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Do the blocked dopamine receptors get broken down by the body and if so how often ?
In other words how long does it take for the dopamine receptors blocked by irreversible dopamine antagonists to degrade ?
Partial Answer and Suggestions
As @De_Novo says, this is a complicated, albeit very interesting, question. There are various reasons for this, such as the fact that the receptors aren't just internalised but also recycled and the fact that there may be antagonist and dose-dependent changes in receptor internalisation. There's the added complexity that receptors can have their expression changed in the short term (by internalisation) but also in the long term (by varying synthesis). You should then note that there's not a set lifespan of the receptors - there's a statistical distribution for how long they'll last at the membrane.
But I'd quite like to stimulate discussion about it so I'm proposing some smaller questions:
- Do irreversible dopamine antagonists change the rates of receptor internalisation, degradation or recycling? This is likely to be the case as internalisation of receptors is often activity-dependent. Also, the shape of the irreversible antagonist could change how the receptor fits into a clathrin-coated pit.
- Do the irreversible antagonists change the rate of receptor synthesis?
- What mathematical models can describe the dynamics of internalisation? This might be a bit tricky since there are feedback mechanisms here (e.g. recycling --> internalisation --> degradation --> less recycling).
- How does the proportion of blocked receptors affect these factors?
By answering these questions (or even by finding an experiment that measures the half life of the receptors with blocking), you could come up with an answer for the half-life of the blocked receptors.
This Is How Your Brain Becomes Addicted to Caffeine
Within 24 hours of quitting the drug, your withdrawal symptoms begin. Initially, they’re subtle: The first thing you notice is that you feel mentally foggy, and lack alertness. Your muscles are fatigued, even when you haven’t done anything strenuous, and you suspect that you’re more irritable than usual.
Over time, an unmistakable throbbing headache sets in, making it difficult to concentrate on anything. Eventually, as your body protests having the drug taken away, you might even feel dull muscle pains, nausea and other flu-like symptoms.
This isn’t heroin, tobacco or even alcohol withdrawl. We’re talking about quitting caffeine, a substance consumed so widely (the FDA reports that more than㻐 percent of American adults drink it daily) and in such mundane settings (say, at an office meeting or in your car) that we often forget it’s a drug—and by far the world’s most popular psychoactive one.
Like many drugs, caffeine is chemically addictive, a fact that scientists established back in 1994. This past May, with the publication of the 5th edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM), caffeine withdrawal was finally included as a mental disorder for the first time—even though its merits for inclusion are symptoms that regular coffee-drinkers have long known well from the times they’ve gone off it for a day or more.
Why, exactly, is caffeine addictive? The reason stems from the way the drug affects the human brain, producing the alert feeling that caffeine drinkers crave.
Soon after you drink (or eat) something containing caffeine, it’s absorbed through the small intestine and dissolved into the bloodstream. Because the chemical is both water- and fat-soluble (meaning that it can dissolve in water-based solutions—think blood—as well as fat-based substances, such as our cell membranes), it’s able to penetrate the blood-brain barrier and enter the brain.
Structurally, caffeine closely resembles a molecule that’s naturally present in our brain, called adenosine (which is a byproduct of many cellular processes, including cellular respiration)—so much so, in fact, that caffeine can fit neatly into our brain cells’ receptors for adenosine, effectively blocking them off. Normally, the adenosine produced over time locks into these receptors and produces a feeling of tiredness.
Caffeine structurally resembles adenosine enough for it to fit into the brain’s adenosine receptors. Image via Wikimedia Commons
When caffeine molecules are blocking those receptors, they prevent this from occurring, thereby generating a sense of alertness and energy for a few hours. Additionally, some of the brain’s own natural stimulants (such as dopamine) work more effectively when the adenosine receptors are blocked, and all the surplus adenosine floating around in the brain cues the adrenal glands to secrete adrenaline, another stimulant.
