what is the role of ach on the direct pathway in the basal ganglia?

[Gooner007]

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in the direct pathway, dopamine excites the GABAnergic striatum cells, which ultimately causes disinhibition of the thalmus, which increases its firing of Glutamate, which in turn leads to 'cortex' activity = increased motion.

in the indirect pathway, dopamine inhibits the D2 receptor, which ultimately disinhibits this inhibitory pathway, which results in increased motion.

so far, everything makes perfect sense.

now the role of Ach. on the indirect pathway, Ach drives this pathway (the opposite of what dopamine does). so its has the effect of Decreasing cortical excitation.

which leads me to my question:

theoretically, Ach should inhibit the activity of the Direct pathway, thereby Decreasing cortical excitation. But according to the First AID book, it shows that it has an Excitatory effect on the direct pathway. I'm not following why this is the case.

Am I overlooking something? or not understanding a concept?

 

[Gooner007]

I'm just doing a first read of FA. maybe the action of Ach on the direct pathway is more detail than i need to worry about?

i was told to know FA cold. and according to FA, Ach has a stimulatory effect on the direct pathway. just didn't make sense, because Dopamine also has a stimulatory effect on the direct pathway, but i remember Ach and Dopamine having opposite effects.

 

[Gooner007]

anybody know what to make of the basal ganglia diagram in FA?

 

[Phloston]

anybody know what to make of the basal ganglia diagram in FA?

The basal ganglia diagram in FA is ******ed. I've never seen something so stupid before. Red for excitatory and green for inhibitory??

They have a good diagram in the 2009 FA. I've just copied that over into my 2012 edition. I'm not sure why they changed it. I'd post an image of it for everyone but I've already been warned by the SDN mods for having illegally posted NBME PrntScr images. So yeah, I'm not trying to get banned.

My thoughts have always been that ACh isn't involved in those pathways directly, but that that's just dopamine, GABA and glutamate working there (the latter only coming from the subthalamic nucleus in the inhibitory pathway).

 

[Akarat]

Maybe it's a matter of how many of those GABAergic neurons project to each pathway. For instance, maybe the indirect pathway has far more GABAergic neurons that project to the indirect pathway than to the direct pathway.

Picture a scenario where in a normal individual, the amount of GABAergic neurons secreting GABA in the direct pathway is maximum, and that the number of GABAergic neurons secreting GABA in the indirect pathway is only at like 50%. The GABAergic neurons in the indirect pathway are only at 50% of maximum because the rest are being inhibited by dopamine binding to the D2 receptors.

Now, remove the dopamine and you have all of the GABAergic neurons in the indirect pathway secreting GABA. This overwhelms the direct pathway by sheer numbers and thus results in decreased motion. Of course, you have dopamine's effects on D1 receptors and their contribution to stimulating the direct pathway.

As I understand ACh's effects on the pathways:

Direct Pathway:
1) The GABAergic neurons in the corpus striatum are excited by ACh, which causes the secretion of more GABA from the corpus striatum that then inhibits the GPi/SNr
2) Inhibited, the GPi/SNr secretes less GABA to inhibit the thalamus

Indirect Pathway:
1) The GABAergic neurons in the corpus striatum are excited by ACh, which causes the secretion of more GABA from the corpus striatum that then inhibits the GPe
2) Inhibited, the GPe secretes less GABA to inhibit the subthalamic nucleus
3) Disinhibited, the subthalamic nucleus secretes more glutamate that increases the excitation of the GPi/SNr
4) Increased excitation of the GPi/SNr leads to an increase in GABA secretion that increases inhibition of the thalamus

GPi = Globus pallidus internus
GPe = Globus pallidus externus
SNr = Substantia nigra pars reticula

This is pure speculation, though.

 

[oceanillusion42]

On a basic level, DA activates the direct pathway, which leads to cerebral excitation, which leads to normal physiology. The direct pathway overrides the indirect pathway in order to accomplish this normal resting state.

When you dont produce enough DA anymore like in Parkinsons, the direct pathway can no longer override the indirect pathway, so the indirect pathway is unchecked which leads to inhibition of the cortex and the typical parkinson's symptoms.

In the excitatory pathway, Ach DISINHIBITS the thalamus, thus allowing for excitation of the cortex.

In the inhibitory pathway, Ach stimulates GABAergic neurons that perpetuate the indirect pathway and thereby decrease contrical excitation and lead to parkinsons. These effects are usually inhibited because DA binds to D2 receptors which then inhibit those GABAergic neurons.

So Ach does not have a SINGLE role in Parkinson's, it's part of both pathways. It is excitatroy in the direct pathway and inhibitory in the indirect pathway.

 

[Phloston]

On a basic level, DA activates the direct pathway, which leads to cerebral excitation, which leads to normal physiology. The direct pathway overrides the indirect pathway in order to accomplish this normal resting state.

