Posts tagged addiction
Posts tagged addiction
A drug that mimics some effects of alcohol but lacks its harmful properties would have real benefit for public health, a leading scientist has argued.
Professor David Nutt, the Edmond J. Safra Professor of Neuropsychopharmacology at Imperial College London, has identified candidate molecules that reproduce the pleasurable effects of alcohol but are much less toxic. He is looking for investors to help develop the product and bring it to the market.
Alcohol mimics a chemical called GABA which is produced in the brain, but it also acts on receptors for other brain chemicals. The alcohol substitute would be designed to target GABA receptors very selectively, avoiding undesirable side effects such as hangovers and loss of coordination. An antidote could also be made to block the receptor, allowing drinkers to sober up quickly.
Professor Nutt told the Today programme on BBC Radio 4 that he first tested such a compound many years ago, but even better substitutes could be developed.
“There’s no question that you can produce a whole range of effects like alcohol by manipulating this system in the brain,” he said. “In some experiments, the effect is indistinguishable from alcohol.
“What we want to do is get rid of any the unwanted effects of inebriation, like aggression and memory impairment, and we just want to keep the pleasure and the sense of relaxation.
“We think by clever molecular modelling we can get rid of the risk of addiction as well.”
Professor Nutt hopes to make a range of cocktails containing his synthetic alcohol substitute. He has spoken to investors about taking the product to market, but many are wary that the drug might be controlled by legislation.
“I would like the government to make a recommendation that we try to improve on the health of our people by allowing these kind of substitute alcohols to be legal.”
Alcohol is responsible for 2.5 million deaths worldwide each year. Making safer alternatives available could reduce the harms significantly, Professor Nutt argued.
“I think this would be a serious revolution in health benefits, just as the e-cigarette is going to revolutionise the smoking of tobacco. I find it weird that we haven’t been talking about this before because it’s such an obvious target for health improvement.”
With the help of a rat casino, University of British Columbia brain researchers have successfully reduced behaviours in rats that are commonly associated with compulsive gambling in humans.
The study, which featured the first successful modeling of slot machine-style gambling with rats in North America, is the first to show that problem gambling behaviours can be treated with drugs that block dopamine D4 receptors. The findings have been published in Biological Psychiatry journal.
“More work is needed, but these findings offer new hope for the treatment of gambling addiction, which is a growing public health concern,” says Paul Cocker, lead author of the study and a PhD student in UBC’s Dept. of Psychology. “This study sheds important new light on the brain processes involved with gambling and gambling addictions.”
For the study, rats gambled for sugar pellets using a slot machine-style device that featured three flashing lights and two levers they could push with their paws. The rats exhibited several behaviours associated with problem gambling such as the tendency to treat “near misses” similar to wins.
Building on previous research, the team focused on the dopamine D4 receptor, which has been linked to a variety of behavioural disorders, but never proven useful in treatment. The study found that rats treated with a dopamine D4 receptor-blocking medication exhibited reduced levels of behaviours associated with problem gambling.
While findings suggest that blocking the D4 dopamine receptor may help to reduce pathological gambling behaviours in humans, the researchers note that further research is needed before the drugs can be considered a viable pharmaceutical treatment for pathological gambling in humans.
“Pathological gambling is increasingly seen as a behavioural addiction similar to drug or alcohol addiction, but we know comparatively little about how to treat problem gambling,” says Cocker. “Our study is the first to show that by blocking these receptors we might be able to reduce the rewarding aspects of near-misses that appear to be important in gambling.”
Methods: In the 16-month study,a cohort of 32 laboratory rats responded to a series of three flashing lights before choosing between two levers. One combination of lights (all lights illuminated) signaled a win and seven combinations (zero, one or two lights) signaled a loss. A “cash-out” lever rewarded the rat with 10 sugar pellets on winning trials, but gave a 10-second “time out” penalty on losing trails. The “roll again” lever allowed the rats to begin a new trial without penalty, but provided no sugar pellets.
