Lightning-Nl
Bluelighter
- Joined
- Nov 11, 2012
- Messages
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Due to the synergistic effects that I have experienced by taking Lamotrigine and Vyvanse at the sametime, I came up with a fact-based explanation as to why Lamotrigine would synergise with Vyvanse. I am asking for input on whether or not you think I'm right, what I missed if anything, etc. This is all just harmless speculation, but interesting none-the-less.
This is about using Calcium channel blockers as a means of blocking homeostasis from being achieved by NMDA neurons, thus slowing or reducing tolerance to Amphetamine and opiates. I am going to use Lamotrigine as an example due to the fact that I experienced this with Lamotrigine.
Lamotrigine is an antiepileptic drug (used to stop seizures). It does this by blocking sodium channels, and to a lesser extent, calcium channels. This inhibits neurons in a literal sense. A lot drugs inhibit excitation by antagonizing a receptor for a neurotransmitter that would cause excitation. Some drugs enhance GABAergic activity which causes inhibition all over the body. But Lamotrigine works but literally blocking the electrical signal to another neuron.
When a neurotransmitter binds to a neuron, it sends the message to either speed-up neuronal firing or slow down neuronal firing. To give an example, when Glutamate binds to a neuron (I'm using Glutamate as an example because it's general purpose is to cause excitation) it causes depolarization of the neuron. This causes a change in a cell's membrane potential that makes it more positive. This rectifies the cell which opens the channel, allowing positively charged ions to move into the cell. Once the mV's inside the cell becomes higher than the charge on the outside of the cell, the cell becomes positively charged, and the outside of the cell becomes negatively charged. Since opposites attract, the now positive charge of the cell makes the positively charged ions want to move out of the cell. However, the activation gate is voltage-sensitive. So it blocks the channel before the ions can leave.
This is what causes the neuron to fire, a positive charge inside the cell. The GABA system works by moving negatively charged Chloride ions inside the cell. If the charge of the inside of the cell is greater than the outside (meaning it's positive on the inside and negative on the outside) this makes Cl- "want" to move into the cell. Because the charge is negative, the activation-gate is attracted towards the inside of the cell which "unplugs" the channel thus allowing Cl- into the cell. This equalizes the charge of the inside of the cell to that of the outside of cell, this making the cell very less excitable.
It's believed that this is how Gabapentin and Pregabalin work. In a way unrelated to the mechanism of action of Benzodiazepines, Gabapentin/Pregabalin cause Cl- to become more freely available (or may even mimic Cl-) which negatively charges the outside of the cell.
Lamotrigine works by "mimicking" the activation gate, because Lamotrigine itself is voltage-gated. Lamotrigine works by blocking the outside of the cell membrane. But it doesn't block the channel, when there's no charge. So when there's no charge, it freely floats around. When one side of the cell is negatively charged, the ions want to move into or out of the cell. Lamotrigine does too, but it's "too big" to fit inside the cell, so when it tried to get in, it gets stuck. Thus blocking the channel.
That means, if the cell is negatively charged on the inside, Lamotrigine will try to move into the cell, but it can't. So it blocks the cell, thus not allowing the cell to become positively charged.
Lamotrigine does this at the sodium channels and, to a lesser extent, calcium channel (this is important)
Lamotrigine and Glutamate
So what does this have to do with tolerance reduction? Well, Lamotrigine blocks excitation of a cell, whether or not a neurotransmitter has "told" the cell to depolarize. This means, the cell has no action potential, so it doesn't fire. Because the message has to be sent to the next neuron that it too, should fire - the firing of that cell would normally release an excitatory neurotransmitters on the other side (usually Glutamate). Because Lamotrigine doesn't allow the neuron to fire, the action potential is broken.
Because Glutamate is the most abundant excitatory neurotransmitter in the body, action-potential is most often created by Glutamate binding. Because Lamotrigine doesn't allow the action-potential to develop, even though there might be sufficient Glutamate, the ions can't change the charge of the cell. Therefore, the message is not sent down the axon and Glutamate transmission is disrupted. This leads to a body wide reduction in Glutamate levels.
