Parkinson’s disease is defined as “a disorder of the brain that leads to shaking (tremors) and difficulty with walking, movement, and coordination.”1 It typically affects people after the age of 50 and has been linked to multiple genetic mutations. Dominant forms of the disease are typically linked to mutations in two genes, alpha-synuclein and dardarin, while recessive forms are linked to mutations in PD, parkin, DJ-1 and PINK-1.2
What is going on in Parkinson’s disease? Parkinson’s patients show a loss of neurons in the brain which release a specific neurotransmitter, dopamine. This loss of dopamine inhibits signals from the brain to the muscles, making muscle control very difficult – this leads to tremors and uncontrollable movement. Furthermore, certain proteins, including one called α-synuclein, build up in the brain of Parkinson’s patients. Masses of these proteins in the body are called Lewy bodies.3
Recent research has shown that Parkinson’s disease is intricately related and dependent upon a signal transduction pathway called the MAPK pathway. The MAPK pathway is a cascade of kinases, or proteins which add a molecule, phosphate, to other proteins. These pathways are often difficult to sort out, but each protein has a pretty simple task – add a phosphate to the next protein which will then become activated and do the same. After many of these phosphorylations, a protein will eventually exert some effect on the cell such as changing DNA expression or signaling cell death (aka apoptosis).
How does MAPK pathway affect Parkinson’s? One way is through α-synuclein’s effect on the central nervous system. When α-synuclein builds up in the brain, the MAPK pathway is stimulated. This stimulation then leads to activation of two types of nervous system supporting cells called astrocytes and microglia. Activated astrocytes and microglia can then go on to produce cytokines (or signaling peptides) which lead to inflammation. Inflammation oftentimes results in neuron death as the brain attempts to rid the body of an abnormal cell.
Another effect α-synuclein has on the cell is that it stresses mitochondria, the energy-producing organelle of the cell. Stressed mitochondria can produce reactive oxygen species (ROS) which can damage the cell. These ROS’s can then stimulate more microglia to cause an inflammatory response. Stressed mitochondria can also produce cytochrome c, a protein which can signal cell death, or apoptosis. Furthermore, the MAPK pathway phosphorylates p53, a protein in the cell. p53 can cause production of Bax, a protein which signals for apoptosis.3
There’s one thing in this story that is very clear: MAPK has a very important role in Parkinson’s disease. There seems to be many intricate loops, cascades, and proteins involved in the web which is Parkinson’s – and the MAPK pathway makes many appearances in this web. Hopefully in the future we can utilize our knowledge of this pathway to create treatments for this very debilitating disease.
1. http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001762/
2. http://www.ncbi.nlm.nih.gov/pubmed/16026116
3. Kim, E.K., Choi, E. Pathological roles of MAPK signaling pathways in human diseases. Biochimica et BIophysica Acta. 1802 (2010) 396-405.
4. http://www.sciencephoto.com/
Where does Lou Gehrig's Disease come from?
This week we explored the pathways leading to neuron cell death which can lead to various diseases including Parkinson’s disease, Alzheimer’s disease, and Amyotrophic Lateral Sclerosis (ALS) in particular. ALS or Lou Gehrig’s disease is a disease in which there is a loss of motor neuron function. Motor neurons allow for voluntary muscle control. Because of cell death of motor neurons, ALS patients lose normal motor skills such as walking, writing, swallowing, which progresses to eventual paralysis and death (usually 3-5 years after diagnosis). ALS affects around 30,000 people in the United States alone. In this blog I’m going to delve into the pathway leading to ALS and try to determine what actually causes the disease and how its progression can be slowed.
Image from: http://www.bioresearchonline.com/article.mvc/Neurons-From-ALS-Patients-Skin-Cells-0001
What exactly causes ALS?
Well, the truth is we do not know exactly what triggers ALS. Research is still being conducted to determine the exact cause of ALS. Only about 10% of cases are passed down genetically within families, so the other 90% of cases are still a mystery as to why ALS occurs. So far researchers have two leads to this rapid motor neuron destruction—both are linked with gene mutations leading to abnormal proteins. The first mutation is in the gene of a protein called ubiquilin-2 which degrades old and abnormal proteins to make room for new ones. When it is not working properly ubiquilin-2 loses its normal function and abnormal proteins build up in the body. Recently a second relation to ubiquilin-2 was discovered as well. Ubiquilin-2 protein itself, can also build-up specifically in the spinal cord without a mutation in the ubiquilin-2 gene of patients with ALS, possibly aiding in the progression of motor neuron loss. This is an important discovery because the ubiquilin-2 protein is increasing the possibility of cell death, even if there is no mutation or abnormality occurring in the protein.