Interestingly, the rats showed a tendency towards choosing the cash-out lever when two lights (near-miss) illuminated, suggesting that rats, like people, are susceptible to the near-miss effect. By blocking the D4 receptors with drugs, the researchers were successfully able to reduce the rat’s choice of the “cash-out” lever on non-winning trials.
The D4 blocker drug used in the study has previously been tested on humans in attempts to treat behaviour disorders like schizophrenia but appeared to have no effect.
Near misses: This common cognitive bias is considered an important factor in the development of pathological gambling problems. The fact that slot machines tend to have a relatively high proportion of near-misses in comparison to other gambling games may be the reason that slot machines are such a particularly addictive form of gambling.
Study authors: Paul Cocker and Prof.Catharine Winstanley (UBC Dept. of Psychology), Bernard Le Foll (University of Toronto, Centre for Addiction and Mental Health) and Robert D. Rogers (Bangor University). The study, A Selective Role for Dopamine D4 Receptors in Modulating Reward Expectancy in a Rodent Slot Machine Task, is available upon request.
UBC’s Laboratory of Molecular and Behavioural Neuroscience, led by Psychology Prof. Catharine Winstanley, focuses on understanding the biological mechanisms of functions such as impulse control and gambling, leading to new and improved treatments for disorders like attention deficit hyperactivity disorder, bipolar disorder, personality disorders, and drug addiction.
Problem gambling: Compulsive gambling affects between three and five percent of North Americans, according to recent statistics.
New research published in JAMA Psychiatry reveals that topiramate, a drug approved by the U.S. Food and Drug Administration (FDA) to treat epilepsy and migraine headaches, also could be the first reliable medication to help treat cocaine dependence.
The study, led by Bankole A. Johnson, DSc. MD., MB.ChB., MPhil., chairman of the Department of Psychiatry at the University of Maryland School of Medicine and head of the School’s new Brain Science Research Consortium Unit, with support from the National Institutes of Health and Agency for Healthcare Research and Quality, is one of the first to establish a pharmacological treatment for cocaine addiction, for which there are currently no FDA-approved medications.
Addiction affects 13.2 to 19.7 million cocaine users worldwide. Cocaine is responsible for more U.S. emergency room visits than any other illegal drug. Cocaine harms the brain, heart, blood vessels, and lungs — and can even cause sudden death.
Professor Johnson, one of the nation’s leading neuroscientists and psychopharmacologists, had previously found that topiramate was a safe and effective treatment for alcohol dependence compared with placebo.
In releasing the new study, Professor Johnson, who conducted the research when he was with Department of Psychiatry and Neurobehavioral Sciences at the University of Virginia, provided full disclosures, which follow the text of this news announcement.*
The study enrolled 142 participants, aged 18 years or older, seeking treatment for cocaine dependence. Following enrollment, participants were randomly assigned into a topiramate group or placebo group. Neither the participants nor the healthcare professionals administering the treatment knew who was in which group (double-blinded study).
Using an intent-to-treat analysis, the researchers found that topiramate was more efficacious than placebo at increasing the participants’ weekly proportion of cocaine nonuse days and in increasing the likelihood that participants would have cocaine-free weeks. Furthermore, compared with placebo, topiramate also was significantly associated with a decrease in craving for cocaine and an improvement in participants’ global functioning.
The study investigators also observed few side effects due to drug treatment. In general, participants in the topiramate group experienced mild side-effects, including abnormal tingling skin sensations, taste distortions, anorexia, and difficulty concentrating.
"Our findings reveal that topiramate is a safe and robustly efficacious medicine for the treatment of cocaine dependence, and has the potential to make a major contribution to the global health crisis of addiction," Professor Johnson said. "However, topiramate treatment also is associated with glaucoma, and higher doses of the drug can increase the risk of side effects; therefore, caution must be exercised when prescribing the drug, especially when given in high doses."
These results build upon earlier work from Professor. Johnson’s group which indicated that individuals dependent on cocaine, but not seeking treatment, who took topiramate were more likely to experience reduced cravings and preference for cocaine, compared with placebo. The findings of the current study indicate that topiramate may be even more effective in treating people with addiction who actively want to quit using cocaine.