For this reason, caffeine isn’t technically a stimulant on its own, says Stephen R. Braun, the author or Buzzed: the Science and Lore of Caffeine and Alcohol, but a stimulant enabler: a substance that lets our natural stimulants run wild. Ingesting caffeine, he writes, is akin to “putting a block of wood under one of the brain’s primary brake pedals.” This block stays in place for anywhere from four to six hours, depending on the person’s age, size and other factors, until the caffeine is eventually metabolized by the body.
In people who take advantage of this process on a daily basis (i.e. coffee/tea, soda or energy drink addicts), the brain’s chemistry and physical characteristics actually change over time as a result. The most notable change is that brain cells grow more adenosine receptors, which is the brain’s attempt to maintain equilibrium in the face of a constant onslaught of caffeine, with its adenosine receptors so regularly plugged (studies indicate that the brain also responds by decreasing the number of receptors for norepinephrine, a stimulant). This explains why regular coffee drinkers build up a tolerance over time—because you have more adenosine receptors, it takes more caffeine to block a significant proportion of them and achieve the desired effect.
This also explains why suddenly giving up caffeine entirely can trigger a range of withdrawal effects. The underlying chemistry is complex and not fully understood, but the principle is that your brain is used to operating in one set of conditions (with an artificially-inflated number of adenosine receptors, and a decreased number of norepinephrine receptors) that depend upon regular ingestion of caffeine. Suddenly, without the drug, the altered brain chemistry causes all sorts of problems, including the dreaded caffeine withdrawal headache.
The good news is that, compared to many drug addictions, the effects are relatively short-term. To kick the thing, you only need to get through about 7-12 days of symptoms without drinking any caffeine. During that period, your brain will naturally decrease the number of adenosine receptors on each cell, responding to the sudden lack of caffeine ingestion. If you can make it that long without a cup of joe or a spot of tea, the levels of adenosine receptors in your brain reset to their baseline levels, and your addiction will be broken.
About Joseph Stromberg
Joseph Stromberg was previously a digital reporter for Smithsonian.
Abilify: The Perfect Antipsychotic?
Abilify (aripiprazole) is out! But you probably already know this, if your mailbox and fax machine have become as saturated with BMSfunded missives from CME, Inc. as mine have been. The hired guns are out in force once again, and so we front-line clinicians are faced with the task of separating the authentic wheat from the hyped-up chaff.
The buzz is about its mechanism of action, which is unique among currently approved antipsychotics. Rather than being a dopamine blocker, it is a dopamine system stabilizer. What does this fancy moniker actually mean?
Lets go back to the basics of antipsychotics. Conventional agents are dopamine antagonists throughout the brain, not distinguishing between the mesolimbic regions (where too much dopamine causes psychosis, we hypothesize) and the nigrostriatal region (where dopamine normally modulates fluidity of movement). Thus, far from stabilizing dopamine, conventional neuroleptics shut down on dopamine indiscriminately, leading to the movement disorders for which they are infamous.
So, along came the atypicals, first Clozaril, and subsequently the first-line atypicals (Risperdal, Zyprexa, Seroquel, and Geodon). Like conventionals, atypicals block dopamine receptors, but they also do something to modulate this effect: they block serotonin 2A receptors, especially in the nigrostriatal cortex. Since decreasing serotonin tends to increase dopamine, blocking 5HT 2A has the effect of releasing more dopamine where it is needed to prevent movement problems. Thus, atypicals tend not to cause EPS or TD. In a very real sense, then, current atypicals already are dopamine system stabilizers. So why the hullabaloo over Abilify?
It is not entirely clear. It may be because Abilifys mechanism of stabilizing the dopamine system is more elegant. Rather than blocking dopamine in one area, then relying on also blocking serotonin to normalize levels, Abilify is a partial agonist of D2 in the first place, meaning that it sits on the dopamine receptor strongly enough to bat away the excess dopamine that causes psychosis, while at the same time exerting enough mild dopamine-like activity to prevent movement disorders. So its dopamine stabilizing mechanism is more direct. But does that make it a better antipsychotic? Probably not.