A second mutation is in superoxide dismutase (SOD1) which is a protein that helps in decreasing oxidative stress to neuronal cells. Oxidative stress can lead to the death of motor neurons (apoptosis) that are still healthy. There are over 150 different genetic mutations in SOD1 that have been linked to ALS—some are more common than others. All tend to lead to the same outcome–loss on motor neurons, resulting in ALS.
How can the progression of ALS be delayed?
Unfortunately, this devastating disease has no cure. Scientists are working diligently to figure out a cause and cure. Right now there is a drug called Riluzole which slows the progression of ALS. The exact mechanism of how the drug works is unknown, however researchers do know that Riluzole helps keep levels of glutamate down. Glutamate-a natural chemical in the body that helps control motor neurons- builds up in ALS patients. At high levels in the body, glutamate can become neurotoxic and harm neural cells. The Riluzole protects these motor neurons by preventing overexposure to glutamate, which helps extend the lives of ALS patients. ALS patients can also take anti-spasticity drugs that help keep muscles loose and relaxed. These include baclofen and diazepam. These drugs do not slow the progression; they only make the patients more comfortable by treating ALS symptoms. More research is in progress to find a cure and hopefully we will find one, and wipe out Lou Gehrig’s disease.
Lou Gehrig's Disease: Causes and Treatment
“Fans, for the past two weeks you have been reading about the bad break I got. Yet today I consider myself the luckiest man on the face of this earth.”
Lou Gehrig’s farewell speech has been immortalized by baseball fans since his early retirement at the young age of 36. After a record-breaking baseball career, the 1938 season started off with a rapid loss of motor function for Gehrig. His power disappeared, he struggled to run and field routine plays, and every game was a miserable struggle to return to the former prowess he had experienced. Lou was brought to the Mayo Clinic in Chicago for diagnosis of this sudden debilitation. It was discovered that Lou Gehrig suffered from a then obscure disease, Amyotrophic Lateral Sclerosis (ALS), and died only two years after his retirement. His widely publicized bout with ALS has lead to the disease adopting the moniker “Lou Gehrig’s Disease”.
A surefire cause of ALS has yet to be fully discovered. While 10% of ALS cases are hereditary, 90% come from an unknown cause. ALS results from the loss of motor neurons, impairing the ability of the body to send messages to muscles, which results in symptoms like weakening, twitching, difficulty swallowing or breathing, speech problems, and even full-fledged paralysis.
While the cause of ALS seems sporadic, recent discoveries in the field of neuroscience have offered ideas for what may cause this devastating disease when it is not simply inherited. A certain signaling pathway in the brain, the p38 MAPK pathway, may have an effect on the development of ALS. The activation and expression of this particular pathway in motor neurons is positively correlated with the degeneration in mice that have a mutation in the enzyme SOD1. Inhibiting this p38 pathway can prevent the death of motor neurons induced by the mutated SOD1 enzyme. p38 MAPK signaling increases the amount of nitric oxide (NO) in motor neurons, which can cause oxidative stress. SOD1 mutations can also lead to other cell death pathways in motor neurons, including the activation of the ASK1 cell death pathway.
Yes, there are a lot of esoteric acronyms to remember. But the important take home message is the development of this disease is starting to be understood more fully, even if the initial cause of the mutations in SOD1 and other causes of ALS are relatively unknown.
Although no cure currently exists for ALS, there are multiple treatments. Riluzole (also known as Rilutek) is perhaps the most well-known pharmaceutical treatment, which can help prolong the life of ALS patients. Riluzole acts by blocking certain channels in the brain and preventing a high influx of calcium, which has been known to activate the ASK1 cell death pathway in motor neurons. The decrease in motor neuron death does extend lifespan, however it is not a cure.
ALS still proves to be an unsolved enigma for many scientists. Although headway is being made in the neurological causes and symptoms of ALS, more research must be conducted in the future to find out more about the mechanism of ALS, which will lead to more effective treatments, and hopefully someday, a cure.
