What does norepinephrine do?

Contents

Neurotransmitters

Neurotransmitters Products

Measuring Neurotransmitter Levels

Neurotransmitter levels can now be determined by a simple and convenient urine test collected at home. Knowing your neurotransmitter levels can help you correct an imbalance today or prevent problems from occurring in the future.

5 Reasons You Should Consider Neurotransmitter testing:

  1. Neurotransmitters control communication throughout your body and brain. Neurotransmitters are complex chemical messengers that coordinate communcation between neruons, which in turn affect every cell, tissue, and system in your body.
  2. Symptoms (and even diagnoses) don’t tell the whole story.
    Although you can articulate a long list of symptoms, you can’t identify the underlying imbalances causing those symptoms. Neurotransmitter testing gives me more information than your symptoms alone can.
  3. You are unique, your symptoms are not.
    Many symptoms, such as fatigue, weight gain, anxiousness, and sleep disturbances can have strikingly different underlying causes. While your poor sleep may be due to low serotonin, someone else’s may be related to high glutamate. Neurotransmitter testing can identify your specific biochemical imbalances.
  4. Complex health conditions require an integrated approach.
    Today’s Diseases of Civilization demand a unified approach that conceptualizes nervous, endocrine and immune functions as an integrated system. Neurotransmitter testing helps me as a clinician uncover adrenal and immune issues that affect proper neural balance.
  5. Testing biomarkers helps us provide customized patient care.
    Most importantly, once we have the personalized, integrated information from your unique lab results, we can better address underlying imbalances. The promise of such an approach is increased care effectiveness and decreased care expenses.

What are Neurotransmitters?

It would be hard to overstate the complexity of the vast network of specialized cells that make up your nervous system. The average human brain houses over 100 billion nerve cells (neurons) with each connected to 10,000 or so other cells which, if you do the math, equals approximately 1000 trillion connections in your brain. This means you have, even on a slow day, roughly 10,000 times more connections in your brain than there are stars in the Milky Way. Everything we do – all of our movements, thoughts, and feelings – is the result of these nerve cells talking with one another via electrical and chemical signals.

Neurons are not in direct contact with each other; in order to communicate with each other, they rely on highly specialized chemicals called neurotransmitters. Neurotransmitters are chemical messengers that coordinate the transmission of signals from one nerve cell (neuron) to the next. These all important brain chemicals interact with target sites called receptors located throughout the brain (and body) to regulate a wide variety of processes including emotions, fear, pleasure, joy, anger, mood, memory, cognition, attention, concentration, alertness, energy, appetite, cravings, sleep, and the perception of pain.

Additionally, neurotransmitters chemically link the brain and spinal cord with the rest of your body: muscles, organs, and glands. Thus, our brain is not only an array of wires (nerve cells/neurons) but also a highly evolved chemical soup (neurotransmitters). Neurotransmitters affect every cell, tissue, and system in your body. And because neurotransmitters are functionally integrated with the immune system and the endocrine system (including the adrenal glands), neurotransmitter imbalances can cause widespread health problems such as:

  • Brain fog – loss of mental focus, ADD, ADHD, impaired memory, poor decision making;
  • Fatigue;
  • Insomnia – difficulty falling asleep, staying asleep, or both;
  • Pain – migraines, fibromyalgia
  • Obesity – metabolic syndrome, insulin resistance, and diabetes;
  • Mood disorders – depression, mood swings, irritability
  • Anxiety – panic, obsessions, PTSD
  • Behavioral disturbances – addictions, binge eating, compulsions impulsivity, gambling, autism; and
  • Hormonal imbalances – PMS, estrogen dominance, low testosterone, hypo-thyroidism.

The good news is that for each neurotransmitter we discover is out of balance, there are usually natural remedies such as vitamins, minerals, amino acids, herbs, or homeopathy that can help restore proper balance.

If you are showing signs of neurotransmitter imbalance, the best thing to do is to get your neurotransmitter levels tested.

Neurotransmitter Balance

Proteins, minerals, vitamins,carbohydrates, and fats are the essential nutrients that make up your body. Proteins are the essential components of muscle tissue, organs, blood, enzymes, antibodies, and neurotransmitters in the brain. Your brain needs the proper nutrients everyday in order to manufacture proper levels of the neurotransmitters that regulate your mood.

Disrupted communication between the brain and the body can have serious effects to ones health both physically and mentally. Depression, anxiety and other mood disorders are thought to be directly related to imbalances with neurotransmitters. The four major neurotransmitters that regulate mood are Serotonin, Dopamine, GABA and Norepinephrine.

When operating properly, your nervous system has natural checks and balances in the form of inhibitory (calming) and excitatory (stimulating) neurotransmitters.

The Inhibitory (Calming) Neurotransmitters

The Inhibitory System comprises mainly GABA and serotonin and serves to, among other things, “cool” your central nervous system engine.

  • GABA (read more about GABA)
  • Serotonin (read more about serotonin)

The Excitatory (Stimulating) Neurotranmitters

Our two principle stimulating neurotransmitters are dopamine and norepinephrine.

  • Dopamine (read more about dopamine)
  • Norepinephrine (NE)(read more about norepinephrine)
  • Epinephrine (read more about epinephrine)
  • Glutamate (read more about glutamate)
  • Histamine (read more about histamine)
  • PEA (read more about PEA)

PEA is an excitatory neurotransmitter made from phenylalanine. It is important in focus and concentration. High levels are observed in individuals experiencing “mind racing”, sleep problems, anxiety, and schizophrenia. Low PEA is associated with difficulty paying attention or thinking clearly, and in depression.

Putting It All Together

Testing of neurotransmitters allows us to identify “upstream” causes of some of the most “downstream” symptoms encountered in contempory society. Without such testing, no matter how educated, we are merely guessing. Personalized treatment requires personalized evaluation of neurotransmitters, and, for that matter, hormones, adrenal output, and inflammation.

If you are showing signs of neurotransmitter imbalance, the best thing to do is to get your neurotransmitter levels tested.

Neurotransmitter Repletion

Neurotransmitter Repletion

Neurotransmitters are the naturally occurring chemicals inside your body that transmit messages between nerve cells. In the brain alone there are 183 different neurotransmitters. Two major neurotransmitters are serotonin and catecholamines, which includes norepinephrine, epinephrine, and dopamine. Although this is the focus of this webpage, sometimes additional neurotransmitters such as acetylcholine, histamine and GABA must be considered in a comprehensive successful program.

For years it has been known in medicine that low levels of Serotonin and/or Norepinephrine can cause many diseases and illness. Some of the diseases and/or illnesses caused by or associated with low levels of Serotonin and/or Norepinephrine include:

  • Depression/Moody
  • Anxiety
  • Panic Attacks
  • Insomnia/Sleep disorders
  • Premenstrual Tension
  • Fibromyalgia
  • Obesity
  • Anorexia
  • Bulimia
  • “Hypoglycemia”
  • Chronic pain states
  • Migraines
  • ADD/ADHD
  • Restless Leg Syndrome

In addition, over 60 diseases and illnesses may be caused by or associated with neurotransmitter deficiency. Low neurotransmitter levels is not only very common, it is epidemic.

“How do the levels of serotonin and catecholamine neurotransmitters get to such critically low levels?” There are several explanations.

