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

[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  :'( :'(

 

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

 

thanks, Luckily only very low dose.

 

We learn lots on this journey out of the drugs often.

 

appreciate your  many informative posts often.

 

 

[[Pl...]]

Dm123;

 

      Thank you so kindly for the very informative research  that you shared and the time that you took to compile and share with me. It means so much to me.

 

And Liberty thank you also for all the research in the past you have shared with me as well.

 

The million dollar question for me is how does one get these sxs under control when one is so sensitized on the drug/paradoxical from prior Benzo use and reducing further precipitates more sxs especially due to hormonal fluctuations and adrenaline surges that are making this impossible to intolerable?

 

The suffering is immense and the extreme stress it is putting on my body.

 

I do have a benzowise doctor overseeing taper who is aware of issues

My doctor believes this is all due to the gaba imbalance and toxicity

 

I am hard pressed to find a ( endocrinologist/ nuerologist) to fix this. I don’t think they can. I could go in for neurological observation; but in the end what could they really do except rule things out?

 

I feel like I’m stuck in a catch 22 situation.  :'(

 

Thank you for listening to my soapbox; I am one hot mess

 

 

[[Re...]]

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4303399/

 

 

 

“Since the development of functional imagery, a plethora of studies have evaluated the activation of different brain regions in response to negative emotional stimuli and in anxiety disorders (reviewed in detail by Etkin15 and Forster et al16). A consistent finding of these studies has been the activation of the amygdala.17–19 Moreover, patients with anxiety disorders appear to activate the amygdala in response to a given stimulus more than non-anxious controls.20 In addition, successful treatment of anxiety disorders with cognitive behavioral therapy leads to extinction of this hyperactivation of the amygdala.21

 

The amygdala is composed of a number of distinct nuclei but, for the purposes of a discussion of the brain circuitry relevant to anxiety, two groups of nuclei are of particular interest, namely the basolateral amygdala complex (BLA) and the centromedial amygdala complex, in particular the central nucleus (CeA).15,22 The BLA receives incoming information on potentially negative emotional signals from the thalamus and the sensory association cortex (Figure 1). The BLA activates the CeA directly through an excitatory glutamatergic pathway as well as activating a relay of inhibitory GABAergic interneurons – the intercalated neurons – that lie between the BLA and the CeA and exert an inhibitory influence upon the latter.23,24 The CeA is the principal output pathway from the amygdala. Inhibitory GABAergic neurons project from the CeA to the hypothalamus and brainstem; the activation of these neurons leads to the somatic manifestations of anxiety.25 Projections to other basal forebrain nuclei such as the ventrotegmental area and the locus ceruleus may be involved in the dysphoria associated with anxiety.16 In addition to activation of the CeA, neurons from the BLA also activate cells in the adjacent bed nucleus of the stria terminalis, which project to the same areas as the CeA and apparently play a similar role.16,22

 

In addition to the role of the amygdala in the regulation of anxiety, forebrain areas such as the medial prefrontal cortex (PFC) and anterior cingulate cortex also appear to play an important role.15 These cortical areas receive and send excitatory glutamatergic projections to and from the BLA, and are activated concomitantly with the amygdala during presentation of emotional stimuli.26

It has been suggested that the medial PFC regulates the experience or expression of anxiety through modulation of neuronal activity in the BLA, with more dorsal cortical areas being responsible for conscious, voluntary control of anxiety and more ventral areas responsible for implicit, subconscious control.15,27–29 This “top-down” control would lead to inhibition of output from the amygdala.

 

Again, neuroimaging studies have shown the medial PFC to be hypoactive in certain anxiety disorders, notably posttraumatic stress disorder20,30 and generalized anxiety disorder.15 Moreover, in subjects exerting voluntary effort to control their emotional reactivity31,32 to negative emotional stimuli, the lateral and medial PFC was strongly activated. Interestingly, anxious individuals needed to achieve higher levels of PFC activation than did non-anxious participants in order to reduce negative emotions successfully. Also of interest in this context is a neuroimaging study that demonstrated activation of the anterior cingulate cortex associated with an anxiolytic response to a placebo in subjects reacting to negatively charged cues, without any change in the activation of the amygdala.33 The strength of the activation of the anterior cingulate cortex was strongly correlated with the robustness of the placebo effect.33 Understanding how these cortical–subcortical regulatory mechanisms work and how they can be harnessed could be very important in developing more effective interventions to reduce anxiety.”

 

Just thought I'd add this quote from a paper that talks about neural circuits.  If you read the whole paper, it discusses Etifoxine quite a bit in the latter half.  However, be aware that this paper was funded by Biocodex of France which produces Etifoxine.  Moreover, a consultancy fee was paid to it's author by Biocodex.  Nevertheless, the first half discusses neural circuits and adds to the conversation taking place in this thread.

 

-RST

 

[[Su...]]

Interesting about the Etifoxine.  the wiki article about it says it is not approved by the FDA. 

Wouldn't it be ironic/horrifying if the medication that does help with anxiety without binding to GABA receptors therefore not producing w/d is the medication that is NOT approved.....

Not a scientist here-- obviously -- but following this thread.

thank you for all you post here!

SS

[[Re...]]

Interesting about the Etifoxine.  the wiki article about it says it is not approved by the FDA. 

Wouldn't it be ironic/horrifying if the medication that does help with anxiety without binding to GABA receptors therefore not producing w/d is the medication that is NOT approved.....

Not a scientist here-- obviously -- but following this thread.

thank you for all you post here!

SS

 

Just want to be clear that Etifoxine DOES bind to the Gabba A Receptor.  It binds to a beta subunit of the 'A' receptor.  So, it is a positive allosteric modulator of Gabba A receptors.  However, it also seems to potentiate the production of endogenous neurosteroids by also binding to another site (TSPO).  The neurosteroids seems to be positive allosteric modulators themselves.  So, Etifoxine should also be put on the list of things to avoid during tapering and withdrawal.  The benefit of it might be for short-term use for those people who need something for anxiety as the risk profile of Etifoxine seems significantly reduced compared to benzodiazepines.  Nevertheless, in some rare cases it has caused hepatitis, so risks remain.  Like I said in my comments, the paper was funded by the company that manufactures Etifoxine, so take that with a grain of salt!!!!

 

-RST

[[li...]]

Pleasebehere, dm123,

 

Something I came across recently:

 

I was googling for 'motor cortex' and dopamine/acetylcholine: this link https://books.google.nl/books?id=vFQFePTM-oAC&pg=PA367&lpg=PA367&dq=clonazepam+striatum&source=bl&ots=RijjNPEXuS&sig=fr1chgO3F9rAmJuiNb4aMpoVzxk&hl=nl&sa=X&ved=0ahUKEwiihPPUxsbaAhWFKewKHYHtC00Q6AEIZjAH#v=onepage&q=clonazepam%20striatum&f=false ,one of many ...  clonazepam has some particular action in the striatum.