1) http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001708/
2)https://moodle.cord.edu/file.php/7816/literature/2011/MAPK_review.pdf
Addicted to Happiness
Drug addiction is a serious problem in society but what is the real cause. Drugs like heroin and morphine are two opioids that are commonly abused. Addiction is described as a physical and psychological dependence of a psychoactive substance and the continued use of the substance despite the negative consequences that are involved. But when does the recreational use of a psychoactive drug become an addiction? To know this we need to look at how the drug affects neurotransmitters and receptors in the brain.
Heroin and morphine are very similar in structure and basically provide the same affects inside the brain. They both bind to receptors that cause euphoria. But after sessions of high levels of opioids in the brain, the brain starts to counter this process by expressing more of these opioid receptors on the neurons. This means the user needs more and more opioids to get the same euphoric feeling they received the first time. As this slippery slope continues, more and more of these receptors are present, but when opioids aren’t around the bind to these receptors to promote happiness. This causes extreme withdrawal symptoms that promote drug-seeking behaviors. Is this chase of euphoria the cause of opioid addiction or is there and underlying reason found in brain processes and neurotransmission?
Glutamate is the most common neurotransmitter and is involved with memory and learning processes. The transmission of glutamate is altered during the use of opioids. The chronic use of opioids increases the level of glutamate in the brain. Associating the strong euphoric feelings with the use of opioids comes from the memory and learning processes involved with glutamate neurotransmissions. This process is similar to associating food with hunger.
The combination of euphoric feelings caused by high levels of opioids in the brain and the memory association that is made by glutamate with using opioids and happiness creates an easy addiction pathway. When this addiction becomes prevalent in a user, trying to reach the same high becomes their only objective. As this process continues, the need and desire only gets worse.
There's drugs in my muffin?
In today’s society we often want to have straight forward answers and prompt results when it comes to our health and well being. When we visit the doctor or family physician we expect answers and direction. When it comes to medications, we put our trust in doctors to provide us with the best and most suitable solution there is. Although the medication may relieve unwanted symptoms, it might be creating an even bigger problem. The problem i am addressing is the possible opioid addiction and dependence that is accompanied by the over administration of opioid drugs acting on the dopamine system.
An opioid is a chemical that works by binding opioid receptors in the body which mediate beneficial and harmful side effects. Opioids are known as the oldest pain analgesic originating from the use of the resin of the opium poppy. Common opioid drugs consist of heroin, morphine and oxycodone just to name a few. While some of these opioid drugs account for relieving pain and blocking unwanted symptoms, they can also be abused by the administrator and eventually cause whats called addiction. Opioid drugs act on the dopamine, or pleasure system, of the brain and cause a euphoric effect. The dopamine pathway is what regulates desires, initiates movements and plays a role in the way we make choices. We can see how the euphoric effects of a drug would fit our requirements as a reward, but was is rewarding when all you have is a feeling induced by unnatural chemicals? In the case of over-administration, or frequent use when it is not needed can cause the dopamine reward system to be down-regulated. What this means is that the effects of a drug aren’t as noticeable with frequent use because of the adaption of the addictive chemical or opioid being present. A chemical tolerance can be originated and more of the drug will be needed to achieve a similar high or affect from the last time it was administered. The dopamine system is altered and eventually the only way reward is achieved is by the presence of an opioid in higher doses.
This leads to the discussion of drugs of abuse such as heroin, codeine and vicodin.Is the event of a broken bone the start of an opioid addiction? The drugs mentioned offer us a small window of relief when we are in pain and we consolidate a memory of euphoria. The implication isn’t that everyone who takes opioid analgesics will develop an addiction, but will notice a euphoric difference. The addictive traits come with the drug, but what if we could administer drugs without the addictive qualities. I think doctor’s and physicians are looking out for their patients by assessing pain before prescribing opiates. So should we trust doctors when they prescribe us drugs with addictive qualities? I don’t think it’s the matter of a physician leading the patients astray, rather the patients motives of drugs administration and the problems, whether it be pain or addiction that they have.
Opioids: Medicine or Recreational Drug?
Everyday people all over the world are using drugs, whether medicinally or recreationally. Opioids have been the drug of choice for relieving intense pain and a drug that many people choose to abuse. Known for its addictive traits, opioids have a long history of use. Since the time of the Egyptions and even the Sumerians, opioids have been used for their pain relieving and euphoric effects.