  • The first is that neurotransmitter depletion is nutritionally based. Neurotransmitters are made from amino acids that must be obtained from protein in the diet. In addition, amino acids, vitamins and minerals eaten in food are required for the creation of the neurotransmitters. If the diet is deficient, neurotransmitter deficiency develops.
  • There are multiple medications that have shown to cause depletion of serotonin and/or catecholamine in the urine. These are the medications prescribed to increase the activity of serotonin in the brain such as fluoxetine (Prozac, Sarafem), paroxetine (Paxil), sertaline (Zoloft), Luvox, Citalopram (Celexa), Lexapro, etc. Apparently as a result of increasing the brain level of serotonin, the body increases the metabolism of serotonin and thus the levels slowly decline because these medications do nothing to increase the level, they just re-circulate the already low level. The same holds true for medications that block the re-uptake of serotonin and catecholamines such as Effexor, Cymbalta, and Pristiq.
  • It has been suggested that several SSRI medications deplete 40-60% of the serotonin receptors in the brain. It is also reported that receptors in the liver, kidneys, and colon are also damaged by SSRIs.
  • Caffeine, ephedrine, ephedra, guarana, and other stimulants including Ritalin, chocolate, etc. also seem to reduce the effectiveness of neurotransmitters thereby creating a resistance to neurotransmitters. Phentermine (of the Phen-Fen diet) actually cause long-term damage to the receptor so that in order to get the effect of serotonin, you have to have an even higher level. This is why so many people gain even more weight after stopping Phen-Fen.
  • Sensory overload. The brain is bombarded by sounds, rapid visual effects from television, movies, electronic monitors flickering faster than the eye can detect, radio waves, fluorescent artificial light, etc. All of this requires the brain to modulate this sensory bombardment so that you can stay focused on the task in front of you. Brain overload means that you have to literally calm yourself down.
  • Rapid lifestyle, stress, over work, chronic pain, etc. may also contribute.
  • Since the largest source of neurotransmitters is the gastrointestinal tract, dysfunction as discussed above could be a major contributory component. This would include congestive bowel toxicity, Candida/yeast overgrowth conditions, increased intestinal permeability (leaky gut syndrome), IBS, & inflammatory bowel.
  • John A. Allocca, M.D. lists a variety of additional mechanisms by which neurotransmitters are lost: ingestion of various food allergens or sensitivities, inhalation or ingestion of various chemicals, chemical sensitivities, rapid changes in hormone levels, rapid changes in barometric pressure, head cold or sinus congestion, rapid changes in blood sugars, dehydration, inadequate exposure to sunlight (hence the excessive conversion of serotonin to melatonin), and hepatobiliary dysfunction. These remarks may be based on the precipitation of migraines, which Dr. Allocca assumes to always be related to serotonin imbalance.

MIXED NEUROTRANSMITTER DYSFUNCTION/DEPLETION

Providing the body with ingredients to make just one neurotransmitter (either serotonin or catecholamines) does not produce uniform results in all patients. It has been the experience of NeuroResearch in treating a group of 100 patients for a given disease with just 5-HTP, only about 10% to 15% will get “good relief”. Overall 30% to 40% of patients will get “some relief” and the majority (60% to 70%) will get “no relief.”

This observation led Dr. Hinz to formulate “Mixed Neurotransmitter Dysfunction Theory.” Five percent of patients with a given neurotransmitter dysfunction disease are purely a serotonin dysfunction, 5% of patients are a purely catecholamine dysfunction, and the remaining 90% of patients are a mixture of both serotonin/catecholamine dysfunction and lie along a spectrum between the two extremes.

This implies for the vast majority of patients with a neurotransmitter related condition, the serotonin system and the catecholamine system (dopamine, norepinephrine, and epinephrine) must both function properly for the entire system to be healthy and free of neurotransmitter disease. This appears to be reflected in urine neurotransmitter testing by the fact that patients with dysfunction of the catecholamine system tend to need higher serotonin levels to compensate and obtain a clinical response.

NEUROTRANSMITTER DEFICIENCY

The treatment methods of Marty Hinz, M.D. for neurotransmitter dysfunction have not only been helpful for patients in whom other methods of treatment haven’t worked, but also for patients with almost any one of the symptoms due to neurotransmitter deficiency.

Afternoon urine specimens have been shown to be a useful indicator of catecholamine and serotonin levels but require proper timing and collection to be of value. According the Dr. Hinz, the urine levels seem to reflect brain levels. Some interpretation is required since high urine levels may indicate excessive loss of the neurotransmitters due to medications, etc. Testing is not done before treatment since it can be confusing and mis-leading. Urine testing during therapy may be necessary for monitoring the proper dosage of neurotransmitter repletion.

PHARMACEUTICAL DRUGS: NOT THE ANSWER

If you have neurotransmitter deficiency, most likely you have been given a medicine that will reduce the symptoms but are not curative. Although effective to some degree in reducing symptoms, in the long run the medications can actually make the underlying neurotransmitter deficiency worse. For example, if you have depressive symptoms caused by low levels of serotonin, taking a “SSRI” medication such as Prozac, Zoloft, Celexa, or Paxil is merely tricking the brain into thinking that it has more serotonin. These medications merely interfere with the body’s normal metabolism of serotonin and do nothing to correct the real cause, which is not a neurotransmitter metabolism problem but rather a deficiency of the neurotransmitter itself. These medications do not stimulate the production of more neurotransmitters. In fact there is solid scientific evidence that they accelerate the depletion of the neurotransmitters over time. This is why many of these medications only work for a short time and then stop being effective. The Neurotransmitter Repletion program pioneered by Dr. Hinz actually enables the body to make more serotonin and other neurotransmitters that naturally corrects the cause of the problem.

The SSRI medications are designed to work just on a very specific part of the brain. While this may temporarily correct the deficiency in that one location, what about the rest of the body’s need for serotonin and catecholamines? There are receptors for these important chemicals throughout the entire body. Medications don’t address the deficiency in these areas, but the neurotransmitter repletion will give the entire body what it needs.

WHAT NEUROTRANSMITTER REPLETION CAN DO

From the Hinz, MD experience in thousands of patients using the same products and program that we have available, he reports…

  • For most patients with migraines, we can get rid of them completely.
  • For people taking medications for migraines, we can get most patients off the medications completely.
  • For patients with depression where the medication quit working, we can get most feeling normal again.
  • For patients with depression where no medications have seemed to work, we can help most.
  • For patients with depression who want to get off their medications, we can help most.
  • Patients with fibromyalgia and chronic pain benefit greatly. Most can stop some or all of their medications soon after treatment starts.
  • In patients with insomnia, most are sleeping 5 to 8 hours a night after the first 3 to 4 weeks of treatment.
  • Most patients with panic attacks find their symptoms are gone in the first month.
  • Most patients find PMS symptoms are much better or completely gone.
  • Chronic anxiety resolves for most patients.
  • For patients with “complex appetite”, we have the only known effective cure.
  • A medical weight management program that is 75-90% successful in reaching the goal weight in participants who also follow the dietary program.

With the exception of treating weight problems, most patients should have their problems brought under control and be free of symptoms in less than 4-6 weeks. Below are some notes from Dr. Hinz’ experience on specific symptoms related to neurotransmitter insufficiency.

Migraine Headaches: In patients with true migraine headaches who have suffered for years, treatment with the process outlined in our patents is remarkable to say the least. Over 95% of patients have no more migraine headaches within 1 to 2 days of starting treatment! Imitrex is a popular and effective medicine for short term relief of migraine symptoms but does not cure the disease nor can it be used to prevent the onset of a migraine. Imitrex is also very expensive. It is not uncommon to see patients taking $200 to $300 or more in Imitrex each month. NeuroReplete programs completely resolves migraine headaches in the first few days of treatment for most people and is less than 1/3rd the cost. It also solves many other conditions related to neurotransmitter insufficiency.

Depression: The evidence is very convincing that low levels of brain serotonin and/or norepinephrine cause depression. Current medicines used by doctors to treat depression work by redistributing serotonin and/or norepinephrine effectively tricking the brain into thinking it has more neurotransmitters, but there is none. They do nothing to increase the amount of the depleted neurotransmitters in the body and thus do nothing to actually correct the underlying cause of the problem. In fact in the long run, they can actually make the underlying problem of low Serotonin and/or Norepinephrine levels lower and worse. For example, there are many stories told by doctors of patients treated for depression with medicines where the medicine worked well initially, but then one day the patient literally woke up and found the medicines were no longer working but they had to stay on the medicine anyway to keep from feeling even worse. Another type of patient is depressed and medicines simply do not work. In both these circumstances, the patented treatment approach has been highly effective in getting them to feel normal once again without medications

Depression is generally divided into two categories. They are “Exogenous depression” and “Endogenous depression”.