In fact, the clinical trials very clearly show that Abilify is no more effective than either Haldol or Risperdal. The most widely read study, by Kane and colleagues, randomized 414 acutely relapsed schizophrenic patients to one of four groups: Abilify 15 mg, Abilify 30 mg, Haldol 10 mg, and Placebo. All three active treatments improved both positive and negative symptoms equivalently. The only significant benefit of Abilify was in its better side effect profile.
In terms of side effects, Abilify may very well be the most perfect antipsychotic yet developed. No EPS, no weight gain, no hyperprolactinemia, less sedation than any of its competitors (but watch out for insomnia, which is common). Abilify is Geodon without QT prolongation, and for this reason TCR predicts that it will become very popular, very quickly.
Dose it like this: Start at 15 mg Q AM, aim for 15 mg to 30 mg for best therapeutic effect. Try to stay at 15 mg though, because at 30 mg there is more sedation. Its a very easy drug to use.
If only the Abilify-boosters would stop harping on its pseud-ounique mechanism of action and emphasize what makes it truly uniquethe best side effect profile in its class.
TCR VERDICT: The most perfect atypicalbut enough about its mechanism!
Cabergoline Tablets, USP are contraindicated in patients with:
- Uncontrolled hypertension or known hypersensitivity to ergot derivatives.
- History of cardiac valvular disorders, as suggested by anatomical evidence of valvulopathy of any valve, determined by pre-treatment evaluation including echocardiographic demonstration of valve leaflet thickening, valve restriction, or mixed valve restriction-stenosis. (See WARNINGS )
- History of pulmonary, pericardial, or retroperitoneal fibrotic disorders. (See WARNINGS )
This is Your Brain on Ecstasy ^ Really!
This slide show will explain the effects of MDMA on your brain. The effects of a normal dose of MDMA last from four to six hours. We will explain what happens in the brain during the various stages of the MDMA experience, and we will describe some changes in the brain that may occur after long-term, frequent use. The slideshow starts off with some fairly basic information and gets more complex as it goes along. Don’t worry about technical terms in the beginning. Everything is explained in easy-to-understand language.
This is a model of a typical human brain, showing some of the basic brain areas. Below are the basics of what each brain area is responsible for. You don’t need to memorize this to understand how MDMA works. It’s really just a warm up, and you can skip to the next section (Brain Cell) if you like.
- Frontal Lobe: Controls planning, organizing, solving problems, and other higher-level functions (like emotions, personality, and understanding consequences)
- Temporal Lobe: Manages visual and verbal memory
- Parietal Lobe: Processes tactile data, like touch or pressure, as well as written and spoken language
- Occipital Lobe: Processes visual information, including shapes, colors and
- Cerebellum: Manages things like movement, balance and muscle coordination
- Brain Stem: Controls basic mechanisms that keep you alive: heart rate, respiration, blood pressure
This is a model of a typical type of brain cell called a neuron. A neuron is a brain cell that carries an electrical signal. Your brain contains billions of brain cells. A brain cell consists of:
- A cell body, which stores the DNA and other things that the cell needs to do it’s job
- Dendrites, which receive chemical signals from other cells and
- An axon, which carries an electrical signal from the cell body to the axon terminals. The axon terminals contain chemicals, called “neurotransmitters,” which are released in order for the cell to communicate with nearby cells.
Serotonin is a neurotransmitter, and some brain cells have axons that contain only serotonin. These are called “serotonin neurons.” Other brain cells produce and release different neurotransmitters, like dopamine or norepinephrine, and some produce and release more than one neurotransmitter. However, your serotonin cells only produce and release serotonin.
Here, you can see how the axon terminals, which contain serotonin (the neurotransmitter that MDMA releases) lie very close to the dendrites of other, nearby neurons. Notice the gap between the axon terminal of the serotonin neuron and the dendrites of the next neuron. This gap is called the “synapse” and is where the serotonin gets released.
Soon we will look at the synapse up close and see what happens when MDMA causes large amounts of serotonin to be released there. But first, let’s look at how serotonin cells are distributed throughout your brain.