Tolerance reduction
It's been discovered in the last decade that tolerance to Amphetamines (but all stimulants apply) and tolerance to opioid drugs are both caused by increased Glutamatergic activity. Specifically, increased sensitivity at the N-Methyl-D-Aspartate (NMDA) receptor. This increased sensitivity leads to much larger amounts of Calcium ions getting into the cell. This makes Glutamate more likely to cause an action-potential and therefore, neuron firing will occur much more often, for a much larger period of time.
Lamotrigine, or any calcium channel blocker therefore, indirectly modifies this channel. Not only does it block Calcium ions from not being able to charge a cell, but this blocking of calcium causes decreased downstream release of Glutamate since the single doesn't need to be sent. This means, less Glutamate will be modulating NMDA. This will block the body from being able to reach homeostasis when modulating bodily function due to amphetamine's presence.
Role in addiction
According to this study, NMDA modulation in dopaminergic neurons is essential to dopamine's role habit-formation. Knock-out mice were impaired when forming-habits when NMDA receptors did not exist on dopaminergic neurons. This leads to the assumptions that Glutamatergic activation is essential to habit-forming behaviors. So, when dopamine neuronal firing is increased, to desensitize these dopaminergic neurons, the NMDA receptor starts firing faster and more often.
Not only does this downregulate dopamine, but when Amphetamine is then - not present, the increased levels of dopamine that it would have produced aren't there. But NMDA is still firing faster and stronger than it should. This leads to the need to execute that habit in order to reach homeostasis. By blocking this receptor from activating, the dopamine neurons will upregulate again and eventually, NMDA won't be hyperactive.
I know this is more specific to NMDA antagonists, but since NMDA firing is Calcium ions moving down the axon - if calcium can't get inside the cell to allow NMDA to fire, wouldn't that have the same effects as an antagonist?
http://www.ncbi.nlm.nih.gov/pubmed/22196339
What do you think?
Now I'm curios as to what everyone else thinks about this. This makes a lot of sense to me, however, the internet loves to point out flaws in your thinking. So is there anything I missed that wouldn't allow this to work? What's you're guys opinion?
Also, do you think Calcium channel blockers can be a means of treating addiction in the future?
This is about using Calcium channel blockers as a means of blocking homeostasis from being achieved by NMDA neurons, thus slowing or reducing tolerance to Amphetamine and opiates. I am going to use Lamotrigine as an example due to the fact that I experienced this with Lamotrigine.
Lamotrigine is an antiepileptic drug (used to stop seizures). It does this by blocking sodium channels, and to a lesser extent, calcium channels. This inhibits neurons in a literal sense. A lot drugs inhibit excitation by antagonizing a receptor for a neurotransmitter that would cause excitation. Some drugs enhance GABAergic activity which causes inhibition all over the body. But Lamotrigine works but literally blocking the electrical signal to another neuron.
When a neurotransmitter binds to a neuron, it sends the message to either speed-up neuronal firing or slow down neuronal firing. To give an example, when Glutamate binds to a neuron (I'm using Glutamate as an example because it's general purpose is to cause excitation) it causes depolarization of the neuron. This causes a change in a cell's membrane potential that makes it more positive. This rectifies the cell which opens the channel, allowing positively charged ions to move into the cell. Once the mV's inside the cell becomes higher than the charge on the outside of the cell, the cell becomes positively charged, and the outside of the cell becomes negatively charged. Since opposites attract, the now positive charge of the cell makes the positively charged ions want to move out of the cell. However, the activation gate is voltage-sensitive. So it blocks the channel before the ions can leave.
This is what causes the neuron to fire, a positive charge inside the cell. The GABA system works by moving negatively charged Chloride ions inside the cell. If the charge of the inside of the cell is greater than the outside (meaning it's positive on the inside and negative on the outside) this makes Cl- "want" to move into the cell. Because the charge is negative, the activation-gate is attracted towards the inside of the cell which "unplugs" the channel thus allowing Cl- into the cell. This equalizes the charge of the inside of the cell to that of the outside of cell, this making the cell very less excitable.