  • Exogenous Depression develops as a reaction to events that happen in the environment around the patient, a sort of situational condition. Dr. Hinz describes the following as an example of exogenous depression, “if your house burns down, your car blows up, and your dog dies all in one day you may feel depressed for a time”.
  • Endogenous depression can appear to start for no particular reason. In many cases, the patient literally wakes up one day to find that he/she is not functioning normally due to depression. Low levels of serotonin and/or norepinephrine in the body causes endogenous depression.

Diagnosis of depression is made using the DSM IV criteria. In diagnosing patients, proper laboratory work-up for thyroid and anemia should be preformed. If 5 of the following 8 items are present for 2 or more weeks, the diagnosis of depression can be made.

  • Change in appetite or weight
  • Sleep disturbance
  • Psychomotor retardation or agitation
  • Loss of energy
  • Decreased ability to concentrate
  • Loss of self worth
  • Decreased interest in daily activities
  • Depressed mood almost every day
  • Suicidal ideation

“Severe depression” is life-threatening depression where the patient is contemplating suicide and this necessitates the referral to a psychiatrist immediately. One study showed that virtually all suicides had been seen by a physician within the previous 7 days. Refractory depression is defined as patients treated with prescription drugs where there is no clinical response. The cause of this problem is simple – “Drugs that work with neurotransmitters do not work if there is not enough neurotransmitters to work with…” In the abstract of a May 2000 Journal of Clinical Psychiatry article by Dr. Delgado (The Role of Norepinephrine in Depression), “Norepinephrine-selective antidepressant drugs appear to be primarily dependent on the availability of norepinephrine for their effects. Likewise, serotonin-selective antidepressants appear to be primarily dependent”. In refractory depression where the drugs quit working, the problem is that the level of neurotransmitters has dropped below the critical level needed the patient to be healthy and disease free and below the level for the drugs to work.

Fibromyalgia: Fibromyalgia is a descriptive term and not really a disease itself. The hallmark of fibromyalgia is chronic pain in muscle and fibrous tissue points throughout the body. There has been no real cure identified for fibromyalgia and treatment has centered on use of multiple medications for partial symptom management and counseling such as support groups. Neurotransmitter Repletion has proven to be extremely effective and economical, and in most cases patients gradually quit taking all other medications for fibromyalgia. One clinic in Kansas using the same methods treated employees of the state of Kansas who had fibromyalgia. Results were so good that the program is covered by insurance for State of Kansas employees.

Insomnia: Using the definition of severe insomnia as “sleeping less than 4 hours a night with frequent wake ups of 20 minutes or more” and including those people who simply do not sleep well at night encompasses a broad range of sleep disorders. The issue of poor sleep is such a large problem that in larger cities many hospitals have sleep clinics. Medications used for sleep obtain marginal results at best and sleeping pills on a chronic basis are not the answer. Correction of sleep problems with Neurotransmitter Repletion usually takes two to four weeks but results are spectacular in most. Patients sleeping only 2 to 3 hours a night with frequent wakeups find they are sleeping five to eight hours a night without waking up, and they report feeling better than they have in years.

Panic Attacks: The hallmark of panic attacks is “an abrupt onset of an impending sense of doom”; the sudden feeling that something bad is going to happen even though there is nothing going on. Many times people with panic attacks will also have agoraphobia, which is the fear of going into public or open places, or other fears. In medicine, for years these have been very hard things to treat effectively. Typically the patient is placed on multiple medicines, which do nothing more than mask the symptoms. Neurotransmitter Repletion has proven to be very effective in actually getting rid of the disease and the symptoms, and in the process, getting patients off the medications.

Premenstrual Syndrome: PMS are experienced by many women in the five to seven days prior to the onset of menses. In some women these monthly symptoms can be severe enough to be disabling and include water weight gain and emotional changes. In one of the more severe cases of PMS we have worked with, the patient would gain 17 pounds in fluid retention and went through extreme changes in personality and emotions. Although some approach PMS with hormones primarily, even hormones (as well as other medications) are merely masking the problem and treating the symptoms without curing the underlying disease. Using methods outlined under the patents has proven to be very effective.

Attention Deficit and Hyperactivity Disorder: Over the last several years, Dr. Hinz has collected ample data that ADHD kids show a pattern of hyperexcretion of neurotransmitters (the kidneys are literally dumping neurotransmitters and depleting the system). Approximately 86% of the kids dump serotonin and 40% dump norepinephrine. Dr. Hinz however has not collected data about the clinical response in ADHD, i.e. “How many kids get better?” “What is the average group dosing to get better?” etc. Following Dr. Hinz lead, our attitude is that “pharmaceutical grade amino acids are safe” under the guidance of a knowledgeable health professional.” If your give kids with ADHD, a trial of neurotransmitter repletion and they improve it suggests that neurotransmitters are involved in that particular child’s case and you are not going to hurt anyone or interfere with other medications. E-mail correspondences from other medical doctors and patients often talk about dramatic beneficial effects of neurotransmitter repletion in ADHD. In fact, there are so many compelling reports that we feel it is worthy of trying even before a formal ADHD study is completed and reported. For now, all we have to go on is anecdotal evidence that in the treatment of ADHD, neurotransmitters are safe and often very effective.

Anxiety: Up until a few years ago, the intense and inappropriate anxiety that interfered with day-to-day activities was treated with tranquilizers. In medicine today, most anxiety is treated with SSRI medications like Prozac, Zoloft, Paxil or Celexa. As noted before, these drugs merely trick the brain into thinking it has more neurotransmitters and does nothing to actually correct the problem. Anxiety, even if it has plagued you for a long time, methods used under the patents may help.

Complex Appetite: Most people have never heard of this problem, but many people suffer from it. Appetites can be categorized into one of two categories:

1. Regular appetite, these are people who can go all day without eating and not experience symptoms. A person with a normal appetite will only consume (on the average) enough calories to maintain their ideal body weight. This is about 10 calories for every pound (Ex: a 150 pound adult should consume on the average 1500 calories/day). Any ongoing intake above 10 calories/pound/day is excessive and suggests an imbalance in the brain centers that control appetite.

2. Complex appetite, these are people who when they do not eat every few hours during the day experience many different symptoms. In some, the label of hypoglycemia has been applied. When diagnostic tests such as the oral glucose tolerance test is performed, there is in fact no hypoglycemia found. The symptoms however are real and may be due to neurotransmitter deficiency. The following is a list of some of the symptoms people with “complex appetite” experience. In general, most patients that we have seen experience only 3 or 4 of the symptoms on the following list, but for many people these symptoms can cause the patient to not only feel bad but they can also interfere with daily activities:

Symptoms seen in complex appetite (misnamed “hypoglycemia”)

Tremor

Dizziness

Nausea

Goose bump skin Headaches

Sweating

Anxiety

Feeling of uneasiness

Lightheadedness

Irritability

Disorientation

Abdominal pain

Patients with a “complex appetite” are often mistakenly labeled by doctors as having hypoglycemia based primarily on the fact that the symptoms got better when the patients ate something. This is NOT hypoglycemia, it is a neurotransmitter deficiency and while “complex appetite” can occur in patients of any weight, patients who are overweight and suffer from “complex appetite” are very much compromised. Whenever they try and diet by eating less food, the complex appetite symptoms get worse. Typical of complex appetite patients is if they do not eat something every 3 to 4 hours they experience symptoms such as headache and tremor. This was can be a very real problem, especially during school, long business meetings, travel, etc. Many patients keep candy with them in case they begin to experience symptoms. The patented treatment method can be very effective in resolving “complex appetite” symptoms.

Obesity and Eating Disorders: Of all the neurotransmitter deficiency diseases, obesity and eating disorders need the most intensive treatment. Treatment of obesity and weight problems is something has not really been truly mastered, but the Hinz program does work with remarkable success. At present, there are over a 100 clinics around the United States using this weight management program. Results of his weight management program are impressive. The average group weight loss the first month is 16.9 pounds and over 90% of patients starting the program make their goal weight and stay there with long-term maintenance.