The ever interesting but mysterious '‘clonazepam binds to receptors that do not bind  diazepam or other benzodiazepines’ (rats).

 

https://www.ncbi.nlm.nih.gov/pubmed/20590830 'The imbalance between cholinergic activity and dopaminergic activity in the striatum causes a variety of neurological disorders, such as Parkinson's disease' etc.

 

I'm also having certain issues that one could attribute tot he 'motor cortex' although it's not quite that visible ... that started after I had been on lorazepam for a while, and went back to K. I can imagine that the pheno throws you out of balance for a while after taking it ... balance is probably the key word.

 

This does not live up to dm123's standards of scientific research !

 

 

 

 

 

 

 

[[Pl...]]

Pleasebehere, dm123,

 

Something I came across recently:

 

I was googling for 'motor cortex' and dopamine/acetylcholine: this link https://books.google.nl/books?id=vFQFePTM-oAC&pg=PA367&lpg=PA367&dq=clonazepam+striatum&source=bl&ots=RijjNPEXuS&sig=fr1chgO3F9rAmJuiNb4aMpoVzxk&hl=nl&sa=X&ved=0ahUKEwiihPPUxsbaAhWFKewKHYHtC00Q6AEIZjAH#v=onepage&q=clonazepam%20striatum&f=false ,one of many ...  clonazepam has some particular action in the striatum.

The ever interesting but mysterious '‘clonazepam binds to receptors that do not bind  diazepam or other benzodiazepines’ (rats).

 

https://www.ncbi.nlm.nih.gov/pubmed/20590830 'The imbalance between cholinergic activity and dopaminergic activity in the striatum causes a variety of neurological disorders, such as Parkinson's disease' etc.

 

I'm also having certain issues that one could attribute tot he 'motor cortex' although it's not quite that visible ... that started after I had been on lorazepam for a while, and went back to K. I can imagine that the pheno throws you out of balance for a while after taking it ... balance is probably the key word.

 

This does not live up to dm123's standards of scientific research !

 

Thank you so much Liberty for answering that truly

;; I’m just wondering if there are any scientific articles that specifically state that drugs such as clonazapam can cause “ drug induced” Parkinson’s or ms;;;;

 

I read somewhere that other factors can cause Parkinson’s/ms besides genetics such as chemicals; I’m assuming this means drugs- this terrifies me as all my sxs represent 100xs of neurological illnesses;

I may have seen only a few people at least on Benzo buddies have close to what I have

 

Some have actually been diagnosed with it while taking the drug with no neuro issues before-

How do they know they actually have it?

Could the drugs actually caused lesions in the brain?

I don’t even know how they check for Parkinson’s; etc;;;

I tremor and shake in all my limbs- but I don’t know if this could be an endocrine issue or not

 

Ativan and kolonopin do not seem like a good combo of benzos to take ; whereas Ativan switch to Valium seems more forgiving - that’s been my observation

Although it could be skewed

 

[[li...]]

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3325428/

 

´ In addition to typical antipsychotics, DIP may be caused by gastrointestinal prokinetics, calcium channel blockers, atypical antipsychotics, and antiepileptic drugs.´ But in your case I wouldn´t worry about that too much. Unless you intend to stay on K for 10 years.

 

[Guest [Sk...]]

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3325428/

 

´ In addition to typical antipsychotics, DIP may be caused by gastrointestinal prokinetics, calcium channel blockers, atypical antipsychotics, and antiepileptic drugs.´ But in your case I wouldn´t worry about that too much. Unless you intend to stay on K for 10 years.

 

thanks liberty for that information.    sadly these  added  DIP symptoms can also take a long time to disappear after cessation of the drugs the study says 

 

Thats a plus as I developed tremors and symptoms too on theses drugs. which they wanted to give that name too 

 

[[Te...]]

In addition to the role of the amygdala in the regulation of anxiety, forebrain areas such as the medial prefrontal cortex (PFC) and anterior cingulate cortex also appear to play an important role.15 These cortical areas receive and send excitatory glutamatergic projections to and from the BLA, and are activated concomitantly with the amygdala during presentation of emotional stimuli.26

 

This is really interesting, Realslimtaper! In fact, I'm excited about it because what happens when I get benzo anxiety (that leads to high blood pressure) is that I feel pressure in this exact same area. I hadn't read that before. I always called it the frontal lobe, but no one that I've read about here has had the same issue that I know of. I had looked it up, and it said something about organization, focus, and planning, but I didn't read anything about anxiety coming from this region. I never had this feeling before benzos and wondered why it was so activated. Thank you!!

[[Pl...]]

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3325428/

 

´ In addition to typical antipsychotics, DIP may be caused by gastrointestinal prokinetics, calcium channel blockers, atypical antipsychotics, and antiepileptic drugs.´ But in your case I wouldn´t worry about that too much. Unless you intend to stay on K for 10 years.

 

Liberty;;;; thank you again so much;;;I read the whole article; I have all the signs for Parkinson’s/ td;eps dystonia and ms; I mean everything ; even cerebral palsy

My dr. Said anything caused by benzos /gaba imbalance can reverse

I don’t believe him :'(

 

About Parkinson’s the 3 neurologists in the Er said no ; but they never did a DAT Scan ;;;; no mri;;; my first regular mri; not a functional mri  in 2014 was completely normal;;;;im sure It isn’t now; I’m convinced I have all this and 10 other neuro illnesses caused by the benzos;:;; I never saw anyone like me on here to this degree;;; with sxs of all the above- I mean everything - pure torture

Why did this happen to me? :'(

 

Thank you for finding this ; I couldn’t do this myself because of my cognition

[[cs...]]

Dm123;

 

      Thank you so kindly for the very informative research  that you shared and the time that you took to compile and share with me. It means so much to me.

 

And Liberty thank you also for all the research in the past you have shared with me as well.

 

The million dollar question for me is how does one get these sxs under control when one is so sensitized on the drug/paradoxical from prior Benzo use and reducing further precipitates more sxs especially due to hormonal fluctuations and adrenaline surges that are making this impossible to intolerable?

 

The suffering is immense and the extreme stress it is putting on my body.

 

I do have a benzowise doctor overseeing taper who is aware of issues

My doctor believes this is all due to the gaba imbalance and toxicity

 

I am hard pressed to find a ( endocrinologist/ nuerologist) to fix this. I don’t think they can. I could go in for neurological observation; but in the end what could they really do except rule things out?

 

I feel like I’m stuck in a catch 22 situation.  :'(

 

Thank you for listening to my soapbox; I am one hot mess

 

Hi Pleasebehere,

 

I went through several of the posts after this, and will try to help explain things from a sceientific viewpoint and also put things in perspective.