Your serotonin axons begin in the brain stem, are very long, and are connected to all areas of your brain.
Most serotonin cells (in red) begin in a specific area of the brain stem called the raphe nuclei. Their dendrites and cell bodies are located here, and they have very long axons that extend into every other part of the brain.
Serotonin axons are much denser and have many more tree-like branches than we are able to show in this drawing. They are also much longer than any diagram can easily depict. If you were to stretch out a serotonin neuron on a table in front of you, it might be a foot long, but you still wouldn’t be able to see it because it would be so thin. Most people think of brain cells as shorter and confined to particular brain regions (in blue). While some brain cells are like this, this is not the case with serotonin cells. This is part of the reason why serotonin plays such an important role in so many brain functions, such as the regulation of mood, heart rate, sleep, appetite, pain and many others.
Actual photograph of serotonin cells (mostly axons) in a rat’s brain.
This is an actual photograph of serotonin cells (mostly axons) in a rat’s brain. Notice the tree-like branching of the axons.
The dark spaces around the serotonin cells are actually densely filled with other brain cells. You can’t see them in this picture, however, because only the serotonin cells were stained to make them visible.
Ecstasy causes your serotonin neurons (yellow) to release large amounts of serotonin.
MDMA causes your serotonin neurons (yellow) to release large amounts of serotonin (the little red dots), which are stored in the axon terminals. This massive serotonin release is responsible for the primary subjective effects of MDMA.
MDMA also indirectly causes the release of other neurotransmitters like dopamine, as well as the hormones oxytocin and prolactin, but this is a secondary result of the serotonin release.
Inside the axon terminal are small vesicles that contain serotonin molecules.
Inside the axon terminal are small vesicles that contain serotonin molecules. When an electrical charge comes down the axon, these vesicles merge with the outer membrane of the axon terminal and release serotonin into the synapse.
Synapse Wide View
A wider view of the synapse, with vesicles releasing serotonin.
Moving in a little closer to the synapse, we can see some serotonin molecules floating around. We also see some serotonin reuptake transporters on the membrane of the axon terminal as well as receptors on the dendrite of the nearby neuron.
In order to understand how MDMA works in the brain and why it produces the effects it does, you need to know what these reuptake transporters and receptors do. But first, just for the fun of it, let’s look at an actual photograph of a synapse…
Actual photograph of a serotonin axon terminal (top), a dendrite (bottom), and the synapse in between.
This is an actual photograph of a serotonin axon terminal (top), a dendrite (bottom), and the synapse in between. Notice the serotonin-filled vesicles inside the axon terminal. In this picture you can’t actually see serotonin molecules, nor the reuptake transporters or receptors. This is because they are so small.
You can, however, imagine serotonin molecules floating around inside the gray area. Also, notice that some other dendrites are visible even though they haven’t been stained like the bright one.
Synapse up close
Serotonin receptor binding is the primary cause of MDMA’s subjective effects.
Here’s where the fun starts. This is a closer view of a vesicle releasing serotonin into the synapse.
On the other side of the synapse, attached to the membrane of the dendrite, are these things called receptors. There are receptors for many neurotransmitters. Let’s say the magenta-colored ones are serotonin receptors and the green ones are for dopamine. Notice how a serotonin molecule can easily fit into the serotonin receptor, but not into the dopamine receptors (or any other type of receptor for that matter). Serotonin receptors are designed specifically for serotonin molecules.
When a serotonin molecule attaches to a receptor, which is called receptor binding, the receptor sends chemical information down the dendrite to the cell body of the neuron. The cell body then decides, based on the information from all its receptors put together, whether or not to fire an electrical impulse down its own axon. If a critical amount of receptor binding occurs, then the axon will fire, causing the release of other neurotransmitters into other synapses. This is how your brain communicates, and something like this is happening in your brain at a normal pace all the time.
Research has shown that your mood is influenced in part by the amount of serotonin receptor binding. When you are happy, it is likely that you have more serotonin receptors activated. Positive events in your life (like falling in love, perhaps) cause greater serotonin release, increasing receptor binding. So does taking ecstasy. Serotonin receptor binding is the primary cause of MDMA’s subjective effects.