REPLENISHING NEUROTRANSMITTERS

Make no mistake serotonin and catecholamines come from only one source. The amino acids, vitamins, and mineral we eat are converted to neurotransmitters. Eat a diet deficient in these things and you will have a neurotransmitter deficiency. The following foods are serotonin-rich: avocado, banana, red plum, tomatoes, pineapples, eggplants, walnuts, and possibly coffee.

However, it is not a simple as eating the right foods. From our database we know that prolonged dietary deficiency requires amino acid intake higher than normal food levels can give. Dr. Hinz reports that neurotransmitter repletion excels in patients in whom medications do not work, “the refractory patient” and it is safe to use with prescription medications. In most cases patients with refractory depression finds that their depression lifts in 3 to 4 weeks. It is his recommendation that 4-6 weeks after the patient begins to experience relief; any medications the patient takes should gradually be tapered by every 2 to 4 weeks.

Since all neurotransmitters are made up of proteins, the diet must contain adequate amounts of protein. Because tryptophan is the amino acid from which serotonin is produced, patients who have mixed neurotransmitter dysfunction probably do not get enough of tryptophan in their diet. Because tryptophan has other uses besides formation of neurotransmitters, using Dr. Hinz’ Neurotransmitter Repletion program alone is not enough to regain mental and physical health. Note in the diagram below that only 2-10% of the tryptophan is metabolized into serotonin, the majority is needed for other proteins and vitamin synthesis. Also note that the vast majority of serotonin is produced in the gut. Thus, a healthy gastrointestinal tract is also required for mental health. Your success with any condition related to neurotransmitters requires more than just taking the NeuroReplete products; you must eat and digest enough high quality protein and have a healthy gastrointestinal tract!

Side Effects of Neurotransmitter Repletion

The undesirable effects of neurotransmitter substrate use include GI upset and on rare occasions drowsiness. Other undesirable effects as reported by Dr. Hinz include:

GI Upset: By far the most come side effect is GI upset. GI upset is divided into two groups “start up” and “carbohydrate intolerance”.

  • Start-up GI upset occurs at the rate of about 1 in every 150 patients and occurs with the first dose and gets worse with every dose until about the third day. At this point the patient can tolerate it no more and stops the program. Apparently the patients who experience this problem in general are the most serotonin depleted. All patients need to be warned about this problem at initiation of therapy to avoid drop out. The problem is best managed by restarting the patient on only one capsule at bed time and increasing the dosing after 3 to 4 days of no symptoms, with subsequent increases in until the normal dosing is achieved in 3-4 weeks.
  • Carbohydrate intolerance. GI upset that develops after the patient has been on neurotransmitter substrates was very difficult to pin down. Up to 70% of patients report periodic GI upset. Although they tended to blame this GI upset on the capsules, it was unrelated to the supplements. What appears to occur is a carbohydrate intolerance that had is uncovered with treatment. Once this is understood and patients are properly educated, the incidence in the database went from 70% to 0.6%. If a patient, who is one or more weeks into treatment, begins to experience GI upset 2 to 3 hours after eating, they should be instructed to remember what they just ate. Usually it is easy to identify the carbohydrate causing the problem. In many cases, it is a favorite food that has been eaten for years.
  • Repletion Pass-throughs: For some patients, a certain level of neurotransmitters provokes certain symptoms. For example – let’s say at a level of 10 you experience panic-like symptoms, at a level of 20 you have anxiety, at 30 perhaps depression, at 40 migraines for example, and normal function between 50-75. If you start out at 15 with anxiety and near panic like symptoms as you take the NeuroReplete, etc. your level will increase to 30 and you may have depression or whatever your unique metabolism expresses at this level. As you continue to the repletion program, the level of neurotransmitter will increase and the depression should resolve. You may have no other symptoms or you may develop TEMPORARY symptoms at another sub-therapeutic level. The important thing to remember is that with continued or increased doses the symptoms will resolve on your way to normal neurotransmitter levels and health.

Dosage: The mainstays of therapy are two supplement groups

    • Neuro-T Supply or NeuroReplete (to balance catecholamines and increase serotonin)
    • GSH Boost or L-Cysteine (to increase catecholamine synthesis or when using Mucuna)
  • Although it was originally recommended for these to be taken on an empty stomach, they can be taken with or without food. Best results are seen when the products are taken throughout the day (breakfast, lunch, dinner, and bedtime if you go to sleep late). Start off slowly and increase the dosage. In general the maximum dosage of Neuro-T Supply or NeuroReplete is 16 capsules a day.

Neurotransmitter Systems in Autism Spectrum Disorder

4. Serotonin

Serotonin is a neuromodulator which acts as a developmental signal . Serotonin is synthesized by the enzyme triptophanhidroksilase which convert triptpohan to 5-hydroxy-tryptophan, and decarboksilation at the end . Serotonin neurotransmitter system has critical role in the regulation of crucial steps of neuronal development such as cell proliferation, differentiation, migration, apoptosis synaptogenesis, neuronal and glial development . Serotonin system in the prefrontal cortex and temporal cortex regulates GABAergic inhibition, therefore it has played a role in the regulation of many aspects of cognitive functions .

Serotonin plays an important role in the development of social skills during gestational period and early childhood. Inadequate stimulation of serotonin in the early stages of life, can lead to the unpreventable abnormalities in serotonin metabolism in subsequent period of life. These defect may cause permanent problems in serotonin metabolism in people who have been deprived serotonin effects necessary for the brains especially early developmental stages of life. This is why, adequate levels of serotonin are necessary for the development of close relationships and social skills in the early stages of life . Social skills and behavior have been shown to be associated with hippocampal neurogenesis in ASD individuals and because of that hippocampal abnormalities are found frequently . Serotonin play a central regulating role in serotonin dependent neurogenesis activity in the hippocampus .

Pathophysiology of ASD has two main hypothesis for serotonin neurotransmitter systems, just like glutamate hypothesis. One widely accepted for a long time and confirmed for many times is hyperserotonin state and while the other one is hyposerotonin hypothesis which became prominent in recent years . Two main findings of hyperserotonin hypothesis in patients with ASD are increased blood serotonin levels (my hiperserotone) and decreased brain serotonin levels . The presence of hyperserotonemia in 25 to 50% of individuals with ASD is important to showing they may have abnormalities in the serotonergic pathway .

Furthermore, first-degree relatives of individuals with ASD found to have hyperserotonemia, as well as parents of these kids more often showed the presence of serotonin associated psychiatric disorders, such as depression and obsessive-compulsive disorder . Other supportive evidence, brain serotonin level decreased and exacerbation of many repetitive behavior was observed (such as spinning, stepping, self-hit and shoot) with tryptophan poor diet (low-tryptophan diet) . Serum levels of tryptophan to large neutral amino acid ratio was shown to be decreased in children with ASD. This rate is an indicative of presence of tryptophan for serotonin synthesis in the brain and this lower ratio demonstrate low tryptophan usability which might suggest one of the mechanisms associated with serotonergic dysfunction in ASD . Another study demonstrated, after L-5-hydroxytryptophan administration young people with ASD, their blood serotonin levels increased, whereas in control group no difference was seen .

Severity of at least one specific behavioral problem in ASD is reported to be associated with 5HT1D receptor sensitivity . Various studies have reported controversial results regarding association of serotonin transporter gene in ASD. In contrast, in accordance with the data regarding the transfer of serotonin transporter gene polymorphic alleles associated with the findings of the degree of the social and communicative deficits, these alleles instead of being risk factor for ASD they might change the severity of clinical presentation in autistic children .

Shown correlation between ASD and serotonin transporter gene and found mutations in genes encode rate-limiting enzyme in the catabolism of L-tryptophan such as 2,3 dioxygenase gene is thought to be responsible for increased serotonin levels . There might be defect in the development of the serotonergic system in patients with ASD. Normally, the serotonin neurotransmitter system follows a pattern of age-related development, for example, developmental studies of serotonin receptor binding in monkeys showed that increment during infancy and throughout childhood, a prepubertal peak, and eventually slowly reduction during adolescence and early adulthood . In humans at 6 year of age serotonin receptor binding is higher than neonatal period or 13-14 year of age . This dynamic changes are impaired in ASD, at the beginning of childhood low serotonin levels are observed compared to normal baseline, but steadily increased from 2 to 15 years of age and reaches higher than adult levels . In various animal models when effect of higher levels of serotonin investigated particılarly in the development of somatosensory system, the deterioration in the formation of thalamo-cortical sensory circuits were observed . Recently “ASD is a hyposerotonergic condition” hypothesis is worth to discuss. In a study of volunteer postmortem brain tissue of ASD patients examined, and the increase in number of serotonergic axons were observed .