 

Since we are not diagnosticians, to answer your question above, i would say a specialist in neurology.  The DAT article on DIP was interesting, and a DAT scan could help differentiate whether then issue is drug induced or pathological.  I would not jump to any conclusions without specific diagnostics.  I don't know if the ER docs were neurologists but it's reassuring at least that they did not confirm PD.

 

I don't know if the dystonia genetic markers can be affordably tested, but i listed one marker in my earlier post, and there's a full list in the Wikipedia listing.

 

I don't see any antipsychotic use in your signature, nor any of the anticonvulsants listed in the DAT DIP article, so i would not really focus on it.  I don't think phenobarbital acts in DA receptors, and I know Benzodiazaphines do not block DA receptors, so as I had mentioned earlier, I personally can't see how you could have drug induced td or DIP.  However only a neurologist could help you rule this out.  I will post some additional info to the other posts on this thread to help you understand DIP and PD from a neural circuit perspective.  I don't expect many to fully understand this, because this particular motor circuit won't be analyzed until module 5 of the neural circuts paper.  However , I will post an explanation to the DIP paper and see how it goes.

 

 

[[cs...]]

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3325428/

 

´ In addition to typical antipsychotics, DIP may be caused by gastrointestinal prokinetics, calcium channel blockers, atypical antipsychotics, and antiepileptic drugs.´ But in your case I wouldn´t worry about that too much. Unless you intend to stay on K for 10 years.

 

Liberty;;;; thank you again so much;;;I read the whole article; I have all the signs for Parkinson’s/ td;eps dystonia and ms; I mean everything ; even cerebral palsy

My dr. Said anything caused by benzos /gaba imbalance can reverse

I don’t believe him :'(

 

About Parkinson’s the 3 neurologists in the Er said no ; but they never did a DAT Scan ;;;; no mri;;; my first regular mri; not a functional mri  in 2014 was completely normal;;;;im sure It isn’t now; I’m convinced I have all this and 10 other neuro illnesses caused by the benzos;:;; I never saw anyone like me on here to this degree;;; with sxs of all the above- I mean everything - pure torture

Why did this happen to me? :'(

 

Thank you for finding this ; I couldn’t do this myself because of my cognition

 

Hi, please also see my post above.  If it's Benzodiazaphine induced, i believe it will reverse.  A neurologist working with your Benzodiazaphine doctor could rule out your concerns.

[[cs...]]

Interesting about the Etifoxine.  the wiki article about it says it is not approved by the FDA. 

Wouldn't it be ironic/horrifying if the medication that does help with anxiety without binding to GABA receptors therefore not producing w/d is the medication that is NOT approved.....

Not a scientist here-- obviously -- but following this thread.

thank you for all you post here!

SS

 

Just want to be clear that Etifoxine DOES bind to the Gabba A Receptor.  It binds to a beta subunit of the 'A' receptor.  So, it is a positive allosteric modulator of Gabba A receptors.  However, it also seems to potentiate the production of endogenous neurosteroids by also binding to another site (TSPO).  The neurosteroids seems to be positive allosteric modulators themselves.  So, Etifoxine should also be put on the list of things to avoid during tapering and withdrawal.  The benefit of it might be for short-term use for those people who need something for anxiety as the risk profile of Etifoxine seems significantly reduced compared to benzodiazepines.  Nevertheless, in some rare cases it has caused hepatitis, so risks remain.  Like I said in my comments, the paper was funded by the company that manufactures Etifoxine, so take that with a grain of salt!!!!

 

-RST

 

Just wanted to add that even traditional Benzodiazaphines have affinity for β subunits on the GABAaR.  The traditional model of αγ site is not rock solid.  There's another posting on here with a link to an article of diazepams effectivity in α knockouts.  You would think after 60 years that they would understand Benzodiazaphines a bit better 

[[cs...]]

Pleasebehere, dm123,

 

Something I came across recently:

 

I was googling for 'motor cortex' and dopamine/acetylcholine: this link https://books.google.nl/books?id=vFQFePTM-oAC&pg=PA367&lpg=PA367&dq=clonazepam+striatum&source=bl&ots=RijjNPEXuS&sig=fr1chgO3F9rAmJuiNb4aMpoVzxk&hl=nl&sa=X&ved=0ahUKEwiihPPUxsbaAhWFKewKHYHtC00Q6AEIZjAH#v=onepage&q=clonazepam%20striatum&f=false ,one of many ...  clonazepam has some particular action in the striatum.

The ever interesting but mysterious '‘clonazepam binds to receptors that do not bind  diazepam or other benzodiazepines’ (rats).

 

https://www.ncbi.nlm.nih.gov/pubmed/20590830 'The imbalance between cholinergic activity and dopaminergic activity in the striatum causes a variety of neurological disorders, such as Parkinson's disease' etc.

 

I'm also having certain issues that one could attribute tot he 'motor cortex' although it's not quite that visible ... that started after I had been on lorazepam for a while, and went back to K. I can imagine that the pheno throws you out of balance for a while after taking it ... balance is probably the key word.

 

This does not live up to dm123's standards of scientific research !

 

Hi,

 

The full article on the ACh-DA hypothesis is available from the link you gave.  I did read it through and it's a very interesting hypothesis.  I will bring it up and comment on it later, but one should note that the ACh overload can only occur at massively depleted dopamine levels.  The ACh overload effectively causes a massive influx of Ca2+ into the indirect MSNs (iMSNs) which triggers an adaptive neuroplastic reduction in the dendritic spine density of the iMSNs, in Parkinson's, rendering the indirect D2 MSN motor pathway dysfunctional.  This combined with the obvious low pathological levels of DA cause many different motor function issues (in both dMSN and iMSN pathways).  The iMSN pathway provides modulation of the thalamus motor pathway by reducing glutamate release and increasing GABA release from the GPi/SNr complex to the thalamus .  The thalamus is mostly excitatory and thus less glutamate is released from the thalamus to the motor neurons in the cerebral cortex.  When iMSN path becomes dysfunctional, this "inhibitory " (less glutamate release from the VTh) function is magnified to a pathologically abnormal degree.

[[cs...]]

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3325428/

 

´ In addition to typical antipsychotics, DIP may be caused by gastrointestinal prokinetics, calcium channel blockers, atypical antipsychotics, and antiepileptic drugs.´ But in your case I wouldn´t worry about that too much. Unless you intend to stay on K for 10 years.

 

Hi all,

The DIP article was interesting.  Since we are discussing neural circuits, I wanted to review the diagram below and the quote below.  Much of this neural circuit will be dissected in detail in Module 5, so some of the material might not make sense yet.

 

DIP and Neural Circuit analysis:

 

Please note that in the figure below there is first a D2 blocker (antipsychotic), part A of the Diagram with DIP symptom development , and the part B of the Diagram wherein the direct dMSN motor pathway becomes dysfunctional as a collateral effect to the D2 blockade, and this causes subsequent dyskinesia.