Opioids are defined by their ability to bind to and influence opiate receptors on cell membranes and can be divided into three classes: naturally occurring, semi-synthetic, and synthetic opioids. Two common types of naturally occurring opioids are morphine and opium. Opium is extracted from the Papaver somniferum plant and morphine is the primary active component of opium. Along with these drugs, endogenous opioids (found within the body) can also be considered naturally occurring, and these include endorphins, enkephalins, dynorphins, and endomorphins. The semi-synthetic opioids are similar to the naturally occurring opioids in the fact that they use compounds isolated from natural resources as starting materials. The difference lies within the synthesis of the finished product. Common types of semi-synthetic opioids include heroin, hydrocodone, and oxycodone. The last type is the synthetic opioids, and these are created solely through chemical synthesis. Beprenorphine, codeine, and methadone are all types of synthetic opioids.
In a society where medicine is key proponent to treating ailments, the risks that come along with its use ought to be recognized. Of the problems associated with opioids, addiction, misuse, abuse, dependence, and overdose are amongst the most common. Considering that there are beneficial effects to using opioids (pain relief, cough suppression, etc.), scientists and researchers are searching to diminish the addictive effects. In the future, a more effective opioid drug is the goal.
Beating the addiction
Papaver somniferum, otherwise known as the opium poppy, has been in medical use for centuries. The sap can be extracted from the poppy to make drugs to treat a variety of problems. There’s evidence that as far back in history as the ancient Sumerians and Greeks used the plant to treat illnesses in their day. Today, we still use products of the opium poppy. Drugs like morphine and codeine are useful for treating severe pain and suppressing a nagging cough. We will all probably benefit from an opium drug at least once in our lifetimes.
Sap from the opium poppy
However, it is more well-known today that these drugs have harmful side effects. Some opium drugs produce a strong euphoric rush, which can make them very addicting. Heroin in particular is a drug that causes a very strong euphoric sensation, and is currently illegal to use because of that reason. If these drugs just produced euphoria, they probably wouldn’t be so much of a problem. But the fact is that if you take these drugs over a period of time, it can have a negative effect on your body, including mood changes and confusion, slowing down of the heart and the lungs, and digestion problems.
So why do people abuse opium drugs?
Many people get into using these drugs to experience the “high” and the euphoric rush that results from the action of the drug. This sensation can keep them coming back for more. But for many other people who experience severe pain or mental illness, using opiate drugs is a way of treating their own problems. These drugs are very useful at treating pain, depression, anxiety, and other mental problems.
Over time as a person gets used to the drug, they need more of it to relieve their pain or anxiety. This causes them to increase the dosage to avoid getting back their symptoms as well as drug withdrawal symptoms—including cramps, pain, nausea, vomiting, chills, diarrhea, and weakness, to name a few. Unfortunately, increasing the dosage increases the likelihood of damage to the body. People have died from opiate overdoses that have caused their hearts to malfunction or lungs to stop working (suffocation).
However, to people addicted to these drugs, the risk is worth it to them if it makes them feel normal, even good for a time. This brings them back to the drug repeatedly and makes it so difficult to stop.
How do opiates work in the brain?
Dopamine is a chemical in the brain that is released whenever we feel good. It produces the sensation of reward and pleasure, as well as the motivation to keep seeking that sensation. Rewarding experiences like food, sex, and drug use can become associated with the “pleasure chemical,” dopamine. This causes people to repeat these experiences and sometimes seek them more strongly, as in the case of drug abuse.
Neurons release chemicals like dopamine in the brain
When people take opium drugs, the levels of dopamine in their brains increase. They experience a very strong “rush” of pleasure from the drug, which can cause them to continue using it. Over time, opium addicts will increase the dosage to keep getting that “rush” and feeling of pleasure and reward.
Drug treatment for opiate addiction
Stopping opium use is very difficult because the drug is so addicting. People who use it for pain relief or to treat mental illness particularly have a tough time coming off of it. However, it is necessary if the drug is threatening the life of the user. Additionally, pregnant women who are addicted to drugs like morphine and heroin have the life of their unborn baby to worry about as well.
People coming off of opium drugs experience intense physical and psychological withdrawal symptoms. Even if addicts make it through the worst of the withdrawal, they often experience intense cravings and depression for years afterward. This puts them at a high risk of relapsing back into drug abuse. Detoxification from the drug is usually not enough to “cure” an opium addict. What addicts really need is long-term care that will diminish their drug-seeking behavior.
