The Brain and Neuroscience

Glutamate:

High Count: Brain plasticity improvement by destroying unused pathways,Also can lead to retain negative memories.
Low count: lower brain platicity, lower ability to destroy unused pathways.

Glutamate is necessary for learning and paying attention

Alcohol inhibits Glutamate

 In the laboratory, researchers have found that lamotrigine also inhibits release of 

the neurotransmitter glutamate

Problem: Glutamate sensitivity^

Many factors contribute to the degeneration and death of nerve cells in people with HD. One aspect of HD is that nerve cells are particularly sensitive to glutamate. Glutamate is a neurotransmitter that is used to pass messages along from one nerve cell to another. (For more information on glutamate and HD clickhere.) Researchers have observed that because glutamate receptors in some nerve cells of people with HD are more sensitive than in people without HD, they are activated more frequently than normal receptors. This increased activity and sensitivity to glutamate has been associated with nerve cell death.

One way to prevent the overstimulation of a nerve cell by glutamate is to inhibit glutamate release from the nerve cells that communicate with it. In order to understand this kind of treatment, we must first understand the steps involved in the nerve impulse. (For more information on how nerve impulses work, click here.) It is important that we understand the steps of the nerve impulse because different treatments can be used to inhibit glutamate release by interfering at different steps. A nerve impulse involves receiving a message at one end of a cell and transmitting it via an electric signal to the other end of the cell. Neurotransmitters such as glutamate are stored at the end of the cell and are released in the last step. They act as a chemical signal, transmitting the message to a neighboring cell.

An important step in the electrical transmission of the nerve impulse involves sodium (Na+) channels. Most of the time, charged particles called ions line up along the inside and outside of the nerve cell membrane, giving the membrane a small electric voltage. Many different types of channels are located in the membrane, acting like guards at an exclusive community, only letting certainmolecules in and out. Some of these channels open or close depending on what the membrane voltage is. One of these voltage-gated channels is the sodium channel, and it opens when the inside of the membrane becomes more electrically positive than usual. When the channel opens, sodium ions are free to enter the cell and continue the messaging cascade that ultimately leads to the release of neurotransmitters such as glutamate.

After the sodium channel lets enough sodium into the cell so that it reaches a maximum voltage, the channel temporarily becomes inactivated. An inactivated channel means that not only can no more sodium get through to relay the current message, but also the channel cannot be immediately reset, and thus will let no new messages be relayed. This intermediate stage between open and closed is called therefractory period. The sodium channel returns to the closed position only after the membrane voltage returns to a normal level (restoring the normal voltage involves the exit and entry of different ions). Once the channel is back in the closed position it can be opened again when the voltage rises enough. (See figure L-5 for a representation of the different sodium channel positions.)

Fig L-5: Sodium Channels

How can lamotrigine reduce glutamate release?^

Studies have shown that lamotrigine may inhibit the release of glutamate. While lamotrigine may act in several different ways, it is primarily thought to act as an anti-glutamate drug by interfering with sodium channels. These channels are a necessary step in the nerve impulse and for normal release of glutamate by a nerve cell. In this way, lamotrigine’s inhibition of glutamate release is similar to that of the drug riluzole. (For more information on riluzole click here.)

Lamotrigine exerts its effects during the refractory period by binding to sodium channels. In overactive nerve cells such as in people with seizure disorders or HD, it takes longer for sodium channels to transition from the open period to the inactivated refractory period. An extended open period is what allows so much glutamate to be released in overactive cells. Lamotrigine targets these overactive cells that are slow to inactivate, leaving normal areas of the brain unaffected. Lamotrigine acts by prolonging the inactive refractory period so that sodium channels cannot return to the closed position. Since the channel must first be closed before it can be re-opened, prolonging the inactive period decreases the time of the open period, thus decreasing glutamate release. To put it another way, during the inactive refractory period, no more sodium can get in, so the membrane’s voltage is stabilized. When sodium is kept out, no more messages can be relayed, and thus no more glutamate is released. Therefore, lamotrigine inhibits glutamate release by interfering with sodium channels.

