ScienceDaily (Jan. 27, 2011) — The growing numbers of new cases of substance abuse disorders are perplexing. After all, the course of drug addiction so often ends badly. The negative consequences of drug abuse appear regularly on TV, from stories of celebrities behaving in socially inappropriate and self-destructive ways while intoxicated to dramatization of the rigors of drug withdrawal on “Intervention” and other reality shows.

Schools now educate students about the risks of addiction. While having a keen awareness of the negative long-term repercussions of substance use protects some people from developing addictions, others remain vulnerable.

One reason that education alone cannot prevent substance abuse is that people who are vulnerable to developing substance abuse disorders tend to exhibit a trait called “delay discounting,” which is the tendency to devalue rewards and punishments that occur in the future. Delay discounting may be paralleled by “reward myopia,” a tendency to opt for immediately rewarding stimuli, like drugs.

Thus, people vulnerable to addiction who know that drugs are harmful in the long run tend to devalue this information and to instead be drawn to the immediately rewarding effects of drugs.

Delay discounting is a cognitive function that involves circuits including the frontal cortex. It builds upon working memory, the brain’s “scratchpad,” i.e., a system for temporarily storing and managing information reasoning to guide behavior.

In a new article in Biological Psychiatry that studied this process, Warren Bickel and colleagues used an approach borrowed from the rehabilitation of individuals who have suffered a stroke or a traumatic brain injury. They had stimulant abusers repeatedly perform a working memory task, “exercising” their brains in a way that promoted the functional enhancement of the underlying cognitive circuits.

They found that this type of training improved working memory and also reduced their discounting of delayed rewards.

“The legal punishments and medical damages associated with the consumption of drugs of abuse may be meaningless to the addict in the moment when they have to choose whether or not to take their drug. Their mind is filled with the imagination of the pleasure to follow,” commented Dr. John Krystal, Editor of Biological Psychiatry. “We now see evidence that this myopic view of immediate pleasures and delayed punishments is not a fixed feature of addiction. Perhaps cognitive training is one tool that clinicians may employ to end the hijacking of imagination by drugs of abuse.”

Dr. Bickel agrees, adding that “although this research will need to be replicated and extended, we hope that it will provide a new target for treatment and a new method to intervene on the problem of addiction.”

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The above story is reprinted (with editorial adaptations by ScienceDaily staff) from materials provided by Elsevier, via AlphaGalileo.

Journal Reference:

1. Warren K. Bickel, Richard Yi, Reid D. Landes, Paul F. Hill, Carole Baxter. Remember the Future: Working Memory Training Decreases Delay Discounting Among Stimulant Addicts. Biological Psychiatry, 2011; 69 (3): 260 DOI: 10.1016/j.biopsych.2010.08.017

Disclaimer: This article is not intended to provide medical advice, diagnosis or treatment. Views expressed here do not necessarily reflect those of ScienceDaily or its staff.

ScienceDaily (Jan. 5, 2011) — Researchers have produced a lasting anti-cocaine immunity in mice by giving them a safe vaccine that combines bits of the common cold virus with a particle that mimics cocaine.

In their study, published Jan. 4 in the online edition of Molecular Therapy and funded by the National Institute on Drug Abuse, the researchers say this novel strategy might be the first to offer cocaine addicts a fairly simple way to break and reverse their habit, and it might also be useful in treating other addictions, such as to nicotine, heroin and other opiates.

“Our very dramatic data shows that we can protect mice against the effects of cocaine, and we think this approach could be very promising in fighting addiction in humans,” says the study’s lead investigator, Dr. Ronald G. Crystal, chairman and professor of genetic medicine at Weill Cornell Medical College.

He says the antibody immune response produced in lab mice by the vaccine binds to, and sequesters, cocaine molecules before the drug reached the brains of these animals — and prevents any cocaine-related hyperactivity. The vaccine effect lasted for at least 13 weeks, the longest time point evaluated.

“While other attempts at producing immunity against cocaine have been tried, this is the first that will likely not require multiple, expensive infusions, and that can move quickly into human trials,” Dr. Crystal says. “There is currently no FDA-approved vaccine for any drug addiction.”

“An approach that works is desperately needed for cocaine addiction, which is an intransigent problem worldwide,” he adds. “There are no therapies now.”