"Because topiramate is the first medication to demonstrate a robust therapeutic effect for the treatment of cocaine or alcohol dependence, its fundamental neurochemical effects provide important clues as to common links in the neurobiological basis of the addictive process in general," remarked Professor Johnson. "These findings also add to our understanding of how addiction affects the brain because it demonstrates the unique concept that dual neurotransmitter modulation, by simultaneously augmenting the inhibitory action of gamma amino butyric acid and inhibiting the excitatory effects of glutamate, can result in therapeutic effects that reduce the propensity to use cocaine."
A. Statement of Disclosure
Professor Johnson reported serving as a consultant for Johnson & Johnson (Ortho-McNeil Janssen Scientific Affairs, LLC) the manufacturer of topiramate, from 2003-2008 and currently has no affiliation with that Company, Transcept Pharmaceuticals, Inc. from 2006-2008, Eli Lilly and Company from 2009-2010, and Organon from 2007-2010. He currently consults for D&A Pharma, ADial Pharmaceuticals, LLC, (with which he also serves as chairman), and Psychological Education Publishing Company (PEPCo), LLC. Topiramate is currently available as a generic medicine in the USA, and Professor Johnson has no commercial affiliation with any generic manufacturer of topiramate. Dr. Liu reported serving as a consultant for Celladon Corporation. No other disclosures were reported.
B. Funding/ Support
This study was supported by NIH grants 501 DAO17296-04 and 5 RC1AA019274-02, and Agency for Healthcare Research and Quality grant 7 RO1 HS020263092.
People with mental illness smoke at much higher rates than the overall population. But the popular belief that they are self-medicating is most likely wrong, according to researchers at the Indiana University School of Medicine. Instead, they report, research indicates that psychiatric disease makes the brain more susceptible to addiction.
As smoking rates in the general population have fallen below 25 percent, smoking among the mentally ill has remained pervasive, encompassing an estimated half of all cigarettes sold. Despite the well-known health dangers of tobacco consumption, smoking among the mentally ill has long been widely viewed as “self-medication,” reducing the incentive among health care professionals to encourage such patients to quit.
"This is really a devastating problem for people with mental illness because of the broad health consequences of nicotine addiction," said R. Andrew Chambers, M.D., associate professor of psychiatry at the IU School of Medicine. "Nicotine addiction is the number one cause of premature illness and death in the United States, and most of that morbidity and mortality is concentrated in people with mental illness."
In a report published recently in the journal Addiction Biology, the research team lead by Dr. Chambers reported the results of experiments using an established animal model of schizophrenia in which rats display a neuropsychiatric syndrome that closely resembles the disease.
Both the schizophrenia-model rats and normal rats were given access to intravenous self-administration of nicotine.
"The mentally ill rats acquired nicotine use faster and consumed more nicotine," Dr. Chambers said. "Then when we cut them off from access to nicotine, they worked much harder to restore access to nicotine than did the normal ‘control’ rats."
In additional testing, the researchers found that administration of nicotine provided equal, but minimal, cognitive benefits to both groups of rats when performing a memory test. When the nicotine was withdrawn, however, both groups of rats were more cognitively impaired, so that any cognitive benefits to nicotine administration were “paid for” by cognitive impairments later.
“These results strongly suggest that what has changed in mental illness to cause smoking at such high rates results in a co-morbid addiction to which the mentally ill are highly biologically vulnerable. The evidence suggests that the vulnerability is an involuntary biological result of the way the brain is designed and how it develops after birth, rather than it being about a rational choice to use nicotine as a medicine,” Dr. Chambers said.
The data, he said, point to neuro-developmental mechanisms that increase the risk of addiction. Better understanding of those mechanisms could lead to better prevention and treatment strategies, especially among mentally ill smokers, Dr. Chambers said.
A video interview of Dr. Chambers discussing his research is available here.
“Heroin itself is an inactive substance,” explains Jørg Mørland, Norwegian forensic medicine and toxicology researcher. “The substances that heroin forms in the body are mainly what enter the brain and cause the narcotic effects.”