Research on lamotrigine^

Kremer, et al. (1999) recognized that prolonged exposure to glutamate leads to the gradual decline and death of nerve cells in diseases such as HD. They therefore hypothesized that inhibiting the release of glutamate would prevent or at least slow the progression of HD. Lamotrigine is known to inhibitglutamine release in vitro, and has been successfully applied to protect nerve cells in other experiments using animal models. Building on these results, the researchers ran a clinical trial on humans lasting 30 months to see if lamotrigine would slow the progression of HD in people who had experienced physical symptoms for less than five years.

The researchers studied the effects of lamotrigine on 28 people with HD; they also gave a placebo to 27 people with HD to control for psychological effects of treatment as well as to have a comparison group. This was a double-blind study, meaning neither the researchers nor the patients knew which group received the lamotrigine and which received the placebo. (The purpose of a double-blind study is to remove any experimenter or patient bias in evaluating the treatment.) The efficacy of the drug was primarily measured using the total functional capacity (TFC) scale. Patients were also assessed using a variety of cognitive and physical tests.

Over the course of the 30 months of the study, both groups significantly declined in their TFC scores, without any significant difference between the group receiving lamotrigine treatment and the group receiving a placebo pill. This led the researchers to conclude that lamotrigine is not effective in slowing the progression of HD. However, there was slightly less deterioration in terms of the physical symptoms known as chorea in the group receiving lamotrigine. Also, when asked about their various symptoms (mood, physical, etc.), a larger percentage of patients in the group receiving lamotrigine reported an improvement. Despite this perception, both groups declined in their performance on physical tasks. In addition, not much change was observed in the cognitive tests, although the placebo group performed better than the lamotrigine group on one test due to better learning.

Sixteen (of 28) people receiving lamotrigine treatment reported several side effects, including nausea, skin rash, insomnia, and severe depression. Eight (of 27) people receiving a placebo reported mild side effects.

While the study reported the overall inefficacy of lamotrigine, it is important to consider the relatively small sample size and the fact that deterioration varied widely among participants. This is why the researchers have not fully ruled out lamotrigine’s ability to treat early HD. The positive results of the study (decreased chorea and improved symptoms such as mood) may be a result of what lamotrigine is already used for – as an anticonvulsant and mood elevator. A possible reason why the clinical results on humans were not as favorable as those on animals is because the effective dose in animals is much too high for humans to tolerate. Increasing the dose in people is not an option because of the harmful side effects associated with the drug.

Higgins, et al. (2002) also focused on decreasing the amount of glutamate released in nerve cells. Since lamotrigine is known to inhibit the release of glutamate, this group tested the safety of various doses of the drug and how well it was tolerated in HD patients. They conducted an open-label study, meaning that the patients knew they were receiving an actual drug and not a placebo. Over the course of seven weeks the researchers increased the amount of lamotrigine given and then continued giving the maximum dose up to six months. The effects of the drug were tested using the Unified Huntington’s disease Rating Scale (UHDRS) and cognitive tests.

The researchers studied only twenty people with HD and ended up collecting data from fifteen (two people’s symptoms got worse while three people did not report back). The researchers did not find any changes in the UHDRS (this includes motor, functional, and behavioral aspects of HD). However, significant improvements were seen in two parts of the cognitive tests, Verbal Fluency and Symbol Digit Modalities.

Overall, the researchers found that the patients were able to tolerate the drug well and that it was safe to use. They were not able to reproduce the results seen in a previous study that found lamotrigine could reduce chorea. Researchers will need to follow up on this study with a longer lasting investigation that is not open-label and includes more patients.

Inflamatory agents 

The miserable collection of symptoms includes lack of energy, difficulty concentrating, sleepiness, loss of appetite, and general malaise.

For most of us these symptoms disappear within a few days. For some, it takes much longer. Although we tend to blame the influenza virus for making us feel miserable, the symptoms are actually a result of our immune system trying to combat the virus.

The symptoms of the flu are brought on by proteins, pro-inflammatory cytokines, our bodies produce in order to fight the flu and other infections.

When the immune system is under attack from physical injury, infections, or toxins, the immune system generates an inflammatory response. Inflammation is a normal physiological process that is now understood to play a major role in many chronic medical illnesses, including cancer, heart disease, diabetes, asthma, and obesity. In each of these cases inflammation causes the release of cytokines. Cytokines, which come in many different classes, including anti- and pro-inflammatory, behave as messengers and signal cells of the immune system.The effects of pro-inflammatory cytokines can cause a diverse array of physical and psychological symptoms. When this happens it is referred to as sickness behavior.  