This situation cannot be explained by the hypothesis of compensatory mechanisms which expected to result reduction of serotonergic axons in hyperserotonergic state . In men with ASD, in one side of the brain of frontal region and thalamus, typically synthesis of serotonin was reduced, in opposite side of the brain of cerebellum, and dentate nucleus serotonin has been shown to be increased .

Several PET and SPECT studies in individuals with ASD has shown serotonin transporter binding amount decreased significantly in various brain regions (frontal cortex, cingulate, thalamus, etc..) . Other study was exhibited that low levels of blood serotonin in mothers of children with ASD compared to normal developing children’s mother . In another study, individuals with ASD were shown to have low levels of gene responsible for synthesis of serotonin . Serotonergic drugs, the main symptoms of ASD respond less to treatment, but some are partially effective in the symptomatic treatment of patients with autism. These drugs include selective serotonin reuptake inhibitors (selective serotonin reuptake inhibitör=SSRI), 5-HT 2A receptor antagonists, tricyclic antidepressants and receptor antagonists (dopamin/5-HT) mix.

Mechanism of action of these treatments are unknown, but they are thought to act on the developmental defects in serotonergic pathways such as serotonin synthesis, catabolism, and transport-related dynamic abnormalities .

As a result, the highest level of evidence for ASD relationship with monoamines is the serotonergic system. Hyperserotonemia in peripheral blood in individuals with ASD, despite the presence of opposite results, has been shown to be present in many studies. Low levels of serotonin in the brain tissue is the common finding of hyposerotonergic and hyperserotonergic hypothesis. Future studies will enlight reson for lower serotonin levels in the brain tissue and will open new horizons both for diagnosis and treatment.

What Is Norepinephrine?

Low levels of this hormone have been shown to play a role in ADHD, depression, and low blood pressure.

Norepinephrine is a naturally occurring chemical in the body that acts as both a stress hormone and neurotransmitter (a substance that sends signals between nerve cells).

It’s released into the blood as a stress hormone when the brain perceives that a stressful event has occurred.

As part of the body’s response to stress, norepinephrine affects the way the brain pays attention and responds to events. It can also do the following:

  • Increase heart rate
  • Trigger the release of glucose (sugar) into the blood
  • Increase blood flow to muscles

As a neurotransmitter in the central nervous system, norepinephrine increases alertness and arousal, and speeds reaction time.

Norepinephrine has been shown to play a role in a person’s mood and ability to concentrate.

Low levels of norepinephrine may lead to conditions such as attention deficit hyperactivity disorder (ADHD), depression, and hypotension (very low blood pressure).

Norepinephrine and ADHD

Norepinephrine and dopamine, another neurotransmitter, help people pay attention and focus in the course of their daily activities.

Low levels of these chemicals in the brain may make it harder to focus, causing symptoms of ADHD.

According to the American Academy of Child and Adolescent Psychology, ADHD can affect areas of the brain that help you solve problems, plan ahead, understand others’ actions, and control impulses.

The following medications can help raise levels of norepinephrine and dopamine in the body, helping you focus:

  • Ritalin or Concerta (methylphenidate)
  • Dexedrine (dextroamphetamine)
  • Adderall (amphetamine and dextroamphetamine)

Strattera (atomoxetine), another drug prescribed for ADHD, only raises levels of norepinephrine, not dopamine.

Norepinephrine and Depression

Depression is a serious medical condition that negatively affects how a person feels, thinks, and acts.

People with depression may be prescribed a class of drugs called serotonin-norepinephrine reuptake inhibitors (SNRIs).

These drugs raise levels of norepinephrine and serotonin, another neurotransmitter, in the brain.

Commonly prescribed SNRIs include:

  • Effexor (venlafaxine)
  • Cymbalta (duloxetine)

Another group of drugs called tricyclic antidepressants may also be prescribed to increase the activity of norepinephrine in the brain.

But these drugs often cause unwanted side effects, such as sedation, dry mouth, constipation, blurred vision, and weight gain.

Norepinephrine and Low Blood Pressure

Norepinephrine is sometimes given intravenously (by IV) to treat hypotension (very low blood pressure) in emergency situations.

Hypotension is usually a sign of shock. One form is septic shock, in which toxins from an infection cause a whole-body inflammatory response.

Another form of shock is neurogenic shock, in which nerve signals throughout the body are disrupted, often due to a spinal cord injury.

Having low pressure can cause you to become dizzy or faint, or — in extreme cases — can damage your heart or brain.

Levophed (norepinephrine bitartrate) is a form of norepinephrine that’s administered in an intensive-care facility through a vein.

Emotional enhancement of memory: how norepinephrine enables synaptic plasticity

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Norepinephrine

Generic Name: norepinephrine (nor ep i NEF rin)
Brand Name: Levophed, Levophed Bitartrate

Medically reviewed by Drugs.com on Jun 28, 2019 – Written by Cerner Multum

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What is norepinephrine?

Norepinephrine is similar to adrenaline. It is used to treat life-threatening low blood pressure (hypotension) that can occur with certain medical conditions or surgical procedures. Norepinephrine is often used during CPR (cardio-pulmonary resuscitation).

Norepinephrine may also be used for purposes not listed in this medication guide.

Important Information

Tell your caregivers at once if you have a serious side effect such as a cold feeling anywhere in your body, blue lips or fingernails, trouble breathing, little or no urination, irritation or skin changes where the medicine was injected, slow heart rate, sudden numbness or weakness, severe headache, or problems with vision, speech, or balance.

Before taking this medicine

If possible before you receive norepinephrine, tell your caregivers if you have:

  • high blood pressure (hypertension);

  • diabetes;

  • coronary artery disease;

  • circulation problems;

  • varicose veins;

  • overactive thyroid; or

  • asthma or a sulfite allergy.

Tell your doctor if you are pregnant or breastfeeding.

In an emergency, you may not be able to tell caregivers about your health conditions or if you are pregnant or breastfeeding. Make sure any doctor caring for you afterward knows you received norepinephrine.

How is norepinephrine given?

Norepinephrine is given as an infusion into a vein. A healthcare provider will give you this injection.

Norepinephrine is usually given for as long as needed until your body responds to the medication. Some people must receive norepinephrine for several days.

Your blood pressure, breathing, and other vital signs will be watched closely while you are receiving norepinephrine.

Tell your caregivers if you feel any pain, irritation, cold feeling, or other discomfort of your skin or veins where the medicine is injected. Norepinephrine can damage the skin or tissues around the injection site if the medicine accidentally leaks out of the vein.

What happens if I miss a dose?

Since norepinephrine is given by a healthcare professional in an emergency setting, you are not likely to miss a dose.

What happens if I overdose?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Overdose symptoms may include slow heartbeats, severe headache, sweating, vomiting, increased sensitivity to light, pale skin, and stabbing chest pain.

What should I avoid while receiving norepinephrine?

Follow your doctor’s instructions about any restrictions on food, beverages, or activity.

Norepinephrine side effects

Get emergency medical help if you have signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Tell your caregivers at once if you have:

  • pain, burning, irritation, discoloration, or skin changes where the injection was given;

  • sudden numbness, weakness, or cold feeling anywhere in your body;

  • slow or uneven heart rate;

  • blue lips or fingernails, mottled skin;

  • little or no urination;

  • trouble breathing;

  • problems with vision, speech, or balance; or

  • severe headache, blurred vision, pounding in your neck or ears.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

What other drugs will affect norepinephrine?

If possible before you receive norepinephrine, tell your doctor about all your other medicines, especially:

  • an antidepressant;

  • blood pressure medication; or

  • an MAO inhibitor–isocarboxazid, linezolid, methylene blue injection, phenelzine, rasagiline, selegiline, tranylcypromine, and others.