The heroin high and feelings of pain relief manifest themselves almost immediately after the drug has been injected. Yet it was shown many years ago that heroin is inactive at the opioid receptors in the brain.
So what is it about heroin that brings about such a pronounced effect? A number of research projects funded under the Programme on Alcohol and Drug Research (RUSMIDDEL) at the Research Council of Norway may help to solve the mystery.
“Gaining a thorough understanding of the effects of heroin and of the neurobiological mechanisms involved will be a valuable basis for the development of new treatments for addiction,” states Jørg Mørland, who is the project manager of an ongoing project on this important subject, the most recent in a long line of such Norwegian projects which he has headed.
Dr Mørland is a senior researcher at the Norwegian Institute of Public Health and Professor emeritus at the University of Oslo. Through studies on rats and mice, he and his colleagues have come up with new findings that may be significant to the development of new treatment methods.
Heroin metabolises rapidly
One widely-held theory has been that heroin passes quickly into the brain where it is converted into morphine, and that what users are actually experiencing are the effects of morphine. As it turns out, however, heroin undergoes a number of important transformations on its way to the brain. Just a few minutes after injection, the conversion of heroin into the metabolite 6-MAM is almost complete.
“Our research shows that it is primarily 6-MAM that crosses the blood-brain barrier and that heroin as such only enters the brain to a small degree. Thirty minutes after injecting heroin, 6-MAM is the predominant substance both in the blood and in the brain,” Dr Mørland explains.
The presence of 6-MAM also results in a sharp increase in the signalling molecule, dopamine, in certain areas of the brain. This plays a pivotal role in the rewarding effect.
“This points towards 6-MAM as the main substance behind all the acute effects of heroin,” says Dr Mørland.
“After about an hour, most of the 6-MAM has been converted into morphine. Morphine acts rapidly on the body and is the dominant component for the next hours, but from six to twelve hours after injection the effects observed are mostly consequences of a metabolite formed from morphine, morphin-6-glucuronide.
Looking for a new treatment
“We are working to understand the roles of all these metabolites and to investigate potential treatments to counter their effects,” Dr Mørland states.
The current approach to treating heroin addiction in Norway is pharmacotherapy – using methadone, subutex or subuxone. These are synthetic substances that all work in the same way as heroin, however, and are addictive in their own right.
“The treatment method involves administering these substances over the course of a day to reduce the rewarding effect. The intent is to diminish the patient’s preoccupation with finding heroin in order to lead a more normal life,” Dr Mørland points out.
Researchers at the Norwegian Centre for Addiction Research (SERAF) in Oslo are examining sustained-release naltrexone – a non-addictive opioid antagonist that blocks the effects of opiates in the brain. Dr Mørland is hopeful that his research will make it possible to affect opiates even before they reach the brain.
An opiate roadblock
“It may be possible to block these substances from ever entering the brain, thereby modifying the effect of heroin,” Dr Mørland adds.
As part of a new project, he and his colleagues will study the effect of a 6-MAM antibody developed by a Norwegian company. The antibody binds to the 6-MAM in the blood, making the 6-MAM molecule too large to cross the blood-brain barrier.
“If we succeed in getting this antibody to work it could block much – and maybe even all – of the effect of heroin,” the researcher concludes.
New research from the University of Missouri indicates escapism, social interaction and rewards fuel problematic video-game use among “very casual” to “hardcore” adult gamers. Understanding individual motives that contribute to unhealthy game play could help counselors identify and treat individuals addicted to video games.
“The biggest risk factor for pathological video game use seems to be playing games to escape from daily life,” said Joe Hilgard, a doctoral candidate in the Department of Psychological Sciences in the MU College of Arts and Science. “Individuals who play games to get away from their lives or to pretend to be other people seem to be those most at-risk for becoming part of a vicious cycle. These gamers avoid their problems by playing games, which in turn interferes with their lives because they’re so busy playing games.”
Problematic video game use is more than just excessive use of video games; it also includes a variety of unhealthy behaviors, such as lying to others about how much time is spent playing games and missing work or other obligations to play games.