After a little while, the serotonin molecule will detach (“unbind”) from the receptor and float back into the synapse. When this happens, the receptor stops sending chemical signals to the cell body, and it waits for another serotonin molecule to come along.
(Those yellow things on the membrane of the axon terminal are serotonin reuptake transporters. Don’t worry about them just yet.)
When you Take Ecstasy
When you take ecstasy, the vesicles release enormous amounts of serotonin into the synapse.
When you take ecstasy, the vesicles release enormous amounts of serotonin into the synapse. This significantly increases serotonin receptor binding (more serotonin in the synapse means a greater chance for some of them to bind to the receptors). This increased receptor activity leads to significant changes in the brain’s electrical firing and is primarily responsible for the MDMA experience (i.e. empathy, happiness, increased sociability, enhanced sensation of touch, etc.).
Notice, there is some dopamine in the synapse as well (the blue things). MDMA also causes dopamine release (from dopamine cells), but lets not discuss that yet. Keep it in the back of your mind (no pun intended) because it will come up later when we get into neurotoxicity. For now, just notice that the dopamine receptors have also been activated.
The effects of a normal dose of ecstasy last about four to six hours. We will be looking at what happens in the brain during the various stages of an ecstasy experience as well as some changes that may occur in the brain after long-term, frequent use. But now, let’s take a look at the “reuptake transporters” (those yellow “H” looking things). To understand how ecstasy works over time in the brain, it is important to know what these things do.
Serotonin reuptake transporters
Serotonin reuptake transporters act like revolving doors, scooping up serotonin from the synapse and bringing it back into the axon.
Along with binding to receptors on the dendrite, serotonin molecules also bind to reuptake transporters on the axon. These transporters take the molecule and transport it back into the axon terminal. They are sometimes called “pumps” and can be thought of as a revolving door. The serotonin enters one side, and the door spins around pushing it out the other side. We have shown here four reuptake pumps in various stages of transporting serotonin. Imagine them spinning and transporting serotonin from the synapse back into the axon.
Reuptake transporters reduce the amount of serotonin in the synapse. Keep in mind that these are one-way doors. Serotonin doesn’t go through them the other direction. It can only be released into the synapse from the vesicles. As the reuptake pumps are pulling the serotonin back into the axon, some of this serotonin makes its way back into the vesicles, where the MDMA may cause it to be released again. However, some of it gets broken down by monoamine oxidase.
Monoamine oxidase breaks down your serotonin.
Monoamine oxidase breaks down your serotonin over time.
Approximately three hours into your ecstasy experience your serotonin transporters have removed much of the serotonin from the synapse, but there is still plenty around to activate the receptors, so you still feel the desired effects of the drug. Pretty soon, however, the reuptake transporters will remove most of the serotonin from the synapse, and you will start coming down.
We said in the last slide that some of the serotonin finds its way back into the receptor, where the MDMA causes it to be released again. This is true, but notice the hammers inside the axon. This is “monoamine oxidase” (MAO), an enzyme that breaks down serotonin (serotonin is a monoamine, remember). After your reuptake pumps remove the serotonin, MAO breaks most of it down. MAO doesn’t really look like a hammer, but thinking of it as a hammer that smashes up serotonin molecules is a good way to remember what it does. Notice too that the dopamine receptors are still activated.
When you start coming down
When you start coming down, there is less serotonin around to bind to receptors.
First, notice that the number of activated serotonin receptors has been reduced because there is less serotonin in the synapse. This means you should be starting to feel somewhat normal again. Also, the reuptake pumps are still removing serotonin from the synapse, as usual, and MAO is still doing its job breaking it down. Notice that the dopamine levels in the synapse haven’t lowered as much as the serotonin. This is because dopamine replenishes itself much more quickly than serotonin. Notice also that there is a lot less serotonin in your vesicles this is mainly why you start coming down. Simply put, there’s no more serotonin left to be released. The MDMA may still be around trying to make your vesicles release more, but there isn’t enough there. In about four hours, ecstasy has used up most of your serotonin.