When you dont produce enough DA anymore like in Parkinsons, the direct pathway can no longer override the indirect pathway, so the indirect pathway is unchecked which leads to inhibition of the cortex and the typical parkinson's symptoms.

In the excitatory pathway, Ach DISINHIBITS the thalamus, thus allowing for excitation of the cortex.

In the inhibitory pathway, Ach stimulates GABAergic neurons that perpetuate the indirect pathway and thereby decrease contrical excitation and lead to parkinsons. These effects are usually inhibited because DA binds to D2 receptors which then inhibit those GABAergic neurons.

So Ach does not have a SINGLE role in Parkinson's, it's part of both pathways. It is excitatroy in the direct pathway and inhibitory in the indirect pathway.

What do you mean "direct pathway overriding the indirect pathway"? When dopamine is present, it activates the excitatory pathway and inhibits the inhibitory pathway. In Parkinson's, not only is the excitatory pathway not activated, but the inhibitory pathway isn't inhibited. This doesn't have anything to do with one pathway "overriding" the other.

 

[oceanillusion42]

What do you mean "direct pathway overriding the indirect pathway"? When dopamine is present, it activates the excitatory pathway and inhibits the inhibitory pathway. In Parkinson's, not only is the excitatory pathway not activated, but the inhibitory pathway isn't inhibited. This doesn't have anything to do with one pathway "overriding" the other.

Yea poor word choice on my part, I just mean the direct pathway is active and because its active, the indirect pathway is inactive. So then when you lose dopamine, the direct is no longer active, so the indirect isn't inhibited any more so the indirect path is unopposed.

We're saying the same thing, I just meant that by the direct path being active, the indirect isn't active... that's what i termed the direct pathway "overriding" the indirect.

 

[Phloston]

Yea poor word choice on my part, I just mean the direct pathway is active and because its active, the indirect pathway is inactive. So then when you lose dopamine, the direct is no longer active, so the indirect isn't inhibited any more so the indirect path is unopposed.

We're saying the same thing, I just meant that by the direct path being active, the indirect isn't active... that's what i termed the direct pathway "overriding" the indirect.

Haha we're not saying the same thing.

The direct pathway doesn't inhibit the indirect pathway. It's not the case that knocking out the direct pathway all of a sudden relieves inhibition on the indirect pathway.

Dopamine from the SNc actually inhibits the putamen, causing inhibition of the inhibitory pathway. In Parkinson's, the inhibition of the inhibitory pathway is removed, and bradykinesia results. This has nothing to do with the direct pathway.

Dopamine activates the excitatory pathway. In Parkinson's, this activation is removed.

So normally, BOTH pathways enable movement.

In Parkinson's, BOTH pathways prevent movement.

One pathway doesn't exert effects over the other.

 

[Gooner007]

Haha we're not saying the same thing.

The direct pathway doesn't inhibit the indirect pathway. It's not the case that knocking out the direct pathway all of a sudden relieves inhibition on the indirect pathway.

Dopamine from the SNc actually inhibits the putamen, causing inhibition of the inhibitory pathway. In Parkinson's, the inhibition of the inhibitory pathway is removed, and bradykinesia results. This has nothing to do with the direct pathway.

Dopamine activates the excitatory pathway. In Parkinson's, this activation is removed.

So normally, BOTH pathways enable movement.

In Parkinson's, BOTH pathways prevent movement.

One pathway doesn't exert effects over the other.

This is pretty much exactly how i remember it for parkinsons. which makes complete sense with regards to dopamine.

as for the action of glutamate on the caudate, the direct pathway AND indrect pathway are activated. leading to excitation of planned movements (direct pathway), and the inhibition of unwanted movements (indirect pathway)

the key player here, is the D2 receptor on the indirect pathway for dopamine. because of its inhibitory effect, it results in dopamine inhibiting the inhibitor, thus BOTH direct and indirect pathways lead to increased movement with dopamine.

the action of Ach is really bugging me though. these neurons have cell bodies within the caudate, and they act to somehow modulate both the direct and indirect pathways initiated in the caudate too. but how they do this, i may never know! lol.

 

[startoverat40]

Ach reduces IPSPs in STN

http://jpet.aspetjournals.org/content/early/2011/12/01/jpet.111.187856

Shen KZ and Johnson SW (2000) Presynaptic dopamine D2 and muscarine M3 receptors inhibit excitatory and inhibitory transmission to rat subthalamic neurones in vitro. Journal of Physiology 525:331-341.
Shen W, Hamilton SE, Nathanson NM and Surmeier DJ (2005) Cholinergic suppression of
KCNQ channel currents enhances excitability of striatal medium spiny neurons. J Neurosci
25:7449-7458.