It's believed that this is how Gabapentin and Pregabalin work. In a way unrelated to the mechanism of action of Benzodiazepines, Gabapentin/Pregabalin cause Cl- to become more freely available (or may even mimic Cl-) which negatively charges the outside of the cell.
Lamotrigine works by "mimicking" the activation gate, because Lamotrigine itself is voltage-gated. Lamotrigine works by blocking the outside of the cell membrane. But it doesn't block the channel, when there's no charge. So when there's no charge, it freely floats around. When one side of the cell is negatively charged, the ions want to move into or out of the cell. Lamotrigine does too, but it's "too big" to fit inside the cell, so when it tried to get in, it gets stuck. Thus blocking the channel.
That means, if the cell is negatively charged on the inside, Lamotrigine will try to move into the cell, but it can't. So it blocks the cell, thus not allowing the cell to become positively charged.
Lamotrigine does this at the sodium channels and, to a lesser extent, calcium channel (this is important)
Lamotrigine and Glutamate
So what does this have to do with tolerance reduction? Well, Lamotrigine blocks excitation of a cell, whether or not a neurotransmitter has "told" the cell to depolarize. This means, the cell has no action potential, so it doesn't fire. Because the message has to be sent to the next neuron that it too, should fire - the firing of that cell would normally release an excitatory neurotransmitters on the other side (usually Glutamate). Because Lamotrigine doesn't allow the neuron to fire, the action potential is broken.
Because Glutamate is the most abundant excitatory neurotransmitter in the body, action-potential is most often created by Glutamate binding. Because Lamotrigine doesn't allow the action-potential to develop, even though there might be sufficient Glutamate, the ions can't change the charge of the cell. Therefore, the message is not sent down the axon and Glutamate transmission is disrupted. This leads to a body wide reduction in Glutamate levels.
Tolerance reduction
It's been discovered in the last decade that tolerance to Amphetamines (but all stimulants apply) and tolerance to opioid drugs are both caused by increased Glutamatergic activity. Specifically, increased sensitivity at the N-Methyl-D-Aspartate (NMDA) receptor. This increased sensitivity leads to much larger amounts of Calcium ions getting into the cell. This makes Glutamate more likely to cause an action-potential and therefore, neuron firing will occur much more often, for a much larger period of time.
Lamotrigine, or any calcium channel blocker therefore, indirectly modifies this channel. Not only does it block Calcium ions from not being able to charge a cell, but this blocking of calcium causes decreased downstream release of Glutamate since the single doesn't need to be sent. This means, less Glutamate will be modulating NMDA. This will block the body from being able to reach homeostasis when modulating bodily function due to amphetamine's presence.
Role in addiction
According to this study, NMDA modulation in dopaminergic neurons is essential to dopamine's role habit-formation. Knock-out mice were impaired when forming-habits when NMDA receptors did not exist on dopaminergic neurons. This leads to the assumptions that Glutamatergic activation is essential to habit-forming behaviors. So, when dopamine neuronal firing is increased, to desensitize these dopaminergic neurons, the NMDA receptor starts firing faster and more often.
Not only does this downregulate dopamine, but when Amphetamine is then - not present, the increased levels of dopamine that it would have produced aren't there. But NMDA is still firing faster and stronger than it should. This leads to the need to execute that habit in order to reach homeostasis. By blocking this receptor from activating, the dopamine neurons will upregulate again and eventually, NMDA won't be hyperactive.
I know this is more specific to NMDA antagonists, but since NMDA firing is Calcium ions moving down the axon - if calcium can't get inside the cell to allow NMDA to fire, wouldn't that have the same effects as an antagonist?
http://www.ncbi.nlm.nih.gov/pubmed/22196339
What do you think?
Now I'm curios as to what everyone else thinks about this. This makes a lot of sense to me, however, the internet loves to point out flaws in your thinking. So is there anything I missed that wouldn't allow this to work? What's you're guys opinion?
Also, do you think Calcium channel blockers can be a means of treating addiction in the future?