Anavex Life Sciences Corp (AVXL)

[sokol]

M4 muscarinic receptors - Dopamine and Acetylcholine - Cognition - Dyskinesia (uncontrolled, involuntary movements).


Motor and cognitive functions depends on the coordinated interaction in the brain of two neurotransmitters — substances produced in response to nerve signals that act as chemical messengers — called dopamine and acetylcholine.

In Parkinson’s, the degeneration of motor neurons that produce dopamine in a brain region called the striatum results in difficulties with voluntary movement control.

Therapies that increase dopamine or activate dopamine receptors, such as levodopa, are currently used to restore motor skills. However, these treatments are not fully effective and their benefits wear off over time.

Researchers have thought that a decline in dopamine levels would increase acetylcholine production. Higher levels of acetylcholine are suggested to cause the dyskinesia — uncontrolled, involuntary movements — observed in Parkinson’s patients under long-term dopamine therapy.

Researchers at Yale University questioned points in these assumptions. They investigated how dopamine affects acetylcholine by looking at a specific type of nerve cell, called striatal interneurons, that is the main source of acetylcholine in the striatum.

To test the effects of dopamine loss, the team used a mouse model genetically modified to mimic Parkinson’s that has a progressive decline in dopamine levels. When motor symptoms appear in these mice, it is estimated that about 30% of dopamine is already lost, increasing to 60–80% at their death.

This progressive dopamine loss, the researchers saw, was matched in the animals by an initial and smaller decrease in the production of acetylcholine by striatal interneurons, creating an imbalance.

“While the concentrations of both dopamine and acetylcholine decline, the balance between these two neurotransmitters shifts to favor acetylcholine,” the researchers wrote.

Subsequent release of dopamine from remaining axon terminals push an increase of acetylcholine, worsening the imbalance between both neurotransmitters.

Under dopamine depleted conditions, proper motor function is dependent on adequate levels of both acetylcholine and dopamine, the study concluded.

Its findings suggest that progressive dopamine deficiency reduces the activity of striatal cholinergic interneurons, resulting in progressive motor difficulties.

https://parkinsonsnewstoday.com/2019/07/23/imbalance-in-neurotransmitters-dopamine-acetylcholine-tied-to-parkinsons-progression/


M4 muscarinic receptors are coupled to Gi/o heterotrimeric proteins.[6]

They function as inhibitory autoreceptors for acetylcholine. Activation of M4 receptors inhibits acetylcholine release in the striatum. The M2 subtype of acetylcholine receptor functions similarly as an inhibitory autoreceptor to acetylcholine release, albeit functioning actively primarily in the hippocampus and cerebral cortex.........

Neurotransmission in the striatum influences extrapyramidal motor control, thus alterations in M4 activity may contribute to conditions such as Parkinson's disease. https://en.m.wikipedia.org/wiki/Muscarinic_acetylcholine_receptor_M4

In anatomy, the extrapyramidal system is a part of the motor system network causing involuntary actions. https://en.m.wikipedia.org/wiki/Extrapyramidal_system

The striatum is one of the principal components of the basal ganglia, a group of nuclei that have a variety of functions but are best known for their role in facilitating voluntary movement. https://www.neuroscientificallychallenged.com/blog/know-your-brain-striatum

M4 muscarinic receptors - Dopamine and Acetylcholine - Cognition - Dyskinesia (uncontrolled, involuntary movements).

Motor and cognitive functions depends on the coordinated interaction in the brain of two neurotransmitters — substances produced in response to nerve signals that act as chemical messengers — called dopamine and acetylcholine.

In Parkinson’s, the degeneration of motor neurons that produce dopamine in a brain region called the striatum results in difficulties with voluntary movement control.

Therapies that increase dopamine or activate dopamine receptors, such as levodopa, are currently used to restore motor skills. However, these treatments are not fully effective and their benefits wear off over time.

Researchers have thought that a decline in dopamine levels would increase acetylcholine production. Higher levels of acetylcholine are suggested to cause the dyskinesia — uncontrolled, involuntary movements — observed in Parkinson’s patients under long-term dopamine therapy.

Researchers at Yale University questioned points in these assumptions. They investigated how dopamine affects acetylcholine by looking at a specific type of nerve cell, called striatal interneurons, that is the main source of acetylcholine in the striatum.

To test the effects of dopamine loss, the team used a mouse model genetically modified to mimic Parkinson’s that has a progressive decline in dopamine levels. When motor symptoms appear in these mice, it is estimated that about 30% of dopamine is already lost, increasing to 60–80% at their death.

This progressive dopamine loss, the researchers saw, was matched in the animals by an initial and smaller decrease in the production of acetylcholine by striatal interneurons, creating an imbalance.

“While the concentrations of both dopamine and acetylcholine decline, the balance between these two neurotransmitters shifts to favor acetylcholine,” the researchers wrote.

Subsequent release of dopamine from remaining axon terminals push an increase of acetylcholine, worsening the imbalance between both neurotransmitters.

Under dopamine depleted conditions, proper motor function is dependent on adequate levels of both acetylcholine and dopamine, the study concluded.

Its findings suggest that progressive dopamine deficiency reduces the activity of striatal cholinergic interneurons, resulting in progressive motor difficulties.

https://parkinsonsnewstoday.com/2019/07/23/imbalance-in-neurotransmitters-dopamine-acetylcholine-tied-to-parkinsons-progression/


M4 muscarinic receptors are coupled to Gi/o heterotrimeric proteins.[6]

They function as inhibitory autoreceptors for acetylcholine. Activation of M4 receptors inhibits acetylcholine release in the striatum. The M2 subtype of acetylcholine receptor functions similarly as an inhibitory autoreceptor to acetylcholine release, albeit functioning actively primarily in the hippocampus and cerebral cortex.........

Neurotransmission in the striatum influences extrapyramidal motor control, thus alterations in M4 activity may contribute to conditions such as Parkinson's disease. https://en.m.wikipedia.org/wiki/Muscarinic_acetylcholine_receptor_M4

In anatomy, the extrapyramidal system is a part of the motor system network causing involuntary actions. https://en.m.wikipedia.org/wiki/Extrapyramidal_system

The striatum is one of the principal components of the basal ganglia, a group of nuclei that have a variety of functions but are best known for their role in facilitating voluntary movement. https://www.neuroscientificallychallenged.com/blog/know-your-brain-striatum


........
The muscarinic acetylcholine M4 receptor is primarily found in the CNS [15, 16, 17], its distribution largely overlapping with that of M1 and M3 subtypes. M4 receptors function as inhibitory autoreceptors for acetylcholine [18, 19], activation of which inhibits acetylcholine release in the striatum.....

Muscarinic acetylcholine receptors possess a regulatory effect on dopaminergic neurotransmission and activation of M4 receptors in the striatum inhibits dopamine-induced locomotor stimulation in mice [20]. M4 receptor-deficient mice exhibit increased locomotor simulation in response to dopamine agonists, such as amphetamine and cocaine [21, 22, 23, 2]. Neurotransmission in the striatum influences extrapyramidal motor control. Therefore, alterations in M4 receptor activity may contribute to conditions such as Parkinson's Disease [24, 25, 26].

https://www.ebi.ac.uk/interpro/entry/InterPro/IPR001432/