This list is not complete. Other drugs may affect norepinephrine, including prescription and over-the-counter medicines, vitamins, and herbal products. Not all possible drug interactions are listed here.

Further information

Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.

Copyright 1996-2018 Cerner Multum, Inc. Version: 5.01.

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Impacts of Drugs on Neurotransmission

Drugs can alter the way people think, feel, and behave by disrupting neurotransmission, the process of communication between neurons (nerve cells) in the brain. Many scientific studies conducted over decades have established that drug dependence and addiction are features of an organic brain disorder caused by drugs’ cumulative impacts on neurotransmission. Scientists continue to build on this essential understanding with experiments to further elucidate the physiological factors that make a person prone to using drugs, as well as the full dimensions and progression of the disorder. The findings provide powerful leads for developing new medications and behavioral treatments.

This second article in our NIDA Notes Reference Series discusses the central importance of studying drugs’ effects on neurotransmission and describes some of the most common experimental methods used in this research. As with other articles in the series (see “Animal Experiments in Addiction Science”), we provide illustrative references from articles published in NIDA Notes.

What Is Neurotransmission?

A person reads. The words on the page enter the brain through the eyes and are converted into information that is relayed, from one neuron to the next, to regions that process visual input and attach meaning and memory. When inside neurons, the information takes the form of an electrical signal. To cross the tiny gap, or synapse, that separates one neuron from the next, the information takes the form of a chemical signal. The specialized molecules that carry the signals across the synapses are called neurotransmitters.

The ebb and flow of neurotransmitters—neurotransmission—is thus an essential feature of the brain’s response to experience and the environment. To grasp the basic idea of neurotransmission, think of a computer. A computer consists of basic units, semiconductors, which are organized into circuits; it processes information by relaying an electric current from unit to unit; the amount of current and its route through the circuitry determine the final output. The brain’s corresponding basic units are the neurons—86 billion of them. The brain relays information from neuron to neuron using electricity and neurotransmitters; the volume of these signals and their routes through the organ determine what we perceive, think, feel, and do.

Of course, the brain, a living organ, is much more complex and capable than any machine. Neurons respond with greater versatility to more types of input than any semiconductor; they also can change, grow, and reconfigure their own circuits.

Getting the Message Across

The task in neurotransmission is to convey a signal from a sending neuron to a receiving neuron across an open space known as a synapse. All neurons accomplish this in approximately the same way.

The sending cell manufactures neurotransmitter molecules and stores them in packets called vesicles. When stimulated sufficiently, the neuron generates an electric signal and causes some vesicles to migrate to the neuron membrane, merge with it, open up, and release their contents into the synapse. Some of the released molecules drift across the synapse and link up, lock-and-key fashion, with molecules called receptors on the surface of the receiving neuron. If the neurotransmitter is stimulatory (e.g., glutamate), its interaction with the receptor will raise the receiving neuron’s level of electrical activity and thereby increase the likelihood that it will, in turn, mobilize its vesicles and emit its own neurotransmitter. If the neurotransmitter is inhibitory (e.g., gamma-aminobutyric acid ), it will dampen the receiving neuron’s electrical activity and reduce its likelihood of releasing the neurotransmitter.

In this way, neurotransmitters relay information about the environment and our internal states from neuron to neuron through the brain’s circuits and, ultimately, shape how we respond. Neurotransmitters’ interactions with receptors can also set processes in motion that can alter the structure of receiving neurons, or raise (potentiate) or lower (depress) how strongly neurons respond when neurotransmitters link to their receptors in the future.

Once a neurotransmitter has interacted with its receptor on the receiving neuron, neuron to neuron communication is complete. The neurotransmitter molecules drop off the receptors. Loose again in the synapse, they meet one of three fates:

  • Some attach to another receptor.
  • Some encounter an enzyme, a chemical that breaks them apart.
  • Some reenter the sending neuron via a special structure that spans the neuron membrane, called a transporter. Once back inside the neuron, they are available for re-release in future neurotransmission episodes.

Normally, when drugs are not present, the cycle of release, breakup, and neuron re-entry maintains the amount of neurotransmitter in the synapse, and hence neurotransmission, within certain limits. In most cases, when an addictive drug enters the brain, it causes neurotransmission to increase or decrease dramatically beyond these limits.

The Basic Research Questions

Neuroscientists seeking to understand why people use drugs and the consequences of drug use focus on two issues:

  • Which neurotransmitter or neurotransmitters does the drug affect?
  • How does the drug alter neurotransmission?

Which Neurotransmitter or Neurotransmitters Does the Drug Affect?

Neurotransmitters Implicated in Drug Use and Addiction
.

A person’s experiences when using a drug reflect the functional roles of the particular neurotransmitter(s) it disrupts. Each individual neuron manufactures one or more neurotransmitters: dopamine, glutamate, serotonin, acetylcholine, and/or any of dozens of others that scientists have identified to date. Each neurotransmitter is associated with particular effects depending on its distribution among the brain’s various functional areas (see Table 1). Dopamine, for example, is highly concentrated in regions that regulate motivation and feelings of reward, and is a strong motivator for drug use. A neurotransmitter’s impact also depends on whether it stimulates or dampens activity of its target neurons.

Some drugs primarily affect one neurotransmitter or class of neurotransmitters. For example, prescription opioids and heroin produce effects that are similar to (but more pronounced than) those produced by the neurotransmitters endorphin and enkephalin: increased analgesia, decreased alertness, and slowed respiration. Other drugs disrupt more than one type of neurotransmitter. Cocaine, for example, attaches to structures that regulate dopamine, leading to increases in dopamine activity and producing euphoria; it also produces changes in norepinephrine and glutamate systems that cause stimulant effects.

Because a neurotransmitter can stimulate or inhibit neurons that produce different neurotransmitters, a drug that disrupts one neurotransmitter can have secondary impacts on others. For example, nicotine stimulates cells directly by activating their receptors for acetylcholine, and indirectly by inducing higher levels of glutamate, a neurotransmitter that acts as an accelerator for neuron activity throughout the brain. A key effect that all drugs that cause dependence and addiction appear to have in common—a dramatic increase in dopamine signaling in a brain area called the nucleus accumbens (NAc), leading to euphoria and a desire to repeat the experience—is in many cases an indirect one.

How Does the Drug Alter Neurotransmission?

As described above, neurotransmission is a cyclic process that transpires in several steps utilizing specialized components of the sending and receiving neurons. Identifying the precise step that a drug disrupts, and how, provides crucial insight into its impact on users, and is key to developing medical and behavioral interventions to inhibit, counter, or reverse the disruption.

Some drugs mimic neurotransmitters. Heroin and prescription opioids, for example, chemically resemble the brain’s natural opioids (endorphin and enkephalin) sufficiently to engage and stimulate their specialized receptors. Since heroin stimulates many more receptors more strongly than the natural opioids, the result is a massive amplification of opioid receptor activity. Marijuana mimics cannabinoid neurotransmitters, the most important of which is anandamide. Nicotine attaches to receptors for acetylcholine, the neurotransmitter for the cholinergic system.

Other drugs alter neurotransmission by interacting with molecular components of the sending and receiving process other than receptors. Cocaine, for example, attaches to the dopamine transporter, the molecular conduit that draws free-floating dopamine out of the synapse and back into the sending neuron. As long as cocaine occupies the transporter, dopamine cannot re-enter the neuron. It builds up in the synapse, stimulating receiving-neuron receptors more copiously and producing much greater dopamine impact on the receiving neurons than occurs naturally. The section “How Cocaine Motivates Drug Use and Causes Addiction” (below) enumerates some of cocaine’s interactions with the mechanisms of dopamine and other neurotransmitter signaling, and how they motivate use of the drug and contribute to dependence and addiction.

Finally, some drugs alter neurotransmission by means other than increasing or decreasing the quantity of receptors stimulated. Benzodiazepines, such as diazepam or lorazepam, produce relaxation by enhancing receiving neurons’ responses when the inhibitory neurotransmitter GABA attaches to their receptors.