“People who play games to socialize with other players seem to have more problems as well,” Hilgard said. “It could be that games are imposing a sort of social obligation on these individuals so that they have to set aside time to play with other players. For example, in games like World of Warcraft, most players join teams or guilds. If some teammates want to play for four hours on a Saturday night, the other players feel obligated to play or else they may be cut from the team. Those play obligations can mess with individuals’ real-life obligations.”
Problematic video game use isn’t all that different from other types of addictive behavior, such as alcohol or drug abuse, which can be spurred by poor coping strategies, Hilgard said.
“Gamers who are really into getting to the next level or collecting all of the in-game items seem to have unhealthier video-game use,” Hilgard said. “When people talk about games being ‘so addictive,’ usually they’re referring to games like Farmville or Diablo that give players rewards, such as better equipment or stronger characters, as they play. People who are especially motivated by these rewards can find it hard to stop playing.”
Understanding individuals’ motives for playing video games can inform researchers, game developers and consumers about why certain games attract certain individuals, Hilgard said.
“Researchers have suspected that Massively Multiplayer Online Role-Playing Games (MMORPGs) are the most addictive genre of video games,” Hilgard said. “Our study provides some evidence that supports that claim. The games provide opportunities for players to advance levels, to join teams and to play with others. In addition, the games provide enormous fantasy worlds that gamers can disappear into for hours at a time and forget about their problems. MMORPGs may be triple threats for encouraging pathological game use because they present all three risk factors to gamers.”
“Consistent with previous research, we did not find a perfect relationship between total time spent playing games and addictive video game behaviors,” said study co-author Christopher Engelhardt, a postdoctoral research fellow in the Department of Health Psychology in the MU School of Health Professions and the MU Thompson Center for Autism and Neurodevelopmental Disorders. “Additionally, other variables, such as the proportion of free time spent playing video games, seem to better predict game addiction above and beyond the total amount of time spent playing video games.”
The open-access journal, Frontiers in Psychology, published the article, “Individual differences in motives, preferences, and pathology in video games: the gaming attitudes, motives, and experiences scales (GAMES),” earlier in September.
A new study in Biological Psychiatry suggests the answer is no
It is often said that once people develop an addiction, they can never completely eliminate their attraction to the abused substance. New findings provide further support for this notion by suggesting that even long-term abstinence from cocaine does not result in a complete normalization of brain circuitry.
Scientists are currently trying to answer some of the ‘chicken and egg’ questions surrounding the abuse of drugs. In particular, one of those questions is whether individuals who abuse psychostimulants like cocaine are more impulsive and show alterations in brain reward circuits as a consequence of using the drug, or whether such abnormalities existed prior to their drug use. In the former case, one might expect brain alterations to normalize following prolonged drug abstinence.
To address these questions, Krishna Patel at Institute of Living/Hartford Hospital and colleagues compared neural responses between three groups of people who were asked to complete a task that resembles bidding on eBay items. The 3 groups consisted of 47 healthy controls, 42 currently drug-abusing cocaine users, and 35 former cocaine users who had been abstinent an average of 4 years. They also compared all three groups on their levels of impulsivity and reward responding.
They found that active users showed abnormal activation in multiple brain regions involved with reward processing, and that the abstinent individuals who were previously cocaine dependent manifested differences in a subset of those regions. Both current and former cocaine users displayed similarly elevated impulsivity measures compared to healthy controls, which may indicate that these individuals had a pre-existing risk for addiction. Indeed, the degree of impulsivity correlated with several of the brain activation abnormalities.
These findings suggest that prolonged abstinence from cocaine may normalize only a subset of the brain abnormalities associated with active drug use.
"The knowledge that some neural changes associated with addiction persist despite long periods of abstinence is important because it supports clinical wisdom that recovery from addiction is a lifelong process," says Dr. John Krystal, Editor of Biological Psychiatry. "Further, it is the start of a deeper question: How do these persisting changes develop and how can they be reversed?"
The authors agree that further studies will be needed to investigate such questions, including the continued attempt to determine the extent to which differences in former cocaine users reflect aspects of pre-existing features, exposure to cocaine, or recovery.