You could take more ecstasy at this point, which a lot of people do. However, this usually doesn’t work. You can’t just take more ecstasy to regain the ecstasy feeling. Why? Because the ecstasy feeling is really a “serotonin feeling,” and you currently don’t have enough serotonin left. (It takes time for your brain to build up more, which we will be discussing soon.) Of course, if you took a lower-than-normal dose, you may not have released most of your serotonin, in which case you may feel the effects come on again if you take more. However, you cannot keep doing this repeatedly all night long. There will come a point (sooner rather than later) when you have depleted your serotonin levels so much that taking more ecstasy will not work.
Coming down some more
After you have come down from ecstasy, you may have less serotonin around than before you took it.
Depending on how much MDMA you took, you may end up depleting so much of your serotonin that fewer receptors are activated than before you took ecstasy, when you were in a normal brain state. This can cause a negative mood and feelings of depression some users experience when they come down. You can become very depressed at this point, feeling extremely non-social, tired and irritable.
Some people at this point are tempted to take more ecstasy because the contrast between how they were feeling an hour earlier and how they feel now is so extreme. But when they take more, it doesn’t work. While it may give the user a little more energy (i.e., increase the speediness), they won’t recapture the empathy and other desirable MDMA effects. Remember, ecstasy releases (and then depletes) the serotonin that you already have. It doesn’t cause more serotonin to be created.
Can these lowered serotonin levels cause depression?
Yes. MDMA use can lead to temporary yet prolonged periods of depression, for a few pharmacological reasons. Perpetually low serotonin levels resulting from weekly MDMA use is one of these reasons. If you take ecstasy on a regular basis, you may be releasing and depleting your serotonin before it has a chance to fully replenish itself. This means you will be operating on lower-than-normal serotonin levels most of the time, and this can lead to depression.
How does your brain make serotonin in the first place? Your serotonin brain cells produce serotonin when an amino acid called 5-Hydroxy-Tryptophan (5-htp) enters the cell and comes into contact with an enzyme called decarboxylese. The decarboxylase strips off a piece of the 5-htp molecule, resulting in 5-ht (another name for serotonin). There is plenty of decarboxylase in your brain cells, but 5-htp levels can vary. Some ecstasy users take 5-htp supplements to restore their depleted serotonin levels more quickly. L-tryptophan is another amino acid that will do the same thing, since it is a precursor of 5-htp. A diet high in tryptophan-containing proteins can also increase the amount of 5-htp in your brain, helping your brain build serotonin more quickly.
Why does it take so long for it to replenish its stores after they have been depleted by MDMA? Normally, it takes a long time for your brain to build serotonin. Why? One reason is that tryptophan must go through a number of metabolic changes before it is turned into 5-htp. Another reason is simply that your brain was not made to make serotonin very quickly. Normally, it doesn’t need to because serotonin is not usually released in very large quantities. As a comparison, dopamine is released in larger quantities under normal circumstances, and your brain is thus built to replenish dopamine much more quickly. Researchers say that the dopamine system is “robust” in this sense, while the serotonin system is “delicate.”
Serotonin Receptor Down-regulation
Down-regulation may lead to depression even after your brain’s serotonin levels have been restored.
Another reason you can become depressed after using MDMA frequently has to do with the down-regulation of serotonin receptors. What does this mean? Well, the brain is built to adapt to changing circumstances. One of the ways your brain adapts is through the up-and-down regulation of receptors. So if your serotonin receptors get hyper-activated by serotonin molecules, they may retreat into the membrane of the dendrite, essentially shutting themselves down for a while. One theory says that they do this in order to avoid getting damaged from over-stimulation. Another theory says that it is just a way for your brain to maintain a balanced, normal state. Whichever one of these theories is true, it has been proven conclusively that serotonin receptors will down-regulate over time if bombarded with large amounts of serotonin.