Opiate replacement therapy has been a successful way to help addicts get their health back, their jobs back, and become productive members of society again. Clinics that use this kind of therapy give opium addicts a man-made version of opium, usually a substance called methadone. This drug blocks the usual euphoric “high” that results from opium, yet prevents the development of withdrawal symptoms. People on this drug lose the motivation and drive to get opium drugs, but at the same time they physically rely on it to keep away their negative symptoms. Additionally, pregnant women can use this drug, which greatly decreases the effects of opium on their unborn babies.
This methadone treatment is called methadone maintenance. People can be maintained on methadone for years at a time. While the goal is to eventually come off of the drug all together, progress can be very slow, and some never come off it. For this reason, some people criticize this therapy and suggest that methadone maintenance merely “substitutes one drug for another.”
However, this is not true. Methadone essentially “un-motivates” an addict from ever seeking the drug again. Counseling and therapy are used in addition to the drug to help the addict deal with the problem of addiction and get their feet under them again. This long-term therapeutic and drug treatment program has been very successful for treating opium addiction. “Some people say methadone is just switching one addiction for another,” Scott, a former heroin addict says. “They couldn’t be farther from the truth. When I was using heroin, I was a drug addict. Now that I’m in a methadone program, I’m a guy with a job, a family and a future.” Michael adds, “Because of my methadone program, I can transition to a drug-free life and a normal routine without being constantly tempted to start using again.”
Opiate replacement therapy like methadone maintenance programs help regular people get their lives back again.
Pain killers and addiction!
Opioid analgesics are both a blessing and a curse. Being well-known pain killers, there is no doubt that they are very effective in alleviating pain but at the same time, their high potency makes the users susceptible to overdose and expose the users to high addictive potentials. Most common pain killers are used to treat pain, suppress cough, and induce anesthesia. Some of the common opioid painkillers include – Morphine, Codeine, Fetanyl, Hydrocodone (Vicodin), and Ocycodone (OxyContin, Percocet, and Percodan).
- http://abcnews.go.com/Health
Addiction and death from opioid overdose has been increasing during the past decade. According to the article “Curtailing Diversion and Abuse of Opioid Analgesics Without Jeopardizing Pain Treatment” in JAMA magazine, since 2002, the US prevalence of high school seniors reporting past-year nonmedical use of opioids has been 8% to 10% for hydrocodone and 4% to 5% for oxycodone. Hydrocone abuse is second only to Marijuana abuse. The article also reports that “emergency department visits related to pharmaceutical opioids have increased from 144 644 to 305 885, between 2004 and 2008, and unintentional opioid-related overdose deaths have increased from about 3000 to 12 000 between 1999 and 2007 which is more than either heroin or cocaine overdose”. According to the article, opioid overdose is now the second leading cause of unintentional death in the United States, second only to motor vehicle crashes.
So, how do these effective medications have addictive and lethal potentials? Let’s take a little look into what these opiates do in the body. The opiates are the substances that can activate the opioid receptors in the brain. Opioid receptors activation is important in eliciting pleasurable or ‘rewarding’ feelings. Dopamine is a neurotransmitter important in inducing pleasurable effects. Dopamine neurons are richly present in the brain areas Ventral Tegmental Area (VTA) and Nucleus Accumbens (NC). Opioid receptors are also present in these areas and the binding of opiates can cause the activation of dopaminergic neurons and subsequent release of dopamine which result in producing rewarding or pleasurable feelings. Hence, effects of opioids are not only pain-relieving but also addicting and make the users susceptible to overdose.
- http://quizlet.com/4038817/b8w2-neurobiology-of-addiction-and-reward
Hence, there should be general education to the public about the safe use of opioid analgesics even though these are prescribed by physicians. These medications should be prescribed with strict regulations and the patients should be well-informed about their side effects and safety margin before they take the medication. It is important not to take any medication without caution and decent knowledge about the potential risks that come together with therapeutic effects. Especially, when it comes to highly potent and addictive drugs like pain killers, we should take extra-care before taking them and consult with a physician before doing so.
Dear Dad, I want more. The basis of addiction.
What makes certain drugs more or less addictive? Why do patients often become addicted to morphine? This week in class we discussed opioids and what causes their addiction. You may recognize the term opioid from the drug opium, but it is actually a higher classification of drugs that also includes morphine, codeine, heroin and even our body’s natural endorphins.