 

Here is the figure from the article above from liberty and here is the quote

 

The article does not tell us how exactly the dMSN pathway becomes dysfunctional, but from the Diagram below, the dMSNs appear to become hyperexcitable.  The dMSNs contain mostly D1 receptors, and so the D1 receptors must become hyperexcitable and sensitized after the long term D2 (iMSN) blockade.  However the article doesn't go into how this happens

D1 receptors are in general, excitable to the membrane, and D2s are inhibitory to the membrane, in general

----------

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3325428/

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3325428/figure/F1/?report=objectonly

 

 

Quote

Dopamine receptors in the brain consist of those of the D1 family, comprising D1 and D5 receptors, and the D2family, comprising D2, D3, and D4 receptors.55 The central dopaminergic system consists of the mesolimbic, mesocortical, tuberoinfundibular, and nigrostriatal pathways. All antipsychotic drugs have potent D2    Receptor blocking capacity and the therapeutic effects of these drugs on psychosis are related to their action on the limbic system, where they reduce dopamine transmission. The blockage of D2 receptors by antipsychotic drugs in the striatum leads to disinhibition of GABA- and encephalin-containing striatal neurons at the origin of the indirect pathway without alteration of the direct pathway, followed by disinhibition of the subthalamic nucleus. This leads to increased GABAergic inhibition of the thalamocortical projection by facilitation of the inhibitory projection from the globus pallidus/substantia nigra pars reticulata (Fig. 1A). This pathway resembles the model of disturbance of the basal ganglia-motor loop in PD. More than 80% of D2receptors were found to be occupied in patients with EPS who were taking neuroleptics,56 in agreement with results showing that clinical symptoms of PD began when over 80% of nigral neurons had degenerated.

 

 

TD, defined as hyperkinetic movement in the orolingual or oromandibular area, is caused by long-term use of dopaminergic blocking agents, and frequently accompanies DIP. The co-occurrence of TD with parkinsonism may be due to dopaminergic receptor supersensitivity resulting from long-term D2 receptor blocking. Chronic administration of these drugs increases dopamine D2 receptor density in the striatum. Moreover, withdrawal from neuroleptics was found to aggravate dyskinetic symptoms, whereas increased doses of neuroleptics transiently suppressed dyskinesia. D1 receptors may also be involved in the development of orolingual dyskinesia when D2 receptors are chronically blocked. Chronic administration of D2receptor blockers also induces changes in the direct pathway of the basal ganglia-motor loop to activate the striatonigral pathway and increase the inhibition of the striatopallidal pathway (Fig. 1B).25,57 This imbalance between direct (D1) and indirect (D2) motor pathways and the resulting alterations in the globus pallidus/substantia nigra pars reticulata complex may lead to hyperkinetic orolingual movements, thus explaining the coexistent and sequential development of parkinsonism and dyskinesia.

End quote

 

 

---------

 

Part A of the Diagram.  The D2 blockade causes the striatal iMSNs to overexcite. This is because D2s are inhibitory and without them, the iMSNs are prone to hyperexcitability.  The output of the iMSN is GABA release, thus there is excessive GABA release and inhibition to the GPe.

 

The GPe is tonically inhibitory, and inhibiting the GPe causes less GABA to be released from GPe to the STN (subthalamic nucleus). 

 

The STN has mostly excitatory neurons, and because there is less GABA from the GPe, the STN becomes overly excited and releases excessive glutamate to the GPi/SNr complex.

 

The GPi is tonically inhibitory, and since too much glutamate is hitting it from the GPi/SNr complex, it releases too much GABA to the thalamus

 

The thalamus (VTh) becomes overly inhibited.  The thalamus has many excitatory neurons, and thus because it’s overly inhibited, it’s going to release less glutamate to the cerebral motor cortex.  The cerebral cortex releases les glutamate than it otherwise would have to the brainstem and spinal cord.

 

The net result is less excitatory effect on the spinal cord and descending motor neurons, resulting in slow movement control , rigidity and Parkinsonism. Note the quote above, for this to occur there is an 80% occupancy of the D2 receptors by the drug, which is similar to a 80% loss of dopamine producing neurons before PD occurs.  So there is some analogy there, but the two aren’t the same in terms of etiology.  One is receptor blockade, vs PD is lack of dopamine producing neurons in the SNr.

 

 

Part B of the Diagram.  After prolonged D2 blockade, it appears that the dMSN pathway becomes overly sensitized , but they don’t tell us why.  Since D1 receptors are the DA receptors on  dMSNs, one could perhaps assume they sensitize as D2s are muted.  D1s are mostly excitable.

 

The dMSNs become overly excited releasing too much GABA to the GPi (note direct path is much different from indirect path above)

 

GPi is tonically inhibitory and so much less GABA is released from its neurons and the SNr neurons, than would otherwise be the case.  Basically the GPi/SNr complex becomes overly inhibited and there is less GABA release and more glutamate release from the complex.

 

With less GABA and more glutamate hitting the thalamus, the thalamus neurons  becomes disinhibited, and too excited.

 

The thalamus, being disinhibited, releases much more glutamate to the cerebral motor cortex, and the cortex overly stimulates the brainstem and the lower spinal neurons become overly stimulated.  This results in hyperkinetic movement and dyskinesia.

 

So Part A had iMSN dominance (less excitatory stimulation to motor neurons) and over time this transitioned to part B where dMSN pathway becomes dominant, and dyskinesia results.

 

 

[[li...]]

I wonder who will correctly memorize all this theory ...

 

Clonazepam affects dopamine in the striatum, example https://www.ncbi.nlm.nih.gov/pubmed/9517437 ´antidopaminergic effect´.

It´s also part of the basal ganglia.

 

´The thalamus is mostly excitatory and thus less glutamate is released from the thalamus to the motor neurons in the cerebral cortex.  When iMSN path becomes dysfunctional, this "inhibitory " (less glutamate release from the VTh) function is magnified to a pathologically abnormal degree.´ It´s complicated with clonazepam since acute use blocks ´traffic´ to the thalamus. What if you´re sensitive to absence epilepsy (or various other forms) ? The GABAB component is associated with absence seizures.

 

I hope this made a little sense. I´m not sure how both lorazepam and clonazepam fit into this ... It seems it´s not good.

 

Pleasebehere, dm123,

 

Something I came across recently:

 

I was googling for 'motor cortex' and dopamine/acetylcholine: this link https://books.google.nl/books?id=vFQFePTM-oAC&pg=PA367&lpg=PA367&dq=clonazepam+striatum&source=bl&ots=RijjNPEXuS&sig=fr1chgO3F9rAmJuiNb4aMpoVzxk&hl=nl&sa=X&ved=0ahUKEwiihPPUxsbaAhWFKewKHYHtC00Q6AEIZjAH#v=onepage&q=clonazepam%20striatum&f=false ,one of many ...  clonazepam has some particular action in the striatum.

