Posts tagged drug addiction
Articles and news from the latest research reports.
Treating Mental Illness by Changing Memories of Things Past
In the novel À larecherche du temps perdu (translated into English as Remembrance of Things Past), Marcel Proust makes a compelling case that our identities and decisions are shaped in profound and ongoing ways by our memories.
This truth is powerfully reflected in mental illnesses,like post traumatic stress disorder (PTSD) and addictions. In PTSD, memories of traumas intrude vividly upon consciousness, causing distress, driving people to avoid reminders of their traumas, and increasing risk for addiction and suicide. In addiction, memories of drug use influence reactions to drug-related cues and motivate compulsive drug use.
What if one could change these dysfunctional memories? Although we all like to believe that our memories are reliable and permanent, it turns out that memories may indeed be plastic.
The process for modifying memories, depicted in the graphic, is called memory reconsolidation. After memories are formed and stored, subsequent retrieval may make them unstable. In other words, when a memory is activated, it also becomes open to revision and reconsolidation in a new form.
"Memory reconsolidation is probably among the most exciting phenomena in cognitive neuroscience today. It assumes that memories may be modified once they are retrieved which may give us the great opportunity to change seemingly robust, unwanted memories," explains Dr. Lars Schwabe of Ruhr-University Bochum in Germany. He and his colleagues have authored a review paper on the topic, published in the current issue of Biological Psychiatry.
The idea of memory reconsolidation was initially discovered and demonstrated in rodents.
The first evidence of reconsolidation in humans was reported in a study in 2003, and the findings have since continued to accumulate. The current report summarizes the most recent findings on memory reconsolidation in humans and poses additional questions that must be answered by future studies.
"Reconsolidation appears to be a fundamental process underlying cognitive and behavioral therapies. Identifying its roles and mechanisms is an important step forward to fully harnessing the reconsolidation process in psychotherapy," said Dr. John Krystal, Editor of Biological Psychiatry.
The translation of the animal data to humans is a vital step for the potential application of memory reconsolidation in the context of mental disorders. Memory reconsolidation could open the door to novel treatment approaches for disorders such as PTSD or drug addiction.
Funded by a $1 million award from the Keck Foundation, biomedical researchers at UCSB will strive to find out who could be more vulnerable to addiction
We’ve all heard the term “addictive personality,” and many of us know individuals who are consistently more likely to take the extra drink or pill that puts them over the edge. But the specific balance of neurochemicals in the brain that spurs him or her to overdo it is still something of a mystery.
“There’s not really a lot we know about specific molecules that are linked to vulnerability to addiction,” said Tod Kippin, a neuroscientist at UC Santa Barbara who studies cocaine addiction. In a general sense, it is understood that animals — humans included — take substances to derive that pleasurable rush of dopamine, the neurochemical linked with the reward center of the brain. But, according to Kippin, that dopamine rush underlies virtually any type of reward animals seek, including the kinds of urges we need to have in order to survive or propagate, such as food, sex or water. Therefore, therapies that deal with that reward system have not been particularly successful in treating addiction.
However, thanks to a collaboration between UCSB researchers Kippin; Tom Soh, professor of mechanical engineering and of materials; and Kevin Plaxco, professor of chemistry and biochemistry — and funding from a $1 million grant from the W. M. Keck Foundation — the neurochemistry of addiction could become a lot less mysterious and a lot more specific. Their study, “Continuous, Real-Time Measurement of Psychoactive Molecules in the Brain,” could, in time, lead to more effective therapies for those who are particularly inclined toward addictive behaviors.
“The main purpose is to try to identify individuals that would be vulnerable to drug addiction based on their initial neurochemistry,” said Kippin. “The idea is that if we can identify phenotypes — observable characteristics — that are vulnerable to addiction and then understand how drugs change the neurochemistry related to that phenotype, we’ll be in a better position to develop therapeutics to help people with that addiction.”
To identify these addiction-prone neurochemical profiles, the researchers will rely on technology they recently developed, a biosensor that can track the concentration of specific molecules in vivo, in real time. One early incarnation of this device was called MEDIC (Microfluidic Electrochemical Detector for In vivo Concentrations). Through artificial DNA strands called aptamers, MEDIC could indicate the concentration of target molecules in the bloodstream.
“Specifically, the DNA molecules are modified so that when they bind their specific target molecule they begin to transfer electrons to an underlying electrode, producing an easily measurable current,” said Plaxco. Prior to the Keck award, the team had shown that this technology could be used to measure specific drugs continuously and in real time in blood drawn from a subject via a catheter. With Keck funding, “the team is hoping to make the leap to measurements performed directly in vivo. That is, directly in the brains of test subjects,” said Plaxco.
