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.
Addicted Babies
Opioid addiction is the topic of this week’s discussion and whenever addiction is mentioned so is withdrawal and rehabilitation. Early symptoms of withdrawal include but not limited to: agitation, anxiety, muscle aches, insomnia, abdominal cramping, diarrhea, nausea, vomiting. These withdrawal symptoms can begin to take place anywhere from 12 to 30 hours after the last usage depending on the drug. More about opioid withdrawal can be found at: http://www.nlm.nih.gov/medlineplus/ency/article/000949.htm
As depressing as it may sound, new babies can be born addicted to drugs. When women addicted to narcotics/opioids become pregnant, they can’t just stop the drug use because of their pregnancy (wanted or unwanted). Therefore, in the womb a baby is fed the opioids taken in by the mother. Eventually the baby will become addicted to the drug as well. After birth, infants, like their mothers, will also experience withdrawal after their last exposure to the drug. For infants especially, withdrawal can be a very painful, trying process. Pharmaceutical agents have been created that can help induce withdrawal specifically in highly intoxicated infants and ease these withdrawal symptoms. These include Suboxone and Suptex, both of which contain a drug called buprenorphine, while Suboxone also includes naloxone. Buprenorphine supposedly speeds up the detoxification process, while naloxone induces withdrawal by blocking opioid receptors in the brain. Naloxone is only used in the most severe cases and has been known to cause side effects worse than withdrawal symptoms in infants, so it is being used with caution for the time being. There are other treatments and drugs that exist as well, some of which are mentioned below and explained at: http://aappolicy.aappublications.org/cgi/reprint/pediatrics;101/6/1079.pdf
Neonatal Abstinence Syndrome
Babies born with an addiction to drugs have what is called Neonatal Abstinence Syndrome or NAS. After birth test are conducted such as a toxicology screen and urinalysis to determine if a baby actually has NAS. When the severity of the infants addiction is understood specific treatments are carried out on a case by case basis. The effects of a drug in the womb leads to symptoms such as low birth weight, birth defects, higher risk for SIDS and being stillborn, premature birth, etc. Most of these infants must stay in the hospital (instead of the normal 48 hour period) for two weeks or longer depending on their state of addiction. In addition to drugs, the best treatment babies can get is comfort via pacifiers, cuddling, swaddling and dark-lit rooms to help with sensitivity to surroundings.
Prevention
According to the March of Dimes around 4% of all pregnant women are on illicit drugs. The best treatment for NAS is simply prevention altogether. By helping moms lose the habit and drug addiction will help stave off this nasty outcome in infants.
If you or anyone you know is trying to stop their narcotics/opioid addiction please contact a doctor, drug treatment facility, Narcotics Anonymous, SMART Recovery or the Here to Help program at 866-973-HERE (4373) or visit http://heretohelpprogram.com/treatment/here_to_help.aspx
Understanding Opioids and Their Importance
This week’s topic deals with Opioid addiction. Opioids are a drug class which includes morphine, hydromorphone, hydrocodone and codeine. Opioids have been used for medicinal purposes, for example the administration of morphine for pain management. Opioids however present problems because of the fact that they are highly addictive. Understands the mechanism of addiction is important for expanding the positive medicinal uses and also for the treatment of addicts. Dopamine is a neurotransmitter that has been researched intensely and shown to be released in Opioid use, leading to addiction. Neurotransmitters are chemical molecules found in the nervous system which send signals and are used for “communication” between cells; they play various roles in important processes from learning to hearing and the feeling of pain. Dopamine is responsible for the “pleasure” feeling associated with the use of many addictive drugs. Simply understanding the actions of dopamine however is not enough. In order to gain a greater perspective the actions of other chemicals in the brain must be elucidated. Glutamate, another neurotransmitter, has been shown to be another major player leading to opioid addiction. Understanding the actions of glutamate in the brain in terms of addiction, and its interaction with other molecules including dopamine can lead to future drug design and treatment options. A major issue with continued drug use is tolerance. Tolerance is undesirable for medical treatment with opioids because its purpose, decreasing pain, will no longer occur without increased dosage. In terms of addicts tolerance can lead to increased drug use, further addiction and dangerously high doses used. The following video shows one mechanism of how opioid tolerance is developed.
A Mechanism of Opioid Tolerance
Further information can be found from the following source article.
https://moodle.cord.edu/file.php/7816/GluR_and_DA_in_opiod_addiction.pdf
It is useful to put into context why research into topics such as this is important. The medical value is easily seen; for example if a patient was to sustain a painful injury this pain could be mediated with the use of a drug such as morphine, it would be important to control the addictive properties of such a treatment. In another vein many countries including the United States have a substantial drug problem and current methods of mediating this issue have been marginal at best. Incarcerating addicts often times leads to relapse upon release and a reoccurring cycle between imprisonment and falling back into addiction can easily occur. Being able to attack this issue from other angles; treating addicts successfully at a biological instead of social level could potentially lead to a reduction in drug related crime, less tax dollars spent on prisons, and a healthier country.