The ever interesting but mysterious '‘clonazepam binds to receptors that do not bind  diazepam or other benzodiazepines’ (rats).

 

https://www.ncbi.nlm.nih.gov/pubmed/20590830 'The imbalance between cholinergic activity and dopaminergic activity in the striatum causes a variety of neurological disorders, such as Parkinson's disease' etc.

 

I'm also having certain issues that one could attribute tot he 'motor cortex' although it's not quite that visible ... that started after I had been on lorazepam for a while, and went back to K. I can imagine that the pheno throws you out of balance for a while after taking it ... balance is probably the key word.

 

This does not live up to dm123's standards of scientific research !

 

Hi,

 

The full article on the ACh-DA hypothesis is available from the link you gave.  I did read it through and it's a very interesting hypothesis.  I will bring it up and comment on it later, but one should note that the ACh overload can only occur at massively depleted dopamine levels.  The ACh overload effectively causes a massive influx of Ca2+ into the indirect MSNs (iMSNs) which triggers an adaptive neuroplastic reduction in the dendritic spine density of the iMSNs, in Parkinson's, rendering the indirect D2 MSN motor pathway dysfunctional.  This combined with the obvious low pathological levels of DA cause many different motor function issues (in both dMSN and iMSN pathways).  The iMSN pathway provides modulation of the thalamus motor pathway by reducing glutamate release and increasing GABA release from the GPi/SNr complex to the thalamus .  The thalamus is mostly excitatory and thus less glutamate is released from the thalamus to the motor neurons in the cerebral cortex.  When iMSN path becomes dysfunctional, this "inhibitory " (less glutamate release from the VTh) function is magnified to a pathologically abnormal degree.

[[cs...]]

I wonder who will correctly memorize all this theory ...

 

Clonazepam affects dopamine in the striatum, example https://www.ncbi.nlm.nih.gov/pubmed/9517437 ´antidopaminergic effect´.

It´s also part of the basal ganglia.

 

´The thalamus is mostly excitatory and thus less glutamate is released from the thalamus to the motor neurons in the cerebral cortex.  When iMSN path becomes dysfunctional, this "inhibitory " (less glutamate release from the VTh) function is magnified to a pathologically abnormal degree.´ It´s complicated with clonazepam since acute use blocks ´traffic´ to the thalamus. What if you´re sensitive to absence epilepsy (or various other forms) ? The GABAB component is associated with absence seizures.

 

I hope this made a little sense. I´m not sure how both lorazepam and clonazepam fit into this ... It seems it´s not good.

 

Pleasebehere, dm123,

 

Something I came across recently:

 

I was googling for 'motor cortex' and dopamine/acetylcholine: this link https://books.google.nl/books?id=vFQFePTM-oAC&pg=PA367&lpg=PA367&dq=clonazepam+striatum&source=bl&ots=RijjNPEXuS&sig=fr1chgO3F9rAmJuiNb4aMpoVzxk&hl=nl&sa=X&ved=0ahUKEwiihPPUxsbaAhWFKewKHYHtC00Q6AEIZjAH#v=onepage&q=clonazepam%20striatum&f=false ,one of many ...  clonazepam has some particular action in the striatum.

The ever interesting but mysterious '‘clonazepam binds to receptors that do not bind  diazepam or other benzodiazepines’ (rats).

 

https://www.ncbi.nlm.nih.gov/pubmed/20590830 'The imbalance between cholinergic activity and dopaminergic activity in the striatum causes a variety of neurological disorders, such as Parkinson's disease' etc.

 

I'm also having certain issues that one could attribute tot he 'motor cortex' although it's not quite that visible ... that started after I had been on lorazepam for a while, and went back to K. I can imagine that the pheno throws you out of balance for a while after taking it ... balance is probably the key word.

 

This does not live up to dm123's standards of scientific research !

 

Hi,

 

The full article on the ACh-DA hypothesis is available from the link you gave.  I did read it through and it's a very interesting hypothesis.  I will bring it up and comment on it later, but one should note that the ACh overload can only occur at massively depleted dopamine levels.  The ACh overload effectively causes a massive influx of Ca2+ into the indirect MSNs (iMSNs) which triggers an adaptive neuroplastic reduction in the dendritic spine density of the iMSNs, in Parkinson's, rendering the indirect D2 MSN motor pathway dysfunctional.  This combined with the obvious low pathological levels of DA cause many different motor function issues (in both dMSN and iMSN pathways).  The iMSN pathway provides modulation of the thalamus motor pathway by reducing glutamate release and increasing GABA release from the GPi/SNr complex to the thalamus .  The thalamus is mostly excitatory and thus less glutamate is released from the thalamus to the motor neurons in the cerebral cortex.  When iMSN path becomes dysfunctional, this "inhibitory " (less glutamate release from the VTh) function is magnified to a pathologically abnormal degree.

 

Hi,

 

Yes, it's very daunting keeping track of all the mechanisms and theories, and flows.  And right now that ACh-dopamine hypothesis is just a theory, but it seems to be very promising given the clinical aspects of the full paper.    I will revisit it again, once Neural circuts Module 5 is presented.  That figure in the DIP article was greatly simplifying , especially the iMSN pathway,    I have a quick edit to the DIP neural circuit flow that I described above.  The full pathway will be explained in detail in module 5.

 

Regarding the antidopaminergenic aspects of clonazepam, I read some ancillary studies to the link you posted below, and you are right, it's not good.  I'm not suprised.

 

Can you elaborate on clonazepam blocking traffic to the thalamus?  I assume you mean the projections from the GPi/SNr complex and/or from the STN (subthalmic nucleus)--> SNr pathway.  The GPi is mostly tonically inhibitory on the thalamus, whereas the SNr has excitatory and inhibitory projections into the thalamus.

 

 

Regarding absence seizures , I don't know much in this area, but I assume the GABAb component is why GABA agonists and gabapentin are contraindicated?  Is there an overabundance of inhibitory inputs into the thalamus with an absence seizure?  Is the GABAb component the reason why clonazepam is effective?

 

 

I haven't had time to dig deep into absence seizures, and the differences in therapeutic pharmacology are very interesting.

 

 

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

 

Quote

 

While ethosuximide is effective in treating only absence seizures, valproic acid is effective in treating multiple seizure types including tonic-clonic seizure and partial seizure, as such it may be a better choice if a patient is exhibiting multiple types of seizures.[14] Similarly, lamotrigine treats multiple seizure types including partial seizures and generalized seizures, therefore it is also an option for patients with multiple seizure types.[15]

 

Clonazepam (Klonopin, Rivotril) is effective in the short term but is not generally recommended for treatment of absence seizure because of the rapid development of tolerance and high frequency of side effects.[16]

 

Contraindicated drugs

Carbamazepine, vigabatrin, and tiagabine are contraindicated in the treatment of absence seizures, irrespective of cause and severity. This is based on clinical and experimental evidence.[4] In particular, the GABA agonists vigabatrin and tiagabine are used to induce, not to treat, absence seizures and absence status epilepticus.[17] Similarly, oxcarbazepine, phenytoin, phenobarbital, gabapentin, and pregabalin should not be used in the treatment of absence seizures because these medications may worsen absence seizures.[15]

 

End quote

[[cs...]]