For this study, the technology would be modified for use in the brain tissue of awake, ambulatory animals, whose neurochemical profiles would be measured continuously and in real time. The subjects would then be allowed to self-dose with cocaine, while the levels of the drug in their brain are monitored. Also monitored are concomitant changes in the animal’s neurochemistry or drug-seeking (or other) behaviors.
“The key aspect of it is understanding the timing of the neurochemical release,” said Kippin. “What are the changes in neurochemistry that causes the animals to take the drug versus those that immediately follow consumption of the drug?”
Among techniques for achieving this goal, a single existing technology allows scientists to monitor more than one target molecule at a time (e.g., a drug, a metabolite, and a neurotransmitter). However, Kippin noted, it provides an average of one data point about every 20 minutes, which is far slower than the time course of drug-taking behaviors and much less than the sub-second timescale over which the brain responds to drugs. With the implantable biosensor the team has proposed, it would be possible not only to track how the concentration of neurochemicals shift in relation to addictive behavior in real time, but also to simultaneously monitor the concentrations of several different molecules.
“One of our hypotheses about what makes someone vulnerable to addiction is the metabolism of a drug to other active molecules so that they may end up with a more powerful, more rewarding pharmacological state than someone with a different metabolic profile,” Kippin said. “It’s not enough to understand the levels of the compound that is administered; we have to understand all the other compounds that are produced and how they’re working together.”
The implantable biosensor technology also has the potential to go beyond cocaine and shed light on addictions to other substances such as methamphetamines or alcohol. It also could explore behavioral impulses behind obesity, or investigate how memory works, which could lead to further understanding of diseases such as Alzheimers.
![Bad learning
University of Iowa researchers have discovered a new form of neurotransmission that influences the long-lasting memory created by addictive drugs, like cocaine and opioids, and the subsequent craving for these drugs of abuse. Loss of this type of neurotransmission creates changes in brains cells that resemble the changes caused by drug addiction.
The findings, published June 22 in the journal Nature Neuroscience, suggest that targeting this type of neurotransmission might lead to new therapies for treating drug addiction.
“Molecular therapies for drug addiction are pretty much non-existent,” says Collin Kreple, UI graduate student and co-first author of the study. “I think this finding at least provides the possibility of a new molecular target.”
The new form of neurotransmission involves proteins called acid-sensing ion channels (ASICs), which have previously been shown to promote learning and memory, and which are abundant in a part of the brain that is involved in drug addiction. The researchers, led by John Wemmie, professor of psychiatry in the UI Carver College of Medicine, reasoned that disrupting ASIC activity in this brain region (the nucleus accumbens) should reduce learned addiction-related behaviors. However, their experiments showed that loss of ASIC signaling actually increases learned drug-seeking in mice.
When mice learned to associate one side of a chamber with receiving cocaine, animals that lacked the ASIC protein developed an even stronger preference for the “cocaine side” than control mice, suggesting that loss of ASIC had increased addiction behavior. The same result was seen for morphine, another drug of abuse, which has a different mechanism of action than cocaine.
"Always before, the data suggested that when you get rid of ASICs, learning and memory are impaired," Wemmie says. "So we expected the same trend when we studied reward-related learning and behavior and we were surprised to find the opposite."
In a second experiment, rats learned to press a lever to self-administer cocaine. Blocking or removing ASIC in the rat brains caused the animals to self-administer more cocaine than control animals. Conversely, increasing the amount of ASIC by over-expressing the protein seemed to decrease the animals’ craving for cocaine.
"There are many forms of addiction," says Wemmie, who also holds appointments in the UI Departments of Molecular Physiology and Biophysics and Neurosurgery, and with the Iowa City VA Medical Center. "We’d like to see if these mechanisms also apply to other addictions besides cocaine and morphine. And, we want to move forward to see if this pathway can be used to target addiction."
Novel neurotransmission
As the name suggests, acid-sensing ion channels are activated by acid, in the form of protons. This research and a second UI study recently published in PNAS show that protons and ASICs form a previously unrecognized neurotransmitter pair that helps neurons communicate in a novel way; and appear to influence several forms of learning and memory, including fear, as well as addiction.
Manipulating the activity of ASICs or the level of protons (acidity) may provide a new way to treat addiction.