Neuroscientists at Western University (London, Canada) have made a remarkable new discovery revealing the underlying molecular process by which opiate addiction develops in the brain. Opiate addiction is largely controlled by the formation of powerful reward memories that link the pleasurable effects of opiate-class drugs to environmental triggers that induce drug craving in individuals addicted to opiates. The research is published in the September 11th issue of The Journal of Neuroscience.
The Addiction Research Group led by Steven Laviolette of the Schulich School of Medicine & Dentistry was able to identify how exposure to heroin induces a specific switch in a memory molecule in a region of the brain called the basolateral amygdala, which is involved importantly in controlling memories related to opiate addiction, withdrawal, and relapse. Using a rodent model of opiate addiction, Laviolette’s team found that the process of opiate addiction and withdrawal triggered a switch between two molecular pathways in the amygdala controlling how opiate addiction memories were formed. In the non-dependent state, they found that a molecule called extracellular signal-related kinase or “ERK” was recruited for early stage addiction memories. However, once opiate addiction had developed, the scientists observed a functional switch to a separate molecular memory pathway, controlled by a molecule called calmodulin-dependent kinase II or “CaMKII”.
“These findings will shed important new light on how the brain is altered by opiate drugs and provide exciting new targets for the development of novel pharmacotherapeutic treatments for individuals suffering from chronic opiate addiction,” says Laviolette, an associate professor in the Departments of Anatomy & Cell Biology, Psychiatry, and Psychology.
Key details of the way nerve cells in the brain remember pleasure are revealed in a study by University of Alabama at Birmingham (UAB) researchers published today in the journal Nature Neuroscience. The molecular events that form such “reward memories” appear to differ from those created by drug addiction, despite the popular theory that addiction hijacks normal reward pathways.
Brain circuits have evolved to encourage behaviors proven to help our species survive by attaching pleasure to them. Eating rich food tastes good because it delivers energy and sex is desirable because it creates offspring. The same systems also connect in our mind’s environmental cues with actual pleasures to form reward memories.
This study in rats supports the idea that the mammalian brain features several memory types, each using different circuits, with memories accessed and integrated as needed. Ancient memory types include those that remind us what to fear, what to seek out (reward), how to move (motor memory) and navigate (place memory). More recent developments enable us to remember the year Columbus sailed and our wedding day.
“We believe reward memory may serve as a good model for understanding the molecular mechanisms behind many types of learning and memory,” said David Sweatt, Ph.D., chair of the UAB Department of Neurobiology, director of the Evelyn F. McKnight Brain Institute at UAB and corresponding author for the study. “Our results provide a leap in the field’s understanding of reward-learning mechanisms and promise to guide future attempts to solve related problems such as addiction and criminal behavior.”
The study is the first to illustrate that reward memories are created by chemical changes that influence known memory-related genes in nerve cells within a brain region called the ventral tegmental area, or VTA. Experiments that blocked those chemical changes — a mix of DNA methylation and demethylation — in the VTA prevented rats from forming new reward memories.
Methylation is the attachment of a methyl group (one carbon and three hydrogens) to a DNA chain at certain spots (cytosine bases). When methylation occurs near a gene or inside a gene sequence, it generally is thought to turn the gene off and its removal is thought to turn the gene on. This back-and-forth change affects gene expression without changing the code we inherit from our parents. Operating outside the genetic machinery proper, epigenetic changes enable each cell type to do its unique job and to react to its environment.
Furthermore, a stem cell in the womb that becomes bone or liver cells must “remember” its specialized nature and pass that identity to its descendants as they divide and multiply to form organs. This process requires genetic memory, which largely is driven by methylation. Note, most nerve cells do not divide and multiply as do other cells. They can’t, according to one theory, because they put their epigenetic mechanisms to work making actual memories.
Natural pleasure versus addiction
The brain’s pleasure center is known to proceed through nerve cells that signal using the neurochemical dopamine and generally is located in the VTA. Dopaminergic neurons exhibit a “remarkable capacity” to pass on pleasure signals. Unfortunately, the evolutionary processes that attached pleasure to advantageous behaviors also accidentally reinforced bad ones.