Minor edit on the DIP neural circuit analysis below in bold

Also see my post above to liberty.

 

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3325428/

 

´ In addition to typical antipsychotics, DIP may be caused by gastrointestinal prokinetics, calcium channel blockers, atypical antipsychotics, and antiepileptic drugs.´ But in your case I wouldn´t worry about that too much. Unless you intend to stay on K for 10 years.

 

Hi all,

The DIP article was interesting.  Since we are discussing neural circuits, I wanted to review the diagram below and the quote below.  Much of this neural circuit will be dissected in detail in Module 5, so some of the material might not make sense yet.

 

DIP and Neural Circuit analysis:

 

Please note that in the figure below there is first a D2 blocker (antipsychotic), part A of the Diagram with DIP symptom development , and the part B of the Diagram wherein the direct dMSN motor pathway becomes dysfunctional as a collateral effect to the D2 blockade, and this causes subsequent dyskinesia.

 

Here is the figure from the article above from liberty and here is the quote

 

The article does not tell us how exactly the dMSN pathway becomes dysfunctional, but from the Diagram below, the dMSNs appear to become hyperexcitable.  The dMSNs contain mostly D1 receptors, and so the D1 receptors must become hyperexcitable and sensitized after the long term D2 (iMSN) blockade.  However the article doesn't go into how this happens

D1 receptors are in general, excitable to the membrane, and D2s are inhibitory to the membrane, in general

----------

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3325428/

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3325428/figure/F1/?report=objectonly

 

 

Quote

Dopamine receptors in the brain consist of those of the D1 family, comprising D1 and D5 receptors, and the D2family, comprising D2, D3, and D4 receptors.55 The central dopaminergic system consists of the mesolimbic, mesocortical, tuberoinfundibular, and nigrostriatal pathways. All antipsychotic drugs have potent D2    Receptor blocking capacity and the therapeutic effects of these drugs on psychosis are related to their action on the limbic system, where they reduce dopamine transmission. The blockage of D2 receptors by antipsychotic drugs in the striatum leads to disinhibition of GABA- and encephalin-containing striatal neurons at the origin of the indirect pathway without alteration of the direct pathway, followed by disinhibition of the subthalamic nucleus. This leads to increased GABAergic inhibition of the thalamocortical projection by facilitation of the inhibitory projection from the globus pallidus/substantia nigra pars reticulata (Fig. 1A). This pathway resembles the model of disturbance of the basal ganglia-motor loop in PD. More than 80% of D2receptors were found to be occupied in patients with EPS who were taking neuroleptics,56 in agreement with results showing that clinical symptoms of PD began when over 80% of nigral neurons had degenerated.

 

 

TD, defined as hyperkinetic movement in the orolingual or oromandibular area, is caused by long-term use of dopaminergic blocking agents, and frequently accompanies DIP. The co-occurrence of TD with parkinsonism may be due to dopaminergic receptor supersensitivity resulting from long-term D2 receptor blocking. Chronic administration of these drugs increases dopamine D2 receptor density in the striatum. Moreover, withdrawal from neuroleptics was found to aggravate dyskinetic symptoms, whereas increased doses of neuroleptics transiently suppressed dyskinesia. D1 receptors may also be involved in the development of orolingual dyskinesia when D2 receptors are chronically blocked. Chronic administration of D2receptor blockers also induces changes in the direct pathway of the basal ganglia-motor loop to activate the striatonigral pathway and increase the inhibition of the striatopallidal pathway (Fig. 1B).25,57 This imbalance between direct (D1) and indirect (D2) motor pathways and the resulting alterations in the globus pallidus/substantia nigra pars reticulata complex may lead to hyperkinetic orolingual movements, thus explaining the coexistent and sequential development of parkinsonism and dyskinesia.

End quote

 

 

---------

 

Part A of the Diagram.  The D2 blockade causes the striatal iMSNs to overexcite. This is because D2s are inhibitory and without them, the iMSNs are prone to hyperexcitability.  The output of the iMSN is GABA release, thus there is excessive GABA release and inhibition to the GPe.

 

The GPe is tonically inhibitory, and inhibiting the GPe causes less GABA to be released from GPe to the STN (subthalamic nucleus). 

 

The STN has mostly excitatory neurons, and because there is less GABA from the GPe, the STN becomes overly excited and releases excessive glutamate to the GPi/SNr complex.

 

The GPi is tonically inhibitory, and since too much glutamate is hitting it from the STN GPi/SNr complex, it releases too much GABA to the thalamus

 

(note: it is not shown in the simplified diagram above, but the GPe projects  to the GPi as well, and GPe is releasing less GABA to the GPi, as well, contributing to the overall increased excitement of the GPi)

 

The thalamus (VTh) becomes overly inhibited.  The thalamus has many excitatory neurons, and thus because it’s overly inhibited, it’s going to release less glutamate to the cerebral motor cortex.  The cerebral cortex releases les glutamate than it otherwise would have to the brainstem and spinal cord.

 

The net result is less excitatory effect on the spinal cord and descending motor neurons, resulting in slow movement control , rigidity and Parkinsonism. Note the quote above, for this to occur there is an 80% occupancy of the D2 receptors by the drug, which is similar to a 80% loss of dopamine producing neurons before PD occurs.  So there is some analogy there, but the two aren’t the same in terms of etiology.  One is receptor blockade, vs PD is lack of dopamine producing neurons in the SNr.

 

 

Part B of the Diagram.  After prolonged D2 blockade, it appears that the dMSN pathway becomes overly sensitized , but they don’t tell us why.  Since D1 receptors are the DA receptors on  dMSNs, one could perhaps assume they sensitize as D2s are muted.  D1s are mostly excitable.

 

The dMSNs become overly excited releasing too much GABA to the GPi (note direct path is much different from indirect path above)

 

GPi is tonically inhibitory and so much less GABA is released from its neurons and the SNr neurons, than would otherwise be the case.  Basically the GPi/SNr complex becomes overly inhibited and there is less GABA release and more glutamate release from the complex.

 

With less GABA and more glutamate hitting the thalamus, the thalamus neurons  becomes disinhibited, and too excited.

 

The thalamus, being disinhibited, releases much more glutamate to the cerebral motor cortex, and the cortex overly stimulates the brainstem and the lower spinal neurons become overly stimulated.  This results in hyperkinetic movement and dyskinesia.

 

So Part A had iMSN dominance (less excitatory stimulation to motor neurons) and over time this transitioned to part B where dMSN pathway becomes dominant, and dyskinesia results.

[[Pl...]]