"We are still a long way from using these findings to create a therapy," notes Yuan Lu, co-first author and UI postdoctoral scholar. "The key significance of this study is that we have found new, different targets [that might allow us to inhibit the addiction behavior].”
Drugs change the brain
Previous research has shown that drug abuse and addiction physically alter the connections between neurons (synapses) that are important for the creation and storage of memories. Although normal learning requires synapses to be dynamic and plastic, exposure to addictive drugs abnormally increases synaptic plasticity in a way that is thought to underlie drug-related learning and addiction behaviors. The UI study found that absence of ASIC-proton mediated neurotransmission also increased synaptic plasticity in a way that resembled the changes created by addiction and drug withdrawal.
"It seemed like everything we looked at (physiology and structural changes) really paralleled what you would see in an animal undergoing drug withdrawal, even though these animals missing ASIC had never been exposed to drugs," Kreple says.
Overall the study findings suggest that ASIC-related neurotransmission in the nucleus accumbens may play a role in reducing synaptic plasticity and appropriately stabilizing synapses.](http://41.media.tumblr.com/7d6d645b6329cc5883fea6a80505aec4/tumblr_n7vibw2xQK1rog5d1o1_500.jpg)
University of Iowa researchers have discovered a new form of neurotransmission that influences the long-lasting memory created by addictive drugs, like cocaine and opioids, and the subsequent craving for these drugs of abuse. Loss of this type of neurotransmission creates changes in brains cells that resemble the changes caused by drug addiction.
The findings, published June 22 in the journal Nature Neuroscience, suggest that targeting this type of neurotransmission might lead to new therapies for treating drug addiction.
“Molecular therapies for drug addiction are pretty much non-existent,” says Collin Kreple, UI graduate student and co-first author of the study. “I think this finding at least provides the possibility of a new molecular target.”
The new form of neurotransmission involves proteins called acid-sensing ion channels (ASICs), which have previously been shown to promote learning and memory, and which are abundant in a part of the brain that is involved in drug addiction. The researchers, led by John Wemmie, professor of psychiatry in the UI Carver College of Medicine, reasoned that disrupting ASIC activity in this brain region (the nucleus accumbens) should reduce learned addiction-related behaviors. However, their experiments showed that loss of ASIC signaling actually increases learned drug-seeking in mice.
When mice learned to associate one side of a chamber with receiving cocaine, animals that lacked the ASIC protein developed an even stronger preference for the “cocaine side” than control mice, suggesting that loss of ASIC had increased addiction behavior. The same result was seen for morphine, another drug of abuse, which has a different mechanism of action than cocaine.
"Always before, the data suggested that when you get rid of ASICs, learning and memory are impaired," Wemmie says. "So we expected the same trend when we studied reward-related learning and behavior and we were surprised to find the opposite."
In a second experiment, rats learned to press a lever to self-administer cocaine. Blocking or removing ASIC in the rat brains caused the animals to self-administer more cocaine than control animals. Conversely, increasing the amount of ASIC by over-expressing the protein seemed to decrease the animals’ craving for cocaine.
"There are many forms of addiction," says Wemmie, who also holds appointments in the UI Departments of Molecular Physiology and Biophysics and Neurosurgery, and with the Iowa City VA Medical Center. "We’d like to see if these mechanisms also apply to other addictions besides cocaine and morphine. And, we want to move forward to see if this pathway can be used to target addiction."
Novel neurotransmission
As the name suggests, acid-sensing ion channels are activated by acid, in the form of protons. This research and a second UI study recently published in PNAS show that protons and ASICs form a previously unrecognized neurotransmitter pair that helps neurons communicate in a novel way; and appear to influence several forms of learning and memory, including fear, as well as addiction.
Manipulating the activity of ASICs or the level of protons (acidity) may provide a new way to treat addiction.
"We are still a long way from using these findings to create a therapy," notes Yuan Lu, co-first author and UI postdoctoral scholar. "The key significance of this study is that we have found new, different targets [that might allow us to inhibit the addiction behavior].”
Drugs change the brain
Previous research has shown that drug abuse and addiction physically alter the connections between neurons (synapses) that are important for the creation and storage of memories. Although normal learning requires synapses to be dynamic and plastic, exposure to addictive drugs abnormally increases synaptic plasticity in a way that is thought to underlie drug-related learning and addiction behaviors. The UI study found that absence of ASIC-proton mediated neurotransmission also increased synaptic plasticity in a way that resembled the changes created by addiction and drug withdrawal.