What Changes Occur With Chronic Drug Use?

During the early phase of an individual’s drug experimentation, neurotransmission normalizes as intoxication wears off and the substance leaves the brain. Eventually, however, repeated drug use leads to changes in neuronal structure and function that cause long-lasting or permanent neurotransmission abnormalities. These alterations underlie drug tolerance (where higher doses of the drug are needed to produce the same effect), withdrawal, addiction, and other persistent consequences.

Some longer-term changes begin as adjustments to compensate for drug-induced increases in neurotransmitter signaling intensity. For example, the brain responds to repeated drug-induced massive dopamine surges in part by reducing its complement of dopamine receptors. This alleviates the drugs’ overstimulation of the dopamine system, but also contributes to features of drug dependence (e.g., susceptibility to drug withdrawal) and of addiction (e.g., compromised ability to respond to normal dopamine fluctuations produced by natural rewards). Similarly, methadone and some other opioids induce neurons to retract a portion of their mu opioid receptors, making them unavailable for further stimulation. The retraction is short-lived, after which the receptors return to the neuron surface, restoring normal responsiveness to subsequent stimulation. This dynamic of reducing and then restoring receptor availability may thwart the development of tolerance to these drugs. (Morphine, in contrast, does not cause receptors to retract, and the resulting opioid overstimulation triggers intracellular adjustments that appear to promote opioid tolerance.)

The drug-related mechanisms producing cumulative changes in neurotransmission sometimes are epigenetic in nature. While a drug cannot change a person’s genes, drugs can prod some genes to increase or decrease their production of proteins, leading to changes in neuron function or even actual reshaping of the physical structure of neurons. For example, in mice, cocaine alters important genetic transcription factors and the expression of hundreds of genes. Some of the resulting changes in the brain’s complement of proteins have been associated with increased drug-seeking and addiction-like behaviors in animals. Other changes, such as proliferation of new dendrites (branchlike structures on neurons that feature neurotransmitter receptors on their surface) may be compensatory. Some epigenetic changes can be passed down to the next generation, and one study found that the offspring of rats exposed to THC—the main psychotropic component of marijuana—have alterations in glutamate and cannabinoid receptor formation that affects their responses to heroin.

Some drugs are toxic to neurons, and the effect accumulates with repeated exposures. For example, the club drug methylenedioxymethamphetamine (MDMA ) damages axons (the branch of a neuron that releases its neurotransmitter into the synapse) that release serotonin; the result is disruption of serotonin neurotransmission that may underlie the memory problems that are sometimes experienced by heavy users. Similarly, methamphetamine damage to dopamine-releasing neurons can cause significant defects in thinking and motor skills; with abstinence, dopamine function can partially recover, but the extent to which cognitive and motor capabilities can recover remains unclear.

Research Methods

Researchers employ a panoply of methods to investigate drugs’ effects on neurotransmitter systems, including brain tissue assays, live studies, brain scans, and genetic studies. To determine whether a drug affects a particular neurotransmitter system, or how, researchers typically will compare animals or people who have a history of drug exposure with others who do not. Researchers investigating whether a drug’s impact on neurotransmission underlies a drug-related behavior or symptom may compare neurotransmitter activity in animals or people who exhibit the behavior or symptom and others who do not. In experiments with animals, drug exposure often takes place under laboratory conditions designed to mimic human drug consumption. Studies can be divided into those in which measurements are made in living animals or people and those in which animal brain tissue is removed and examined.

Brain Tissue Assays

Scientists may perform chemical assays on brain tissue to quantify the presence of a neurotransmitter, receptor, or other structure of interest. In a recent experiment, scientists assayed brain tissue from 35-day-old rat pups and found that pups that had been exposed to nicotine in utero had fewer nicotinic acetylcholine receptors in the reward system than unexposed rats. The researchers speculated that if nicotine exposure has the same effect in humans, people whose mothers smoked while pregnant may require more puffs of a cigarette to obtain nicotine’s rewarding effect.

A second experimental method using brain tissue enables researchers to view a drug’s effects on neurotransmission in action. Scientists place the tissue in a laboratory solution of nutrients (cell culture) that enables neurons to survive outside of the body. The researchers may then, for example, add the drug being investigated to the solution and observe whether or not the neurons respond by increasing their release of neurotransmitters. Alternatively, they may measure neurons’ membrane or electrical properties that stimulate or inhibit neurotransmitter release or response.

In both living animals and extracted tissue, the techniques for measuring neurotransmitter quantities and fluctuations include microdialysis and fast-scan cyclic voltammetry (FSCV). Microdialysis involves taking a series of samples of the intercellular fluid containing the neurotransmitter through a microscopic tube inserted into the tissue or living brain. FSCV, which was developed by NIDA-funded scientists, monitors neurotransmitter fluctuations at tenth-of-a-second intervals by measuring electrical changes related to neurotransmitter concentrations.

Live Studies

Studies with living animals or people are essential for tying drugs’ effects on neurotransmitters to behaviors or symptoms. A common design for experiments with either animals or people is to give study subjects a chemical that has a known effect on a particular neurotransmitter, and then observe the impact on behavior. Typically, the chemical is either an agonist (promoter) or antagonist (blocker) of signaling by the neurotransmitter.

In one experiment, for example, researchers showed that glutamate levels fell when rats were withdrawn from cocaine after a period of self-administration, and restoring the animals’ glutamate levels with the medication acetylcysteine reduced their motivation to resume seeking the drug. Another team using a similar strategy showed that nicotine-induced disruption of glutamate signaling contributed to aspects of nicotine withdrawal. Both findings point to manipulation of the glutamate system as a potential strategy for treating some addictions.

A new research technique, optogenetics, enables researchers to raise and lower the activity of specific neurons or precisely targeted brain regions in living animals and observe the effects on the animals’ behavior. Using this technique, researchers shut down rats’ compulsive cocaine-seeking by increasing activity in the animals’ prelimbic cortex, a region that, like the human orbitofrontal cortex, contains many dopamine-responsive neurons and participates in value-based decision-making. Researchers are now attempting to parlay this discovery into a novel treatment for cocaine addiction.

Brain Scans

Brain imaging techniques enable neuroscientists to directly assess neurotransmission in people and living animals. With positron emission tomography (PET), researchers can compare people with and without a drug addiction, quantifying differences in their levels of a particular neurotransmitter (e.g., dopamine) or neurotransmission component (e.g., a receptor or transporter). One set of PET studies, for example, disclosed that smokers experienced cravings as long as nicotine occupied fewer than 95 percent of one type of receptor (α4β2*-nACh) in the brain, but that smoking nicotine-free cigarettes partially reduced craving. The findings indicated that the need to saturate these receptors is the primary driver of smoking behavior, but that sensory aspects of smoking, such as handling and tasting cigarettes, also play a role. With PET, researchers also can correlate a drug’s transit through the brain with fluctuations in a target neurotransmitter. Or, they can elicit a drug-related behavior or symptom (e.g., feeling high, craving) and correlate neurotransmitter fluctuations to the rise and fall in its intensity.

Researchers use several imaging techniques, including PET, functional magnetic resonance imaging (fMRI), and computerized tomography to monitor metabolic activity in selected regions of the brain. Because each neurotransmitter has a unique distribution among the regions of the brain, information on locations of heightened or decreased activity provides clues as to which neurotransmitter is affected under the conditions of the study. Another technique, diffusion tensor imaging, provides information about the white matter (neuron fiber) pathways through which sending neurons extend to receiving neurons, often over long distances.

Genetic Studies

Studies that link genetic variants to contrasting responses to drugs and drug-related behaviors provide another avenue of insight into drugs and neurotransmission. Such studies have shown, for example, that one rare variant of the gene for the mu opioid receptor is twice as common in the general population of European Americans as it is among European Americans who are addicted to cocaine or opioids. The finding suggests that receptors that are built based on the DNA sequence of the variant gene confer resistance to those addictions. Another study linked a different variant of the same mu opioid receptor gene to reduced incidence and severity of neonatal abstinence syndrome among infants born to mothers who used opioids while pregnant. Medicinal chemists may be able to use such information to design new pain relievers that are as effective as opioids but avoid opioids’ undesirable effects. Eventually, doctors may be able to use a patient’s genetic information to guide their pain treatment strategies, weighing patients’ genetic risks for addiction when deciding whether to use opioids to treat their pain.