Down-regulation may lead to depression even after your brain’s serotonin levels have been restored. This is because the serotonin cannot bind to down-regulated receptors. Many ecstasy users report periods of depression that can last many months, even after they have stopped using ecstasy. Keep in mind, however, that these are simply anecdotal reports, and most users do not experience prolonged periods of depression after using MDMA. It could very well be that these people would have been depressed anyway, even if they had not used MDMA. Causality, therefore, is difficult to determine. Nonetheless, it seems likely that frequent MDMA use can exacerbate depression in people who are predisposed to it. For more information on MDMA and depression, see our page MDMA and depression.
How does ecstasy cause the release of serotonin?
MDMA releases serotonin by entering the reuptake transporters
We’ve been neglecting this issue for a while because it would have been confusing to present in the beginning. But now is the time to discuss it. MDMA enters the serotonin axon terminal by going through the reuptake transporters. Researchers say MDMA has a greater affinity for the transporter than serotonin (so does Prozac). This means that the MDMA will be the first thing to get into the axon terminal. Once there, it interacts with the vesicle, causing it to pour its serotonin into the synapse.
Another theory is that MDMA causes the serotonin transporters to work backwards. Perhaps both mechanisms are at work.
Another theory gaining wider acceptance among researchers is that MDMA causes the reuptake transporters work backwards, transporting serotonin from inside the axon directly into to the synapse, without involving the vesicles at all. According to this theory, once the MDMA enters the transporter, it falls off inside the axon terminal, leaving the transporter in such a state that a serotonin molecule now binds to the place where the MDMA fell off. The transporter then spins around and deposits the serotonin molecule into the synapse, where another MDMA molecule binds to where this serotonin molecule fell off.
(Note: The transporter is basically a group of proteins that can change configuration or shape. It doesn’t actually spin. Depending on its configuration, certain molecules are more likely to bind to it. This is called affinity. When a molecule with a high affinity binds to a transporter, it changes the transporter’s configuration, which eventually causes the molecule to unbind or fall off, possibly on the other side. This is what makes the transporter capable of “transporting” molecules between the synapse and the axon.)
Drug or other interactions
Patients should consult their physician before taking any additional prescriptions, over-the-counter medications, nutritional supplements or herbal medications.
Certain medications may interfere with dopamine precursors such as levodopa (also known as L-Dopa). These include:
- Antiseizure drugs
- Dopamine blockers (e.g., antipsychotics, tranquilizers)
- MAO inhibitors
- Certain illegal drugs (e.g., cocaine)
- Vitamin preparations with pyridoxine (vitamin B6) and other vitamins
In addition, a diet that is high in protein or vitamin B6 may prevent levodopa from being efficiently absorbed. Foods rich in vitamin B6 include beans, fish, liver, peas and whole-grain cereals. Protein can delay levodopa absorption. On the other hand, sugar may increase the speed of levodopa absorption. In general, taking levodopa on an empty stomach increases its therapeutic effect, but also increases certain side effects such as nausea. Patients are urged to discuss with their physician how to plan a proper diet while taking dopamine precursors.
Post-acute withdrawal syndrome mechanisms
The specific mechanisms responsible for post-acute withdrawal syndrome are generally a result of the particular drug that a person is withdrawing from. A person experiencing PAWS from benzodiazepines may exhibit deficiencies in the neurotransmission of GABA, whereas a person experiencing PAWS from opioids likely has abnormally low levels of endorphins. If you want to pinpoint some specific mechanisms behind your PAWS, just look at the drug(s) that you were taking.
If you were taking an SSRI antidepressant, chances are that your brain is now failing to produce as much serotonin as it was getting while you were on the drug. In fact, your pre-drug baseline level of serotonin was likely greater than following your discontinuation. This is due to the fact that your brain became reliant on the drug for its serotonin supply and now needs to work harder to manufacture that particular neurotransmitter.
If you were taking multiple drugs, the mechanisms behind your PAWS may get more complicated. Theoretically it could be possible that someone taking high doses of amphetamines and high doses of opioids simultaneously over a long-term may exhibit PAWS as a result of both drugs. In this case, a dopaminergic depression as well as an endorphin depression may be experienced.