Addiction to all four major classes of abused drugs — psychostimulants, opiates, ethanol and nicotine — has been linked to increased dopamine transmission in the same parts of the brain associated with normal reward processing. Cues that predict both normal reward and effects of cocaine or alcohol also make dopamine nerve cells fire as do the experiences they recall. That had led to idea that drug addiction must take over normal reward-memory nerve pathways.
Along those lines, past research has argued that dopamine-producing neurons in the VTA — and in a region that receives downstream dopamine signals from the VTA called the nucleus accumbens (NAC) — both were involved in natural reward and drug-addiction-based memory formation. While that may true to some extent, this study revealed that blocking methylation in the VTA with a drug stopped the ability of rats to attach rewarding experiences to remembered cues but doing so in the NAC did not.
“We observed an important distinction, not in circuitry, but instead in the epigenetic regulation of that circuitry between natural reward responses and those that occur downstream with drugs of abuse or psychiatric illness,” said Jeremy Day, Ph.D., a post-doctoral scholar in Sweatt’s lab and first author for this study. “Although drug experiences may co-opt normal reward mechanisms to some extent, our results suggest they also may engage entirely separate epigenetic mechanisms that contribute only to addiction and that may explain its strength.”
To investigate the molecular and epigenetic changes in the VTA, researchers took their cue from 19th century Russian physiologist Ivan Pavlov, who was the first to study the phenomenon of conditioning. By ringing a bell each day before giving his dogs food, Pavlov soon found that the dogs would salivate at the sound of the bell.
In this study, rats were trained to associate a sound tone with the availability of sugar pellets in their feed ports. This same animal model has been used to make most discoveries about how human dopamine neurons work since the 1990s, and most approved drugs that affect the dopamine system (e.g. L-Dopa for Parkinson’s) were tested in it before being cleared for human trials.
To separate the effects of memory-related brain changes from those arising from the pleasure of the eating itself, the rats were separated into three groups. Rats in the “CS+” rats got sugar pellets each time they heard a sound cue. The “CS–” group heard the sound the same number of times and received as many sugar pellets — but never together. A third tone-only group heard the sounds but never received sugar rewards.
Rats that always received sugar with the sound cue were found to poke their feed ports with their noses at least twice as often during this cue as control rats after three, 25-sound-cue sessions. Nose pokes are an established measure of the degree to which a rat has come to associate a cue with the memory of a tasty treat.
The team found that those CS+ rats (sugar paired with sound) that were better at forming reward memories had significantly higher expression of the genes Egr1 and Fos than control rats These genes are known to regulate memory in other brain regions by fine-tuning the signaling capacity of the connections between nerve cells. In a series of experiments, the team next revealed the methylation and demethylation pattern that drove the changes in gene expression seen as memories formed.
The study demonstrated that reward-related experiences caused both types of DNA methylation known to regulate gene expression.
One type involves attaching methyl groups to pieces of DNA called promoters, which reside immediately upstream of individual gene sequences (between genes), that tell the machinery that follows genetic instructions to “start reading here.” The attachment of a methyl group to a promoter generally interferes with this and silences a nearby gene. However, ancient organisms such as plants and insects have less methylation between their genes, and more of it within the coding regions of the genes themselves (within gene bodies). Such gene-body methylation has been shown to encourage rather than silence gene expression.
Specifically, the team reported that two sites in the promoter for Egr1 gene were demethylated during reward experiences and, to a greater degree, in rats that associated the sugar with the sound cue. Conversely, spots within the gene body of both Egr1 and Fos underwent methylation as reward memories formed.
“When designing therapeutic treatments for psychiatric illness, addictions or memory disorders, you must profoundly understand the function of the biological systems you’re working with,” Day said. “Our field has learned from experience that attempts to treat addiction with something that globally impairs normal reward perception or reward memories do not succeed. Our study suggests the possibility that future treatments could dial down drug addiction or mental illness without affecting normal rewards.”