The novelty of this possible treatment is that it hooks a chemical that is very similar in structure to cocaine, onto components of the adenovirus, a common cold virus. In this way, the human immune system is alerted to an infectious agent (the virus) but also learns to “see” the cocaine as an intruder as well, Dr. Crystal says. Once the structure of the new intruder is recognized, natural immunity builds to cocaine particles, so any time cocaine is snorted or used in any way, antibodies to the substance are quickly produced and the cocaine molecules are engulfed by the antibodies and prevented from reaching the brain.

“The human immune system doesn’t naturally tag cocaine as something to be destroyed — just like all small-molecule drugs are not eliminated by antibodies,” he says. “We have engineered this response so that it is against the cocaine mimic.”

In this study, a team of researchers — scientists from Weill Cornell Medical College, Cornell University in Ithaca, and the Scripps Research Institute in La Jolla, Calif. — ripped apart an adenovirus, retrieving only the components that elicit an immune response and discarding those that produce sickness. They then hooked the cocaine analog on to these proteins to make the vaccine. “We used the cocaine analog because it is a little more stable than cocaine, and it also elicits better immunity,” Dr. Crystal says.

The researchers then injected billions of these viral concoctions into “garden variety” laboratory mice (mice that are not genetically engineered). They found a strong immune response was generated against the vaccine, and that these antibodies, when put in test tubes, gobbled up cocaine.

They then tested the vaccine’s effect on behavior, and found that mice that received the vaccine before cocaine were much less hyperactive while on the drug than mice that were not vaccinated. The effect was even seen in mice that received large, repetitive doses of cocaine. Proportionally, the cocaine doses reflected amounts that humans might use.

The vaccine needs to be tested in humans, of course, says Dr. Crystal, but he predicts that if it works, it will function best in people who are already addicted to cocaine and who are trying to stop using the drug. “The vaccine may help them kick the habit because if they use cocaine, an immune response will destroy the drug before it reaches the brain’s pleasure center.”

In addition to Dr. Crystal, the study’s authors included Martin J. Hicks, Bishnu P. De, Jonathan B. Rosenberg, Jesse T. Davidson, Neil R. Hackett, Stephen M. Kaminsky and Miklos Toth of Weill Cornell Medical College; Jason G. Mezey of Weill Cornell Medical College and Cornell University in Ithaca, N.Y.; Amira Y. Moreno, Kim D. Janda, Sunmee Wee and George F. Koob of the Scripps Research Institute in La Jolla, Calif.

The study was funded by the National Institute on Drug Abuse (NIDA) of the National Institutes of Health.

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The above story is reprinted (with editorial adaptations by ScienceDaily staff) from materials provided by Weill Cornell Medical College.

Journal Reference:

1. Martin J Hicks, Bishnu P De, Jonathan B Rosenberg, Jesse T Davidson, Amira Y Moreno, Kim D Janda, Sunmee Wee, George F Koob, Neil R Hackett, Stephen M Kaminsky, Stefan Worgall, Miklos Toth, Jason G Mezey and Ronald G Crystal. Cocaine Analog Coupled to Disrupted Adenovirus: A Vaccine Strategy to Evoke High-titer Immunity Against Addictive Drugs. Molecular Therapy, 2011; DOI: 10.1038/mt.2010.280

Disclaimer: This article is not intended to provide medical advice, diagnosis or treatment. Views expressed here do not necessarily reflect those of ScienceDaily or its staff.

ScienceDaily (Dec. 22, 2010) — Nearly one in five whites could carry a genetic variant that substantially increases their odds of being susceptible to severe cocaine abuse, according to new research.

This genetic variant, characterized by one or both of two tiny gene mutations, alters the brain’s response to specific chemical signals. In the study, led by Ohio State University researchers, the variant was associated with a more than threefold increase in the odds that carriers will be susceptible to severe cocaine abuse leading to fatal overdosing, compared to non-carriers.

Among whites, one or both mutations were found in more than 40 percent of autopsy brain samples taken from people who had abused cocaine, compared to 19 percent of samples from people who lived drug-free. Overall, one in five samples from whites in the control group and one in two to three samples in the cocaine overdose group contained the genetic variant, compared to one in eight African Americans, in whom the variant is less prevalent.

The mutations — either alone or in combination — affect how dopamine modulates brain activity. Dopamine, a neurotransmitter, is a chemical messenger vital to the regular function of the central nervous system. Previous research has established that cocaine blocks dopamine transporters from absorbing dopamine after its release, leaving the chemical outside the brain cells and creating a feeling of euphoria.