Thank you guys for your research; but in the end can it be reversed all this td ; involuntary movement stuff if it’s from benzos like clonazapam and phenobarbitol?

[[li...]]

DM123,

 

'Can you elaborate on clonazepam blocking traffic to the thalamus?  I assume you mean the projections from the GPi/SNr complex and/or from the STN (subthalmic nucleus)--> SNr pathway.  The GPi is mostly tonically inhibitory on the thalamus, whereas the SNr has excitatory and inhibitory projections into the thalamus. ' I'm not going to look up terms like GPi and study neurology right now ...

 

I just noticed it.neurosim.downstate.edu/pdfs/neurrep8:3339.pd

 

But I was really referring to studies like https://core.ac.uk/download/pdf/22871130.pdf rats, I know. There are many of those older studies. They seem to be based on more or less the same source material.

'thalamic reticular nucleus' GABAB

 

'Can you elaborate on clonazepam blocking traffic to the thalamus? ' I'm just doing this by memory, but in laymen's terms one can think of the thalamic reticular nucleus like a 'shell' around the thalamus. If you affect the TRN you affect the thalamus. I hope I got that right !

 

Pleasebehere,

 

'Thank you guys for your research; but in the end can it be reversed all this td ; involuntary movement stuff if it’s from benzos like clonazapam and phenobarbitol?' While I can't be 100 % sure, I think in your case it's possible and quite likely if you manage to get off those drugs.

 

[[cs...]]

Thank you guys for your research; but in the end can it be reversed all this td ; involuntary movement stuff if it’s from benzos like clonazapam and phenobarbitol?

 

I think so, but in my own taper I've noticed changes occur very slowly and subtly.  Things sometimes get a bit worse before they get better.  Windows and waves, and overall progression is positive (for the better) over time.    Unfortunately you can't rush things.

 

You have no antipsychotic drug use either, and i did not see phenobarbital in the list  of anticonvulsant medications in the DIP article.  So you have a lot in your favor.

[[cs...]]

This is a continuation of the Neural circuts paper module 4(PART 2) page 44 of this blog/thread.

It’s very academic but required background material for module 5

 

You needn’t understand all the nitty gritty details.  Understanding the  flow from one region of the brain to the next region (or adjacent regions, projection-wise) is the key.

 

The other important takeaways are

-route differentiation between indirect and direct MSN pathways, ....

-and, of course, a persistent theme throughout this paper: that of the importance and sheer abundance of GABAergic projections in these regions of the brain.

 

 

EDIT ADD: for any newcomers, the summary of the Benzodiazaphine wd model Is on page 40 of this blog thread.....

 

Be well.

 

 

========================================================

 

4.  Module 4 (PART 2):  Introduction to brain architecture and brain neuroanatomy, microcircuits, and a brief introduction to some neural brain circuits

 

 

 

(4.4)Basic brain architecture: the globus palladis (dorsal pallidum; not to be confused with the ventral pallidum described in a later module)

 

 

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

 

 

 

 

The globus palladis forms a major part of the basal ganglia, both intrinsic and output nuclei.  So what exactly do these nuclei do?

 

 

It’s no surprise that the dorsal aspect of the globus palladis is involved in motor control.  It’s probably not a great surprise that they receive large amounts of GABAergic afferent aborisations through the striatum (via MSNs), which is the input nuclei of the basal ganglia.    We will run into the terms afferent and efferent again in much more detail, when we discuss neural circuitry. 

 

Suffice it to say, that for now just think of afferent as something (information, action potential) coming into the spinal cord/CNS.  In this case, it’s inward bound from the striatum.  Aborisations ( or aborizations) are branches.  We can think of these as GABAergic axon terminals coming from MSNs of the  striatum into the globus palladis.

This wonderful quote lets us realize how important the globus palladis is to our movement control (note that risk reward signaling goes through here as well). It’s primarily inhibitory (GABAergic) and counterbalances the excitatory movement control of the cerebellum, but the inhibitory signaling from the GP can vary greatly depending on the type of MSN that provided striatal input to the GP.  In reading the quote below one can readily understand why disturbances in the amount of DA released to the striatum can cause movement disorders.

 

  When functioning properly, the GP provides involuntary movement control that we don’t think about, as well as smooth voluntary motor movement that is required during proper walking and locomotion , for example….

 

 

 

 

Quote

The globus pallidus is a structure in the brain involved in the regulation of voluntary movement. It is part of the basal ganglia, which, among many other things, regulate movements that occur on the subconscious level.

 

If the globus pallidus is damaged, it can cause movement disorders, as its regulatory function will be impaired. There may be cases in which damage is deliberately induced, as in a procedure known as a pallidotomy,[6] in which a lesion is created to reduce involuntary muscle tremors. When it comes to regulation of movement, the globus pallidus has a primarily inhibitory action that balances the excitatory action of the cerebellum. These two systems evolved to work in harmony with each other to allow smooth and controlled movements.

 

Imbalances can result in tremors, jerks, and other movement problems, as seen in some people with progressive neurological disorders characterized by symptoms like tremors. The basal ganglia acts on a subconscious level, requiring no conscious effort to function.

 

When someone makes a decision to engage in an activity such as petting a dog, for example, these structures help to regulate the movement to make it as smooth as possible, and to respond to sensory feedback. Likewise, the globus pallidus is involved in the constant subtle regulation of movement that allows people to walk and engage in a wide variety of other activities with a minimal level of disruption

 

End quote

 

 

 

Note: the globus palladis is referred to as the dorsal pallidum and this is involved in motor control.  There is a ventral pallidum that is also part of the basal ganglia, and this is involved in the reward and risk system.  We will explore the ventral pallidum aspect in a later module.

 

 

 

 

Quote

In primates, the dorsal pallidum, or globus pallidus, is divided into two parts by the medial medullary lamina. These are often termed "internal" and "external" (the internal globus pallidus [GPi] and the external globus pallidus [GPe]); both are composed of closed nuclei surrounded by myelinic walls.

 

The ventral pallidum lies within the substantia innominata (Latin for unnamed substance) and receives efferent connections from the ventral striatum (the nucleus accumbens and the olfactory tubercle). It projects to the dorsomedial nucleus of the dorsal thalamus, which, in turn, projects to the prefrontal cortex; it also projects to the pedunculopontine nucleus and tegmental motor areas. Its function is to serve as a limbic-somatic motor interface, and it is involved in the planning and inhibition of movements from the dorsal striatopallidal complex.

 

End quote

 

 

 

 

 

The GPi and GPe provide route differentiation for direct MSN vs indirect MSN signaling.

The circuitry is as expected: GABAergic axonal terminal branches from the (dorsal) striatum project out.  The striatum has mostly GABAergic MSNs that project out to the  globus pallidus .  The data can be routed

 

 

1. either “directly” to the thalamus (VTh) via what are called direct MSNs(will be discussed later) or dMSNs, in which case the data goes through the GPi (internal) and SNr , and then directly to the thalamus.