Within 24 hours of quitting the drug, your withdrawal symptoms begin. Initially, they’re subtle: The first thing you notice is that you feel mentally foggy, and lack alertness. Your muscles are fatigued, even when you haven’t done anything strenuous, and you suspect that you’re more irritable than usual.
Over time, an unmistakable throbbing headache sets in, making it difficult to concentrate on anything. Eventually, as your body protests having the drug taken away, you might even feel dull muscle pains, nausea and other flu-like symptoms.
This isn’t heroin, tobacco or even alcohol withdrawl. We’re talking about quitting caffeine, a substance consumed so widely (the FDA reports thatmore than 80 percent of American adults drink it daily) and in such mundane settings (say, at an office meeting or in your car) that we often forget it’s a drug—and by far the world’s most popular psychoactive one.
Like many drugs, caffeine is chemically addictive, a fact that scientists established back in 1994. This past May, with the publication of the 5th edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM), caffeine withdrawal was finally included as a mental disorder for the first time—even though its merits for inclusion are symptoms that regular coffee-drinkers have long known well from the times they’ve gone off it for a day or more.
Why, exactly, is caffeine addictive? The reason stems from the way the drug affects the human brain, producing the alert feeling that caffeine drinkers crave.
Soon after you drink (or eat) something containing caffeine, it’s absorbed through the small intestine and dissolved into the bloodstream. Because the chemical is both water- and fat-soluble (meaning that it can dissolve in water-based solutions—think blood—as well as fat-based substances, such as our cell membranes), it’s able to penetrate the blood-brain barrier and enter the brain.
Structurally, caffeine closely resembles a molecule that’s naturally present in our brain, called adenosine (which is a byproduct of many cellular processes, including cellular respiration)—so much so, in fact, that caffeine can fit neatly into our brain cells’ receptors for adenosine, effectively blocking them off. Normally, the adenosine produced over time locks into these receptors and produces a feeling of tiredness.
When caffeine molecules are blocking those receptors, they prevent this from occurring, thereby generating a sense of alertness and energy for a few hours. Additionally, some of the brain’s own natural stimulants (such as dopamine) work more effectively when the adenosine receptors are blocked, and all the surplus adenosine floating around in the brain cues the adrenal glands to secrete adrenaline, another stimulant.
For this reason, caffeine isn’t technically a stimulant on its own, says Stephen R. Braun, the author or Buzzed: the Science and Lore of Caffeine and Alcohol, but a stimulant enabler: a substance that lets our natural stimulants run wild. Ingesting caffeine, he writes, is akin to “putting a block of wood under one of the brain’s primary brake pedals.” This block stays in place for anywhere from four to six hours, depending on the person’s age, size and other factors, until the caffeine is eventually metabolized by the body.
In people who take advantage of this process on a daily basis (i.e. coffee/tea, soda or energy drink addicts), the brain’s chemistry and physical characteristics actually change over time as a result. The most notable change is that brain cells grow more adenosine receptors, which is the brain’s attempt to maintain equilibrium in the face of a constant onslaught of caffeine, with its adenosine receptors so regularly plugged (studies indicate that the brain also responds by decreasing the number of receptors for norepinephrine, a stimulant). This explains why regular coffee drinkers build up a tolerance over time—because you have more adenosine receptors, it takes more caffeine to block a significant proportion of them and achieve the desired effect.
This also explains why suddenly giving up caffeine entirely can trigger a range of withdrawal effects. The underlying chemistry is complex and not fully understood, but the principle is that your brain is used to operating in one set of conditions (with an artificially-inflated number of adenosine receptors, and a decreased number of norepinephrine receptors) that depend upon regular ingestion of caffeine. Suddenly, without the drug, the altered brain chemistry causes all sorts of problems, including the dreaded caffeine withdrawal headache.
The good news is that, compared to many drug addictions, the effects are relatively short-term. To kick the thing, you only need to get through about 7-12 days of symptoms without drinking any caffeine. During that period, your brain will naturally decrease the number of adenosine receptors on each cell, responding to the sudden lack of caffeine ingestion. If you can make it that long without a cup of joe or a spot of tea, the levels of adenosine receptors in your brain reset to their baseline levels, and your addiction will be broken.