In people who carry one or both of the mutations, the function of a gene responsible for transmitting dopamine signals in the brain is altered. Researchers speculate that this altered gene function sets up a vicious circle of chemical signals that could lead to a craving for a substance that can maintain elevated levels of dopamine in the brain.

The researchers say many questions about cocaine abuse susceptibility remain unanswered: Do the mutations increase the chances someone will try cocaine in the first place? Or do they deepen the cocaine craving and lead to heavy abuse? And how strong is the overall effect of this trait?

But what the research does show is the first strong connection in brain tissue between the mutations and the presence of severe cocaine abuse.

“We now have both good biological rationale and clinical association showing that this has an impact on the way cocaine abuse might progress or might be initiated,” said Wolfgang Sadee, professor of pharmacology and director of the Program in Pharmacogenomics at Ohio State and senior author of the study. “We have found a frequent variant in one of the key candidate genes that can affect cocaine abuse, but more importantly, it also opens the avenue to explore how this variant affects response to therapies for a variety of psychiatric disorders that involve dopamine.”

The research appears online and is scheduled for later print publication in the journal Neuropsychopharmacology.

The mutations described in this study are single-nucleotide polymorphisms, or SNPs (pronounced “snips”). Each gene contains two alternative forms — called alleles — that are identical in most people. However, in some cases, the activity level, or expression, of an allele can differ from its partner allele in a single gene. Each small difference is a SNP.

SNPs have become the primary study target of Ohio State’s Program in Pharmacogenomics. But the mutations Sadee studies aren’t just any SNPs. Up until about 10 years ago, most biological research focused on these tiny mutations in areas of genes that produce proteins. But Sadee’s lab explores the role of SNPs that are present earlier in a gene’s existence, located in regions called introns.

A better understanding of the human genome has led scientists to determine that about 90 percent of the mutations that can lead to disease or govern behavior actually are located in these deeper and often overlooked regions of genes, and that they regulate the genes’ functions long before protein production begins.

In this work, Sadee and colleagues examined allele differences in a gene called dopamine receptor D2. This receptor has a short form and a long form, each of which has a distinct function in the process of regulating dopamine after it is released so its levels stay normal in the brain.

In people who carry these polymorphisms, however, the ratio of the short form to long form of the gene is disrupted. One mutation shortens the short form, and the other lengthens the long form. When this happens with either one or both of the SNPs, most of the short form of the gene is wiped out, and the receptor’s dopamine regulatory role malfunctions.

Sadee’s lab identified these SNPs and showed in previous studies that their presence influenced cognitive processing, another brain function that is affected by dopamine. The researchers then turned to behaviors and disorders associated with dopamine regulation, including cocaine abuse.

To test the clinical relevance of the SNPs, the researchers examined human brain autopsy tissues of people who had died of cocaine overdose and from age-matched drug-free controls. The researchers used a technique that measures for what is known as allelic messenger RNA expression imbalance, which was developed in Sadee’s pharmacogenomics core lab.

Among whites, more than 40 percent of the samples taken from people who had abused cocaine contained these polymorphisms, compared to less than one in five of the drug-free brain samples.

The finding suggests that whites with at least one of these mutations are 3.4 times more likely to be susceptible to cocaine abuse than are whites without either mutation. The study suggested that whites with both mutations, known as homozygous carriers, are at even higher risk for susceptibility to cocaine abuse, but the results were not significant when subjected to statistical analysis, meaning this higher risk could occur just as often by chance.

Sadee noted that more research is needed to collect enough evidence to merit a warning to people who might be at higher risk for sensitivity to cocaine. “But this work is pointing in the right direction. There is very little in the genetics literature that points as strongly to a specific problem as this paper does,” he said.

No test currently exists for these polymorphisms. Sadee said the scientific community wants to ensure that all SNPs that are considered potential biomarkers for genetic traits must first be carefully vetted to ensure there is ample evidence of risks or benefits associated with each mutation before testing is available.

Because the dopamine receptor D2 is a primary target for nearly all antipsychotic drugs, Sadee and colleagues are now investigating how these mutations might affect carriers’ response to drugs that act on this gene.

“We now have found that this gene contains frequent variants that affect some fundamental behavior. There are a few other genes that do, too. Now we want to look at how those genes interact,” Sadee said. “On top of that, in some psychiatric disorders there are treatments that depend on the dopaminergic system, and only 50 percent are effective. So now the question becomes, would these SNPs, together with another gene, predict whether or not somebody responds to these treatments or becomes worse?”

This work is supported by the National Institutes of Health.