"It seemed like everything we looked at (physiology and structural changes) really paralleled what you would see in an animal undergoing drug withdrawal, even though these animals missing ASIC had never been exposed to drugs," Kreple says.
Overall the study findings suggest that ASIC-related neurotransmission in the nucleus accumbens may play a role in reducing synaptic plasticity and appropriately stabilizing synapses.
Autism-related protein shown to play vital role in addiction
In a paper published in the latest issue of the neuroscience journal Neuron, McLean Hospital investigators report that a gene essential for normal brain development, and previously linked to Autism Spectrum Disorders, also plays a critical role in addiction-related behaviors.
"In our lab, we investigate the brain mechanisms behind drug addiction – a common and devastating disease with limited treatment options," explained Christopher Cowan, PhD, director of the Integrated Neurobiology Laboratory at McLean and an associate professor of Psychiatry at Harvard Medical School. "Chronic exposure to drugs of abuse causes changes in the brain that could underlie the transition from casual drug use to addiction. By discovering the brain molecules that control the development of drug addiction, we hope to identify new treatment approaches."
The Cowan lab team, led by Laura Smith, PhD, an instructor of Psychiatry at Harvard Medical School, used animal models to show that the fragile X mental retardation protein, or FMRP, plays a critical role in the development of addiction-related behaviors. FMRP is also the protein that is missing in Fragile X Syndrome, the leading single-gene cause of autism and intellectual disability. Consistent with its important role in brain function, the team found that cocaine utilizes FMRP to facilitate brain changes involved in addiction-related behaviors.
Cowan, whose work tends to focus on identifying novel genes related to conditions such as autism and drug addiction, explained that FMRP controls the remodeling and strength of connections in the brain during normal development. Their current findings reveal that FMRP plays a critical role in the changes in brain connections that occur following repeated cocaine exposure.
"We know that experiences are able to modify the brain in important ways. Some of these brain changes help us, by allowing us to learn and remember. Other changes are harmful, such as those that occur in individuals struggling with drug abuse," noted Cowan and Smith. "While FMRP allows individuals to learn and remember things in their environment properly, it also controls how the brain responds to cocaine and ends up strengthening drug behaviors. By better understanding FMRP’s role in this process, we may someday be able to suggest effective therapeutic options to prevent or reverse these changes."
(Source: eurekalert.org)
New Ways to Prevent Relapse in Cocaine-Addicted Patients
Relapse is the most painful and expensive feature of drug addiction—even after addicted individuals have been drug-free for months or years, the likelihood of sliding back into the habit remains high. The National Institute on Drug Abuse estimates that 40 to 60 percent of addicted individuals will relapse, and in some studies the rates are as high as 80 percent at six months after treatment. Though some relapse triggers can be consciously avoided, such as people, places and things related to drug use, other subconscious triggers related to the brain’s reward system may be impossible to avoid— they can gain entry to the unconscious brain, setting the stage for relapse.
Researchers at Penn Medicine’s Center for Studies of Addiction have now found that the drug baclofen, commonly used to prevent spasms in patients with spinal cord injuries and neurological disorders, can help block the impact of the brain’s response to “unconscious” drug triggers well before conscious craving occurs. They suggest that this mechanism has the potential to prevent cocaine relapse. The new findings are reported in the Journal of Neuroscience.
Natural Compound Mitigates Effects of Methamphetamine Abuse
Studies have shown that resveratrol, a natural compound found in colored vegetables, fruits and especially grapes, may minimize the impact of Parkinson’s disease, stroke and Alzheimer’s disease in those who maintain healthy diets or who regularly take resveratrol supplements. Now, researchers at the University of Missouri have found that resveratrol may also block the effects of the highly addictive drug, methamphetamine.
(Image: Wikipedia)
Dennis Miller, associate professor in the Department of Psychological Sciences in the College of Arts & Science and an investigator with the Bond Life Sciences Center, and researchers in the Center for Translational Neuroscience at MU, study therapies for drug addiction and neurodegenerative disorders. Their research targets treatments for methamphetamine abuse and has focused on the role of the neurotransmitter dopamine in drug addiction. Dopamine levels in the brain surge after methamphetamine use; this increase is associated with the motivation to continue using the drug, despite its adverse consequences. However, with repeated methamphetamine use, dopamine neurons may degenerate causing neurological and behavioral impairments, similar to those observed in people with Parkinson’s disease.