Recently, scientists have been able to demonstrate how the symptoms of sickness behavior mirror those of depression. Researchers and health professionals are now beginning to understand the connection between inflammation and depression.

  1. One study found that patients with major depressive disorder had significantly higher levels of the pro-inflammatory cytokine TNF-alpha than their non-depressed counterparts. In addition, patients with depression had low levels of anti-inflammatory cytokines.
  2. Researchers have also found that eight weeks of Zoloft treatment was able to decrease some pro-inflammatory cytokines seen in depressed patients. On Zoloft, the depressed patients also saw an increase in anti-inflammatory cytokines.
  3. A study involving depressed patients classified as non-responders supplemented the patients' standard antidepressant treatment with the addition of aspirin, an anti-inflammatory. More than 50% of these patients responded to this combination treatment. At the end of the study more than 80% of the group responsive to the anti-inflammatory went into remission

GABA: Alcohol, depressants

Alcohol
Opium

Barbituates
Benzodiazapan
non Benzodiazapan

Naturally occuring beta-carboline
coffee seems to stimulate
Wormwood Ultimate GABA agonist

Adenosine: COFFEE

coffee trigonelline quinolinic and pyrogallic acid tannic acid also many antioxidants

Antioxidant [edit]

Coffee contains polyphenols such as flavan-3-ols (monomers and procyanidins), hydroxycinnamic acidsflavonols and anthocyanidins.[47] These compounds have antioxidative effect and potentially reduce oxidative cell damage. One particular substance with putative anticarcinogenic effect is methylpyridinium. This compound is not present in significant amounts in other foods. Methylpyridinium is not present in raw coffee beans but is formed during the roasting process from trigonelline, which is common in raw coffee beans. It is present in both caffeinated and decaffeinated coffee, and even in instant coffee.[48] Research funded by Kraft Foods shows that roast coffee contains more lipophilic antioxidants and chlorogenic acid lactones and is more protective against hydrogen peroxide-induced cell death in primary neuronal cells than green coffee.[17] The espresso method of extraction yields higher antioxidant activity than other brewing methods.[49]


Chocolate: 


Brain Parts:


Cerebral cortex

Association areas [edit]

Association areas function to produce a meaningful perceptual experience of the world, enable us to interact effectively, and support abstract thinking and language. The parietaltemporal, and occipital lobes - all located in the posterior part of the cortex - organize sensory information into a coherent perceptual model of our environment centered on our body image. The frontal lobe or prefrontal association complex is involved in planning actions and movement, as well as abstract thought. In the past it was theorized that language abilities are localized in the left hemisphere in areas 44/45, the Broca's area, for language expression and area 22, the Wernicke's area, for language reception. However, language is no longer limited to easily identifiable areas. More recent research suggests that the processes of language expression and reception occur in areas other than just the perisylvian structures, such as the prefrontal lobebasal gangliacerebellumponscaudate nucleus, and others. The association areas integrate information from different receptors or sensory areas and relate the information to past experiences. Then the brain makes a decision and sends nerve impulses to the motor areas to give responses. [20]

Vision is 30% of cortex, 100s of millions of cells:

"Fifty percent of the brain's pathways are devoted to vision," said Dr. Laura Balcer, study co-author, who added that eye movement provides a window into overall brain function. "By doing this test, we can potentially catch a lot of what's going on with overall cognitive function and how impaired an athlete can be following a concussion."

The test, called "King-Devick," is based on subtle, constant vibration in the eyes, called saccadic movements, which allow them to focus on specific spots. A problem with the eyes' ability to track and focus suggests impairment involving brain pathways.

Corpus Collosum: difference in shape between sexes, when male born w female shape and v.v. gender identity is often reversed


GABA/Glutamate cycle in withdrawal from psychotropics– SSRIs, benzos, and Lamictal

JULY 14, 2010 BY 

This is a response to a post a while back written by Rhiannon Griffith on theGABA/Glutamate cycle as it applies to Lamictal withdrawal and benzodiazepine withdrawal. This article continues with comments in regards to how SSRI withdrawal might be involved. It is written  and submitted Alto Strata who can be found at Surviving Antidepressants.org

update There is now a response to this post here.