Co-authors include Robert Moyer, Danxin Wang, Audrey Papp and Ryan Smith of the Program in Pharmacogenomics at Ohio State, and Linda Duque and Deborah Mash of the University of Miami School of Medicine. The university’s Miami Brain Endowment Bank supplied the autopsy brain tissue samples used in the study.

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The above story is reprinted (with editorial adaptations by ScienceDaily staff) from materials provided by Ohio State University. The original article was written by Emily Caldwell.

Journal Reference:

1. Robert A Moyer, Danxin Wang, Audrey C Papp, Ryan M Smith, Linda Duque, Deborah C Mash, Wolfgang Sadee. Intronic Polymorphisms Affecting Alternative Splicing of Human Dopamine D2 Receptor Are Associated with Cocaine Abuse. Neuropsychopharmacology, 2010; DOI: 10.1038/npp.2010.208

Disclaimer: This article is not intended to provide medical advice, diagnosis or treatment. Views expressed here do not necessarily reflect those of ScienceDaily or its staff.

ScienceDaily (Dec. 16, 2010) — MDMA — commonly known as ecstasy — increases feelings of empathy and social connection. These ’empathogenic’ effects suggest that MDMA might be useful to enhance the psychotherapy of people who struggle to feel connected to others, as may occur in association with autism, schizophrenia, or antisocial personality disorder.

However, these effects have been difficult to measure objectively, and there has been limited research in humans. Now, University of Chicago researchers, funded by the National Institute on Drug Abuse, are reporting their new findings in healthy volunteers in the current issue of Biological Psychiatry.

Dr. Gillinder Bedi, author, explained: “We found that MDMA produced friendliness, playfulness, and loving feelings, even when it was administered to people in a laboratory with little social contact. We also found that MDMA reduced volunteers’ capacity to recognize facial expressions of fear in other people, an effect that may be involved in the increased sociability said to be produced by MDMA.”

These data suggest that MDMA produces effects that make others seem more attractive and friendly, which may serve as a significant motivator in its use as a recreational drug. Importantly, it also makes others appear less threatening, which could increase users’ social risk-taking.

“Within the context of treatment, these effects may promote intimacy among people who have difficulty feeling close to others,” observed Dr. John Krystal, Editor of Biological Psychiatry. “However, MDMA distorts one’s perception of others rather than producing true empathy. Thus, MDMA may cause problems if it leads people to misinterpret the emotional state and perhaps intentions of others.”

Certainly, further research in controlled settings is necessary before MDMA could be considered for use as a psychotherapy treatment. But, these findings also underscore the need to understand more about the ways in which different drugs affect social experiences, given that abused drugs are so commonly used in social settings.

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The above story is reprinted (with editorial adaptations by ScienceDaily staff) from materials provided by Elsevier, via AlphaGalileo.

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1. Gillinder Bedi, David Hyman, Harriet de Wit. Is Ecstasy an ‘Empathogen’? Effects of ±3,4-Methylenedioxymethamphetamine on Prosocial Feelings and Identification of Emotional States in Others. Biological Psychiatry, 2010; 68 (12): 1134 DOI: 10.1016/j.biopsych.2010.08.003

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ScienceDaily (Nov. 26, 2010) — An international team of immunologists studying the effects of cannabis have discovered how smoking marijuana can trigger a suppression of the body’s immune functions. The research, published in the European Journal of Immunology, reveals why cannabis users are more susceptible to certain types of cancers and infections.

The team, led by Dr Prakash Nagarkatti from the University of South Carolina, focused their research on cannabinoids, a group of compounds found inside the cannabis plant, including THC (delta-9 tetahydrocannabinol) which is already used for medical purposes such as pain relief.

“Cannabis is one of the most widely used drugs of abuse worldwide and it is already believed to suppress immune functions making the user more susceptible to infections and some types of cancer,” said Dr Nagarkatti. “We believe the key to this suppression is a unique type of immune cell, which has only recently been identified by immunologists, called myeloid-derived suppressor cells, MDSCs.”

While most immune cells fight against infections and cancers to protect the host, MDSCs actively suppress the immune system. The presence of these cells is known to increase in cancer patients and it is believed that MDSCs may suppress the immune system against cancer therapy, actually promoting cancer growth.

Dr Nagarkatti’s team demonstrated that cannabinoids can trigger a massive number of MDSCs through activation of cannabinoid receptors. This research reveals, for the first time, that marijuana cannabinoids may suppress the immune system by activating these unique cells.