Common Herbs With MAO Inhibitor Activity
Research on the physiological basis of psychosis really only began to progress once it was realized that hallucinogens such as LSD and mescaline are serotonin agonists 1. What this means is that these drugs activate the same receptors in the brain that are activated by one of many neurochemical signaling molecules (or neurotransmitters) called serotonin 1. Serotonin normally functions in the brain to regulate arousal. In other words, it controls how awake or asleep you are.
Working under the hypothesis that patients with psychosis might have some internal hallucinogen in their bodies due to the similarities between the drugs' effects and the diseases symptoms, researchers searched for such substances in the blood, urine and brains of psychiatric patients. They were unable to find anything, but they did discover which serotonin receptor specifically caused the drugs' effects (called 5-HT2A). They realized that blocking this specific receptor would stop a psychotic patient's hallucinations and delusions in the same way that blocking it would stop LSD or mescaline from working 1.
Researchers also discovered that some drugs they already used to treat psychosis acted on the dopamine system, another neurotransmitter. One of the functions of dopamine is to inhibit areas of the brain 3. For example, people with Parkinson's disease lose the inhibitory function of dopamine in certain areas, and this leads to the characteristic tremor 13. The anti-psychotic drugs being used blocked dopamine. This did help some symptoms, but what is apparent now is that blocking dopamine too strongly has several negative side effects, such as problems with movement similar to a patient with Parkinson's.
New drugs were discovered that blocked the serotonin system (to stop psychotic symptoms) and left the dopamine system relatively alone (so there were less Parkisonian side effects). These were called “atypical antipsychotics” because of their unusual properties, but they are now the most commonly used antipsychotic medications.
- Research on the physiological basis of psychosis really only began to progress once it was realized that hallucinogens such as LSD and mescaline are serotonin agonists 1.
- New drugs were discovered that blocked the serotonin system (to stop psychotic symptoms) and left the dopamine system relatively alone (so there were less Parkisonian side effects).
“On” and “Off” Periods With Parkinson’s
As your Parkinson’s progresses over the years, you will probably start to notice even though you’re still taking your carbidopa-levodopa regularly, you experience periods where it’s working effectively (aka “on”) and then periods where the medication seems to not be working (aka “off”). When you’re “on,” you should feel like you can move more normally, with less tremor, stiffness and/or slowness. And then when you’re “off,” all those stiff, rigid, slow movements and your tremor return, almost as if your medications have decided to stop working. Frustratingly, it can be hard to predict exactly how long your “on” and “off” periods will last.
“Off” periods are a result of the disease progressing and becoming harder to control through medication. When you first start medication, it’s common to go through a “honeymoon period” of several years, where it’s working well and you can hardly tell you have Parkinson’s. 23 Then, as the condition progresses, your body produces less dopamine, making you more dependent on your dopamine-replacement medication. Over time this leads to more and more instances where the medication is supposed to kick in, or supposed to last for several hours, but is less effective. 31
To manage these “off” periods, your doctor will first make sure you are taking your medication as prescribed — it’s important to follow your medication schedule since it can take time for the effects to fully kick in. You can make things worse by changing the times and dosages without a doctor’s approval. 25 Then, your doctor can start tinkering with your medication, perhaps having you take your levodopa more frequently, or adding a MAO-B inhibitor, COM-T inhibitor or dopamine agonist to try and smooth out the fluctuations of levodopa in your system. 31 However, if you’re trying these strategies and still not able to control or manage your motor symptoms, that’s when it may be time to talk about levodopa-carbidopa intestinal gel (discussed earlier) or deep brain stimulation surgery.
This whole process, from when you start taking medication to when you start considering surgery, can take 10 years or more. 31 Another option some experts suggest is to go for surgery earlier in your disease progression, like within the first three to five years, to potentially avoid having to deal with medication fluctuations and side effects.
Related: This story explains what it feels like to be “on.”
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