As I’ve been suffering from Paxil withdrawal syndrome since October 2004, I’ve studied the medical literature on antidepressant withdrawal syndrome. I am a lay expert on the topic — but I haven’t studied benzo withdrawal per se. What I’ve learned about the glutamatergic system in antidepressant withdrawal syndrome may be informative.

Antidepressants cause downregulation of serotonin receptors. In a mechanism of brain self-defense, the receptors actually disappear, becoming more sparse so as to take in less serotonin. It is thought among withdrawal researchers that people who experience the worst withdrawal are slower than others to repopulate serotonin receptors.

In a parallel action, benzos cause downregulation of benzodiazepine receptors.

Relative slowness to upregulate receptors doesn’t mean there’s anything intrinsically wrong with our brains, it just means there’s variability (of course) among nervous systems.

Even among people suffering the most severe antidepressant withdrawal syndrome, repopulation of serotonin receptors probably occurs long before symptoms disappear. However, while the serotonin system is repairing itself, an imbalance occurs in the autonomic nervous system and the “fight or flight” glutamatergic system becomes more active than normal. This is called disinhibition of the glutamatergic system, and it generates symptoms that are awful: panic, anxiety, sleeplessness, and dreadful imagery among them.

This paper explains the mechanism in withdrawal causing glutamatergic disinhibition: Harvey, et al: Neurobiology of antidepressant withdrawal: implications for the longitudinal outcome of depression;Biological Psychiatry. 2003 Nov 15;54(10):1105-17. The PDF is available at Paxil Progress, if you register to become a member first. Registration is free.

Once disinhibition of the glutamatergic system takes hold, it becomes self-perpetuating. The whole question of neurotransmitter imbalance — a chimera of psychiatry anyway — becomes moot. No manipulation of serotonin, norepinephrine, or dopamine is going to help. In fact, it usually makes the condition worse.

Noradrenergics — buproprion or Wellbutrin; mirtazapine or Remeron; SNRIs such as Cymbalta, Serzone, Effexor; and St. John’s Wort, rhodiola —  and stimulate “fight or flight” activation, as will most SSRIs. Drugs and substances that are stimulating should be avoided.

My guess is: The first phase of withdrawal, the acute phase, is the initial shock of withdrawal, with the most defined symptoms, such as brain zaps and nausea. The second phase is when the serotononergic receptors are repopulating, with waves of depression and anxiety. The third phase is when glutamatergic disinhibition and autonomic instability take over. Often the autonomic instability causes hypersensitivity to drugs and certain supplements.

Out of control, the glutamatergic system sends signals to the adrenals, which produce the stress hormones cortisol and adrenaline.

This is not strictly brain damage. Brain damage means some physical part has been permanently removed and can never be recovered. Rather, this is iatrogenic neuropsychiatric damage. According to established principles of neuroplasticity, the nervous system can repair itself and regain functioning that is close to normal. In cases where there is no apparent iatrogenic cause for autonomic dysfunction, it often spontaneously resolves. Low stress, good nutrition, and as much sleep and gentle exercise as possible are key.

Ironically for those suffering from lamotrogine (Lamictal) withdrawal — too-fast Lamictal withdrawal causing glutamatergic rebound — lamotrigine is the drug that most effectively tempers the activity of the glutamatergic system and incidentally reinforces an intact GABA system. Microdoses of lamotrigine can assist recovery from antidepressant withdrawal syndrome. I am currently taking about 5mg and it is helping me recover.

I am being treated in San Francisco by one of the very, very few doctors in the world who address iatrogenic damage from psychiatric drugs.** If you would like to correspond with me, send me (altostrata) a private message on paxilprogress.org. Paxilprogress is an absolutely non-commercial patient support site for withdrawal from all types of psych drugs, not just Paxil.***

In the medical literature on antidepressant withdrawal, symptoms of glutamatergic disinhibition — anxiety, panic, sleeplessness, irritability, agitation among them– are sometimes misidentified as “unmasking” or emergence of bipolar disorder. It’s always the victim who’s blamed, not the drug. This leads the clinician to medicate with a cocktail of drugs upon which the patient does poorly, the neuropsychiatric damage from antidepressant withdrawal being compounded. In Anatomy of an Epidemic, Robert Whitaker describes this process as the way many children, suffering adverse effects from antidepressants, are led into a lifetime of medications for misdiagnosed bipolar disorder.

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