The brain chemical that causes addiction is called dopamine. When it is released it causes our brain to think that whatever we are experiencing is very pleasurable. We want this pleasurable experience to happen again and again so we keep going back to that thing that causes the release of dopamine, like drugs. After so much release of this chemical we gain a tolerance to the drug, which means more is needed to reach the same desired effect. Since opioids are sometime used for pain relief, this is can cause serious drug tolerance when the morphine levels are increased over time. That is typically why long term morphine use is not used in clinical settings and why the hospitals have settings that max out the dosage.
Another portion of our paper talked about different portions of the brain that may also play a role in our drug addiction. Two of these brain regions are the amygdala, which is responsible for all of our emotions and our prefrontal cortex which is responsible for cognitive functions such as planning and decision making. Although our article didn’t explicitly say anything about how drugs may affect our moods and decision making process another article that I found discussed how opioids are used in individuals diagnosed with bipolar disorder to elevate their mood when they are down. For more information about the mood aspect of this you can check out this link: http://neuro.psychiatryonline.org/cgi/content/full/19/4/449 Since this chemical also activates our decision making area of our brain, it may show why some people become addicted to these various drugs even though they know of its harmful effects. Maybe we could even generalize it to say that we aren’t making the decision to do the drugs continually, our brain has taken over control?
What's Up With Nitric Oxide?
http://www.badasssupplements.com/index.php?act=viewProd&productId=271
If you are one of those dietary supplement followers, you may have heard of nitric oxide. It’s rumored to have healthy effects concerning weight loss, sports nutrition, heart disease prevention, increased blood flow, and building muscle mass. Although I seriously doubt the scientific evidence in some of these areas (what happened to good old fashioned exercise and a healthy diet?), nitric oxide is a hot new topic in research circles. In fact, in 1998, Robert F Furchgott, Louis J Ignarro and Ferid Murad won the Nobel Prize in Physiology or Medicine for their discovery of “nitric oxide as a signaling molecule in the cardiovascular system.”1
Furthermore, nitric oxide has been found to have very important roles in the immune system. According to Christian Bogdan, a researcher at the Institute of Clinical Microbiology at the Friedrich-Alexander-University of Erlangen-Nuremberg, “It is involved in the pathogenesis and control of infectious diseases, tumors, autoimmune processes and chronic degenerative diseases”2 Additionally, “Chronic expression of NO is associated with various carcinomas and inflammatory conditions including juvenile diabetes, multiple sclerosis, arthritis and ulcerative colitis.”3 So apparently this little gaseous molecule is important.
This week in class we talked about opioid addiction, withdrawal, and tolerance. We learned that when someone uses opioid drugs like heroin, codeine, or morphine, they bind to cell receptors and cause dopamine release in some areas of the brain. This dopamine gives you the euphoric, blissful, painless response. However, after prolonged use of these drugs, the brain chemistry changes to become tolerant to the drugs so larger quantities must be used to obtain the same effects. Furthermore, without the drugs, a person will then have withdrawal symptoms due to the body’s previous adaptations.
So….what does this have to do with nitric oxide? Apparently, along with the many previously mentioned functions, this molecule could also have effects in opioid addiction and withdrawal. According to Yuan Guo et al. a newly researched pathway inside the cell increases nitric oxide concentration which then leads to withdrawal symptoms.4
So what does this mean? According to Gerlach et al., a research team focused on nitric oxide’s role in alcoholism, targeting nitric oxide could be a possible treatment for withdrawal symptoms.5 Could we selectively target nitric oxide’s effects in the brain and help those with life-threatening addictions by blocking withdrawal?
I don’t think it’s far-fetched to say that maybe someday another group of scientists will earn a Nobel Prize for their work on the peculiar molecule, nitric oxide.
http://troll.me/am-i-a-fan-of-nitric-oxide-no/
1. http://www.nobelprize.org/nobel_prizes/medicine/laureates/1998/illpres/
2. http://www.nature.com/ni/journal/v2/n10/abs/ni1001-907.html
3. http://en.wikipedia.org/wiki/Nitric_oxide
4. Guo, Yuan, Wang, Hui-Ling, Xiang, Xiao-Hui, Zhao, Yan. 2009. The role of glutamate and its receptors in mesocorticolimbic dopaminergic regions in opioid addiction. Neuroscience and Biobehavioral Reviews. 33, 864-873.
5. Gerlach, M., Blum-Degen, D., Ransmayr, G. Leblhuber, F., Pedersen, V., Reiderer, P. 2001. Expression, but not activity of neuronal nitric oxide synthase is regionally increased in the alcoholic brain. Alcohol and Alcoholism. 36, 65-69.