoms.  This is why antidepressants can have some therapeutic effect on wd.  Please note I'm not for or against antidepressant use during Benzodiazaphine wd.  Each person needs to do what's best for them.  Note that GABABRs are metabotropic receptors and call into this bucket of GPCRs as well.

 

2. Adult neurogenesis.  Many of these neurotransmitters are very potent neurogenic substances, i.e. They affect the rate of neurogenesis in a brain region specific way.  Serotonin and dopamine fall into this bucket.  We know that adult neurogenesis and the stress system play a very large role in PWS, and disruptions of adult neurogenesis manifest themselves as wd symptoms.  We also know that the stress system via negative stressors plays a role in perpetuating wd symptoms, and that the stress system and hormones directly affect adult neurogenesis and neuroplasticity (for example, cortisol)

 

3. neural circuit dynamics and homeostatic plasticity.  We know that neurons do not live alone in real bilogical systems.  Neuromodulators "coordinate" plastic changes between neurons (synapses) and affect conductances of receptors on neurons in a dynamic fashion in response to perturbations or stressors on the neural circuit.  Benzodiazaphines are an enormous stressor on the inhibitory signaling present between neurons in a neural circuit.  All neural circuits rely very very heavily on a properly working inhibitory system to maintain physiological function (which we will see in the neural circuts paper).  Neuromodulators literally number in the 100s.  And serotonin and dopamine, and other GPCRs  are potent neuromodulators. 

[Guest [Sk...]]

https://www.drugabuse.gov/news-events/nida-notes/2012/04/well-known-mechanism-underlies-benzodiazepines-addictive-properties

 

:thumbsup:   How they worked for me  :'( :'(

[[cs...]]

https://www.drugabuse.gov/news-events/nida-notes/2012/04/well-known-mechanism-underlies-benzodiazepines-addictive-properties

 

:thumbsup:   How they worked for me  :'( :'(

 

Hi skyblue,

Yes, unfortunately they are addictive substances.  We are not addicts in the typical sense,  but we are dependent, and what they do to our dopamine levels doesn't help the situation.

 

 

Hope you are doing ok