“These results raise interesting questions on whether increased susceptibility to certain types of cancers or infections caused from smoking marijuana results from induction of MDSCs,” said Nagarkatti. “MDSCs seem to be unique and important cells that may be triggered by inappropriate production of certain growth factors by cancer cells or other chemical agents such as cannabinoids, which lead to a suppression of the immune system’s response.”

In a related study, also published in the European journal of Immunology, Dr Christian Vosshenrich from the Institut Pasteur in Paris, reveals that when cancer cells grow they produce a molecule called interleukin-1 β (IL-1β), which also triggers MDSCs. This study identifies how MDSCs produced during cancer growth also weaken the ability of immune cells to kill cancer cells.

“Marijuana cannabinoids present us with a double edged sword,” concluded Dr Nagarkatti. “On one hand, due to their immunosuppressive nature, they can cause increased susceptibility to cancer and infections. However, further research of these compounds could provide opportunities to treat a large number of clinical disorders where suppressing the immune response is actually beneficial.”

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The above story is reprinted (with editorial adaptations by ScienceDaily staff) from materials provided by Wiley-Blackwell, via EurekAlert!, a service of AAAS.

Journal Reference:

1. Venkatesh L. Hegde, Mitzi Nagarkatti and Prakash S. Nagarkatti. Cannabinoid receptor activation leads to massive mobilization of myeloid-derived suppressor cells with potent immunosuppressive properties. European Journal of Immunology, 2010; 40 (12): 3358-3371 DOI: 10.1002/eji.201040667

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ScienceDaily (Nov. 18, 2010) — Two separate discoveries by researchers at the University of Wisconsin-Milwaukee (UWM) offer potential for development of a first-ever pharmacological treatment for cocaine addiction.

In one study, a common beta blocker, propranolol, currently used to treat hypertension and anxiety, has shown to be effective in preventing the brain from retrieving memories associated with cocaine use in animal-addiction models, according to Devin Mueller, UWM assistant professor of psychology and a co-author with James Otis of the research.

The work was presented November 17 at the annual meeting of the Society for Neuroscience in San Diego.

This is the first time that a therapeutic treatment has been shown to block the retrieval of memories associated with drug addiction, a major reason many addicts experience relapse, says Mueller.

Along with the discovery of propranolol’s cocaine-memory blocking effects, the researchers also have identified the primary players in the brain responsible for “extinction” learning — the ability to replace cocaine-associated memories with associations that have no drug “reward.”

Understanding the neural mechanisms for extinction learning can also point to a possible pharmacological target for treating drug addiction, says Mueller.

Cocaine is one of the worst drug addictions to kick, with about 80 percent of those trying to quit experiencing a relapse within six months.

“Right now, there are no FDA-approved medications that are known to successfully treat cocaine abuse,” says Mueller, “only those that are used to treat the symptoms of cocaine withdrawal, which are largely ineffective at preventing relapse.”

The effects of propranolol were long-lasting and could be permanent, he says, even without subsequent doses and even in the presence of stimuli known to induce relapse.

Currently, “exposure therapy” is used to help recovering addicts suppress their drug-seeking behavior. In this therapy, the patient is repeatedly exposed to stimuli that provoke cravings but do not satisfy them. Done repeatedly over time, the patient experiences less craving when presented with those stimuli.

The success of exposure therapy, however, is limited. Combining therapy with the use of propranolol, says Mueller, would boost the effectiveness of the treatment.

Propranolol was chosen for the memory study because it has been used before to ease some withdrawl symptoms experienced recovering cocaine addicts. Those using the drug were able to continue exposure therapy for longer periods than those without the drug.

But Mueller adds that propranolol has never been tested for use with memory extinction before.

In order to develop a drug treatment for overcoming relapse, the next step in the research is to determine where in the brain propranolol acts to mediate the retrieval of cocaine-associated memories.

The team already has found the part of the brain that mediates the process of extinction learning and also has identified certain neuroreceptors — specifically, a variant of the NMDA receptor containing the NR2B subunit — that are necessary for extinction of cocaine-seeking.

“Our research supports the idea that drugs that enhance the function of NR2B-containing NMDA receptors could also augment exposure therapy and increase its effectiveness in preventing relapse,” says Mueller.

The researchers are now examining exactly how these receptors allow extinction learning and whether stimulating them will facilitate or even take the place of extinction training.

The studies were funded by the National Institute on Drug Abuse, one of the National Institutes of Health, and by the UWM Research Growth Initiative.

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