In another type of study, researchers knock down or knock out specific genes in laboratory animals and observe whether drug-related behavior—for example, pacing restlessly after being given a stimulant—increases or decreases. Researchers have used this technique to explore how different subtypes of nicotinic acetylcholine receptor influence smoking behaviors, including how much a person smokes and susceptibility to symptoms of nicotine withdrawal.

Finally, researchers may implant modified genes into animals. In one such project, researchers, starting from clues provided by a South American caterpillar that eats coca leaves, modified the dopamine transporter gene to produce a transporter that is insensitive to cocaine. Mice who were implanted with this gene showed no preference for the drug over a saline solution. This result could point researchers toward medications capable of preventing or treating cocaine use disorders.

How Cocaine Motivates Drug Use and Causes Addiction

Research on cocaine illustrates how a drug can disrupt neurotransmission in multiple ways to promote intensified drug use, dependence, and addiction. Like all drugs that cause dependence and addiction, cocaine alters dopamine signaling. Studies, mostly with animals, indicate that the interactions of cocaine with the dopamine and other neurotransmitter systems influence the risk of drug use, progression to addiction, and relapse after abstinence through a variety of pathways.

Reward

  • Cocaine causes pleasurable feelings that motivate drug use by sharply elevating dopamine concentrations in the synapses of the reward system
  • Cocaine raises synaptic dopamine levels by preventing dopamine transporters from removing dopamine from the synapse and by stimulating dopamine-releasing neurons to release dopamine that they normally hold in reserve.
  • Cocaine-induced increases in dopamine signaling promote repeated cocaine use by increasing the activity of dopamine type D1 receptors in a circuit that supports the conversion of urges into action, while suppressing the activity of dopamine type D2 receptors in an opposing circuit, and by increasing the activity of dopamine type D3 receptors.
  • An animal’s higher social position or exposure to a stimulating environment may limit cocaine’s power to motivate repeated use by increasing the activity of dopamine D2 receptors.

Transition to Addiction

  • Cocaine sensitizes dopamine-releasing neurons in the reward system, such that repeated exposures trigger the release of increasing amounts of dopamine, potentially ratcheting up urges to use the drug again.
  • The increase in dopamine-releasing neurons’ responsiveness to cocaine begins with the first exposure to the drug and even occurs with only modest doses.
  • The enhanced urge for the drug with diminished control over the urge that occurs briefly following cocaine use may become an abiding state, as repeated exposure to the drug prolongs the activity imbalance in favor of urge-promoting dopamine type 1 neurons over inhibitory dopamine type 2 neurons (see also here).
  • With repeated cocaine exposure, some glutamate receptors in the reward system become sensitized to cocaine cues, programming the brain to assign primary importance to reacting to the cues.
  • Cocaine appears to limit the brain’s ability to alter neurotransmission pathways in response to new experiences, which potentially limits a user’s ability to develop new behavioral alternatives to drug taking.

Craving and Relapse

  • Cocaine craving builds in intensity during early abstinence, linked to the proliferation of a rare type of glutamate receptor.
  • Even after extended abstinence, encounters with drug cues (i.e., things in the environment that are associated with previous drug experiences) cause dopamine to tick up in the reward system, and can rekindle powerful urges to take the drug.
  • Mu opioid receptors in the frontal and temporal regions of the cortex appear to affect the intensity of a person’s craving for cocaine during his or her first few months of abstinence from the drug.
  • Stress increases the likelihood that a former cocaine user’s single lapse will turn into an extended relapse because the stress hormone corticosterone augments the dopamine surge caused by cocaine

Summary

By altering neurotransmission, drugs can produce effects that make people want to use them repeatedly and induce health problems that can be long lasting and profound. Some important effects are shared by all drugs that cause dependence and addiction, most prominently disruption of the dopamine neurotransmitter system that results in initial pleasurable feelings and, with repeated use, potential functional and structural changes to neurons. There are also drug-specific effects: Each drug disrupts particular neurotransmitters in particular ways, and some have toxic effects on specific types of neurons.

Scientists use a wide variety of experimental tools and techniques to study drugs’ effects on neurotransmission, and their consequences, in both animals and people. Their findings enhance our understanding of the experiences of drug users and the plight of people who are addicted, point the way to new behavioral and medication treatments, and provide potential bases for prevention strategies and monitoring progress in treatment.

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Norepinephrine, also called noradrenaline, substance that is released predominantly from the ends of sympathetic nerve fibres and that acts to increase the force of skeletal muscle contraction and the rate and force of contraction of the heart. The actions of norepinephrine are vital to the fight-or-flight response, whereby the body prepares to react to or retreat from an acute threat.

Read More on This Topic nervous system: Epinephrine and norepinephrine These related hormones, also called adrenaline (epinephrine) and noradrenaline (norepinephrine), act to increase the heart rate, blood pressure,…

Norepinephrine is classified structurally as a catecholamine—it contains a catechol group (a benzene ring with two hydroxyl groups) bound to an amine (nitrogen-containing) group. The addition of a methyl group to the amine group of norepinephrine results in the formation of epinephrine, the other major mediator of the flight-or-flight response. Relative to epinephrine, which is produced and stored primarily in the adrenal glands, norepinephrine is stored in small amounts in adrenal tissue. Its major site of storage and release are the neurons of the sympathetic nervous system (a branch of the autonomic nervous system). Thus, norepinephrine functions mainly as a neurotransmitter with some function as a hormone (being released into the bloodstream from the adrenal glands).

Norepinephrine, similar to other catecholamines, is generated from the amino acid tyrosine. Norepinephrine exerts its effects by binding to α- and β-adrenergic receptors (or adrenoceptors, so named for their reaction to the adrenal hormones) in different tissues. In the blood vessels, it triggers vasoconstriction (narrowing of blood vessels), which increases blood pressure. Blood pressure is further raised by norepinephrine as a result of its effects on the heart muscle, which increase the output of blood from the heart. Norepinephrine also acts to increase blood glucose levels and levels of circulating free fatty acids. The substance has also been shown to modulate the function of certain types of immune cells (e.g., T cells). Norepinephrine activity is efficiently terminated through inactivation by the enzymes catechol-O-methyltransferase (COMT) or monoamine oxidase (MAO), by reuptake into nerve endings, or by diffusion from binding sites. Norepinephrine that diffuses away from local nerve endings can act on adrenergic receptors at distant sites.

Norepinephrine is used clinically as a means of maintaining blood pressure in certain types of shock (e.g., septic shock). Swedish physiologist Ulf von Euler identified norepinephrine in the mid-1940s; he received a share of the 1970 Nobel Prize for Physiology or Medicine for his discovery.

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Blood Pressure

To examine if high cholesterol in blood acutely affects the blood pressure, we partly exchanged the blood of normal rats for that of hypercholesterolemic rats. Male Sprague–Dawley rats were fed for 8 weeks with a high‐cholesterol diet (4% cholesterol; HC) or a normal diet (NC). The rats were catheterized, and blood of animals in NC was partly exchanged with that of HC (N‐H) or other animals in NC (N‐N). Systolic blood pressure (SBP) and the pressor response to norepinephrine (NE) in N‐H were compared with those of N‐N. Serum lipids and malondialdehyde (MDA), and urinary excretion of protein (UP) and NE (UNE) were determined. After 8 weeks, SBP, serum total cholesterol (TC), MDA, UP and UNE were higher in the HC. Blood exchange caused an increase in TC, MDA and SBP in only the N‐H. Increases in SBP caused by NE injection were rather less in the N‐H than in the N‐N. The blood pressure increase induced by a high‐cholesterol diet seemed to be caused by certain factors in the blood of hypercholesterolemic rats. Excessive lipid oxidation induced by hypercholesterolemia may be involved in the blood pressure elevation.

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