Oh No Opioids
Dangerous, even in moderation
Opioids and opioid addiction are common problems in our highly medicated society. They are prescribed in cases of severe and chronic pain to assist patients in overcoming pain so they can continue an active and productive lifestyle. Unfortunately, opioid analgesics can produce addiction, tolerance and dependence after prolonged use. Such prescription drugs as hydrocodone, hydromorophone, oxycodone, fentanyl, meperidine, methadone and morphine, have all been shown to increase user morbidity and have strong drug dependence rates. North America has the highest prevalence of opioid painkiller dispension in the world and it has been related to increasing rates of medication illness and death. The rate of unintentional medication poisoning has been rising for 15 years and is now the second highest cause of unintentional injury hospitalization in the United States. There are obviously dangers associated with the prescription of opioid analgesics, but can the dangers be overcome.
http://www.physorg.com/news189747766.html
http://medicalxpress.com/news/2011-08-prescription-opioids.html
A Poor Reward
The review paper for this week describes opioid addiction and some current research into the topic. Opioids are so addictive because they manipulate the reward system in the brain. When an opioid reacts with the brain it causes a release of dopamine and glutamate. These reduce the feelings of pain and can facilitate feelings of euphoria and pleasure. The body recognizes these effects as beneficial and activates the reward system, which basically tells the brain that this may be an effective way to resolve pain in the future. However, continued use of opioids in this fashion is what begins the spiral to tolerance and dependence. When opioids are used consistently, dosing needs to be steadily increased to feel the same level of relief, this is tolerance at work. Dependence, on the other hand, occurs because the brain recognizes its inability to naturally generate pain relief as effective as opioid medications. Therefore, cravings of the medication are created to signal the desire to return to the state of relief undergone after the use of opioids. Eventually this state becomes perceived as the “normal state” and without the opioid the person can feel depressed and anxious as well as other negative symptoms. These negative symptoms felt after stopping or lessening a drug the body has become dependant upon is known as withdrawal.
Hope-ioids
Good news, there is hope for opioid addiction. The study describes medications used to help block the feelings of withdrawal or even circumventing addiction all together by manipulating the function of dopamine and glutamate, the chemicals mentioned earlier that are released by the brain in the presence of opioids and are suspected in the development of addiction and dependence. Most of these medications have only been tested in animals and are a ways from being available for human use, but the progress is encouraging. Even though the mechanism for addiction in the brain is complex and the scientific and medical community have not reached consensus on the subject, pieces of the puzzle are slowly but surely being uncovered and fit together. I think we can all look forward to a day when chemical dependence has less sway over people requiring medications for chronic health issues.
Mickey wants some morphine: CPP and its ramifications for drug addiction
How can one test the addictive qualities of certain substances? The most reliable way would be to get some honest (and willing) human subjects to try the substances themselves and describe in perfect detail the psychological and physical results of their use. However, its not easy to obtain willing human subjects (and even if they were willing, there are experimental ethics dilemmas as well) so our scientific community has come up with the alternative solution, albeit a controversial one, animal testing. The lucky animals that receive the brunt of our initial testing focus are mice and rats. However, because we don’t live in a Disney movie, we can’t simply speak with the animals and ask how they’re feeling. The inability of mice and rats to communicate with us directly requires some clever experimental design.
A common way to trust substances for addictive qualities is through the monitoring of conditioned place preference (CPP). An addictive substance will influence a mouse to attach itself to the certain area of the cage where the drug was administered, a portrayal of drug seeking behavior that characterizes so many chemical addictions.
1
The above picture displays a common apparatus used for testing CPP. A rat is initially habituated, allowed to free roam the cage until it is shut inside a certain section, and subsequently given a dose of a certain substance/drug. This process is repeated a certain number of times. Finally, the rat is allowed to free roam the cage. If the drug is addictive, the rat often lingers in the place it was administered. If the drug it was given produced undesirable effects, the rat will avoid the area the drug was administered (conditioned place aversion or CPA).
Many commonly consumed drugs by humans are tested on rats in this way. Morphine, heroine, cocaine, opioids (ex. endorphins), and methamphetamine all result in CPP. Some substances, like alcohol and nicotine, can produce CPP in some cases and CPA in other cases. Drugs that inhibit our dopamine release (which causes the “feel-good” feeling or “runner’s high” strongly associated with addiction) produce CPA. By extension, drug treatments can be found by finding substances that can counteract CPP for addictive substances.
Is CPP/CPA tested on rats and mice a reliable model for humans? Do the possible rewards (enhanced drug addiction treatment, knowledge of what drugs can be addicting) outweight the possible drawbacks (getting mice addicted to potentially harmful substances)?
1) http://www.accuscan-usa.com/product/CPP—Conditioned-Place-Preference/1012
2) http://www.sciencedirect.com/science/article/pii/S0301008298000604#sec3.1.1