 

 

 

2. Or “indirectly” to the thalamus (VTh)  via what are called indirect MSNs (will be discussed later) or iMSNs.  The data is first passed to the GPe (external) , and then to the GPi(internal) output nuclei of the basal ganglia, and then to the ventrolateral thalamus.

It’s important to note that although 95% of the neurons in the striatum are MSNs, only 40% of these MSNs have both D1 and D2 receptors, i.e. Only 40% of the MSNs are both iMSN and dMSN capable. I know I keep repeating this, but it’s only to emphasize how important the MSN GABAergic signaling and dopamine is to our motor and reward systems.  Dopamine is one of many  inputs into MSNs, but it’s function is critical to fine movement control, etc.  The key takeaway is that MSNs ultimately release GABA through their projections.  In this particular case, the projections are into the GP.

 

 

 

Quote

 

The two parts] (GPe and GPi) receive successively a large quantity of GABAergic axonal terminal arborisations from the striatum through the dense striato-pallidonigral bundle. The synaptology is very peculiar (see primate basal ganglia system).[4][5] The striatal afferents contribute more than 90% of synapses.[citation needed] The two pallidal nuclei receives dopaminergic axons from the pars compacta of the substantia nigra.

….

This area of the basal ganglia receives input from another area, called the (dorsal) striatum, which has two parts, the caudate nucleus and the putamen. This data is routed to the thalamus, either directly or indirectly.

 

In the case of the interna, one area of the globus pallidus, the structure can feed directly to the thalamus. The externa, which lies on the outside of this structure, feeds information to the interna (dm123: through the subthalamic nucleus part of the basal ganglia)where it can be passed on to the thalamus.

 

End quote

 

 

 

 

 

 

(4.5)Basic brain architecture: the substantia nigra pars reticulata (SNr)

 

 

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

 

 

This can be considered one of the “pit stops” on the neural circuit on the way out towards the cortex.

Although most of the neural projections from the SNr are GABAergic, when we do the circuit analysis we will see that it is the excitatory neurons in this region of the brain that have a big effect on the ultimate destination of the cerebral cortex.  Interestingly, the circuit for eye movement passes through the SNr, to a portion of the brain called the superior colliculus. It’s involved in the motor circuitry for both eye movement and voluntary skeletal movement (for example limbs, walking, etc)

I’ve included in the quote below, information about the motor circuitry, and the SNr’s involvement in that.  It’s not expected that one fully understands the circuit at this point.  We will dissect the motor circuit in a later module.  For now just focus on the bold parts as key takeaways from this module.

 

 

 

 

Quote

The pars reticulata is a portion of the substantia nigra. Most of the neurons that project out of the pars reticulata are inhibitory GABAergic neurons (i.e., these neurons release GABA, which is an inhibitory neurotransmitter).

 

The neurons of the pars reticulata produce the neurotransmitter gamma-aminobutyric acid (GABA). The neurons of the pars reticulata through the nigrothalamic bundle send axons to a particular part of the motor thalamus.

 

The nigral territory corresponds to the nucleus ventralis anterior (VA) (see also List of thalamic nuclei) (different from the pallidal VO). VA is the origin of one output of the basal ganglia system. It sends axons to the frontal and oculomotor cortex. In addition the pars reticulata sends neurons to the pars parafascicularis of the central region of the thalamus and to the pedunculopontine complex). The particularity of the pars lateralis is to send its axons to the superior colliculus,[2] which is a too minimized output of the basal ganglia system.

….

The neurons of the pars reticulata are fast-spiking pacemakers (dm123: we will learn a lot more about pacemaker neurons in a later module), generating action potentials in the absence of synaptic input.[3] In primates they discharge at a mean rate of 68 Hz in contrast to dopaminergic neurons (below 8 Hz).[4] They receive abundant afferrences from the striatum (mainly from the associative striatum) with the same very peculiar synaptology as the pallidum. It receives axons from the subthalamic nucleus and a dopaminergic innervation from the dopaminergic ensemble.

 

 

The pars reticulata is one of the two primary output nuclei of the basal ganglia system to the motor thalamus (the other output is the internal segment of the globus pallidus). The nigral neurons have their own territory distinct from the cerebellar and the pallidal in the nucleus ventralis anterior VA. This sends axons to the frontal and oculomotor cortex. Hikosaka and Wurtz[5][6][7][8] devoted four papers to "the visual and oculomotor functions of the monkey substantia nigra pars reticulata". This is largely involved in orientation and the control of eye movements in stabilisation of gaze and in saccades.

End quote

 

 

 

 

Note once again the importance of adequate DA, for the circuit through this SNr path to work properly.  DA dysfunction is implicated in both Parkinsonism and epilepsy symptoms relative to this region of the brain.

 

 

 

 

Quote

The function of the neurons of the pars compacta (not reticulata) is profoundly changed (60% of Dopamine secreting neurons, 80% decrease in dopamine in striatum) in parkinsonism and epilepsy. These changes are thought to be mostly secondary to pathology elsewhere in the brain, but may be crucial to understanding the generation of the symptoms of these disorders.

End quote

[[cs...]]

Adding this post to this thread/blog

It’s on subunit bindings, and Benzodiazaphines, barbiturates, etc.  page 2 has an interesting clinical paper on crosstalk between various anesthetics (one of which is a barbiturate).  Unfortunately the study did not involve Benzodiazaphines, and this area of research, as I noted in the post below page 2 needs more research.  I haven’t had a chance to take a look,

 

http://www.benzobuddies.org/forum/index.php?topic=200364.10#lastPost

 

The original link in the post on page 1 is very interesting.  After Effectively knocking out the alpha subunit, diazepam binds to β+γ-

 

If one looks a schematic representation of binding sides on the most common isoforms of GABAaRs, it’s easy to visualize that in the absence of alpha, the β+ side of the beta subunit would be “adjacent” to the γ- side of the gamma subunit, permitting the unusual binding of the Benzodiazaphine at the junction between β+ And γ-.    Something very similar happens with endogenous GABA.  in the alpha knockout, one can visualize an “adjacency” between the β+ And β-, permitting unusual binding of GABA at the junction between β+ And β-

 

Quote

Thus, the β2 subunit can take over the role of the α1 subunit for the formation of both sites, its minus side for the GABA binding site and its plus side for the diazepam binding site.

End quote

[[cs...]]

Hi all, I’ve gotten a few requests on mold illness.

 

 

I recommend Richie Shoemakers work.  I’ve read severa of his books, but you can find most of his framework of research online.  It’s a very interesting area of research.  His website is called surviingmold and the technical name of the illness is

CIRS or chronic inflammatory response syndrome, which is primarily an immune system mediated syndrome.  There’s a great white paper on CIRS online for free.  You can find it by searching on CIRS.