“Dopamine is critical to the development of methamphetamine addiction—the transition from using a drug because one likes or enjoys it to using the drug because one craves or compulsively uses it,” Miller said. “Resveratrol has been shown to regulate these dopamine neurons and to be protective in Parkinson’s disease, a disorder where dopamine neurons degenerate; therefore, we sought to determine if resveratrol could affect methamphetamine-induced changes in the brain.”
Using procedures established by Parkinson’s and Alzheimer’s disease research, rats received resveratrol once a day for seven days in about the same concentration as a human would receive from a healthy diet. After a week of resveratrol, researchers measured how much dopamine was released by methamphetamine. Researchers found that resveratrol significantly diminished methamphetamine’s ability to increase dopamine levels in the brain. Furthermore, resveratrol diminished methamphetamine’s ability to increase activity in mice, a behavior that models the hyperactivity observed in people that use the stimulant.
“People are encouraged by physicians and dieticians to include resveratrol-containing products in their diet and protection against methamphetamine’s harmful effects may be an added bonus,” Miller said. “Additionally, there are no consistently effective treatments to help people who are dependent on methamphetamine. Our initial research suggests that resveratrol could be included in a treatment regimen for those addicted to methamphetamine and it has potential to decrease the craving and desire for the drug. Resveratrol is found in good, colorful foods, and has few side effects. We all ought to consume resveratrol for good brain health; our research suggests it may also prevent the changes in the brain that occur with the development of drug addiction.”
(Source: munews.missouri.edu)
Nurture impacts nature: Experiences leave genetic mark on brain, behavior
New human and animal research released today demonstrates how experiences impact genes that influence behavior and health. Today’s studies, presented at Neuroscience 2013, the annual meeting of the Society for Neuroscience and the world’s largest source of emerging news about brain science and health, provide new insights into how experience might produce long-term brain changes in behaviors like drug addiction and memory formation.
The studies focus on an area of research called epigenetics, in which the environment and experiences can turn genes “on” or “off,” while keeping underlying DNA intact. These changes affect normal brain processes, such as development or memory, and abnormal brain processes, such as depression, drug dependence, and other psychiatric disease — and can pass down to subsequent generations.
Today’s new findings show that:
- Long-term heroin abusers show differences in small chemical modifications of their DNA and the histone proteins attached to it, compared to non-abusers. These differences could account for some of the changes in DNA/histone structures that develop during addiction, suggesting a potential biological difference driving long-term abuse versus overdose (Yasmin Hurd, abstract 257.2, see attached summary).
- Male rats exposed to cocaine may pass epigenetic changes on to their male offspring, thereby altering the next generation’s response to the drug. Researchers found that male offspring in particular responded much less to the drug’s influence (Matheiu Wimmer, PhD, abstract 449.19, see attached summary).
- Drug addiction can remodel mouse DNA and chromosomal material in predictable ways, leaving “signatures,” or signs of the remodeling, over time. A better understanding of these signatures could be used to diagnose drug addiction in humans (Eric Nestler, PhD, abstract 59.02, see attached summary).
Other recent findings discussed show that:
- Researchers have identified a potentially new genetic mechanism, called piRNA, underlying long-term memory. Molecules of piRNA were previously thought to be restricted to egg and sperm cells (Eric Kandel, MD, see attached summary).
- Epigenetic DNA remodeling is important for forming memories. Blocking this process causes memory deficits and stunts brain cell structure, suggesting a mechanism for some types of intellectual disability (Marcelo Wood, PhD, see attached summary).
"DNA may shape who we are, but we also shape our own DNA," said press conference moderator Schahram Akbarian, of the Icahn School of Medicine at Mount Sinai, an expert in epigenetics. "These findings show how experiences like learning or drug exposure change the way genes are expressed, and could be incredibly important in developing treatments for addiction and for understanding processes like memory."
(Source: eurekalert.org)
Study Suggests Possibility of Selectively Erasing Unwanted Memories
The human brain is exquisitely adept at linking seemingly random details into a cohesive memory that can trigger myriad associations—some good, some not so good. For recovering addicts and individuals suffering from post-traumatic stress disorder (PTSD), unwanted memories can be devastating. Former meth addicts, for instance, report intense drug cravings triggered by associations with cigarettes, money, even gum (used to relieve dry mouth), pushing them back into the addiction they so desperately want to leave.
Now, for the first time, scientists from the Florida campus of The Scripps Research Institute (TSRI) have been able to erase dangerous drug-associated memories in mice and rats without affecting other more benign memories.
The surprising discovery, published this week online ahead of print by the journal Biological Psychiatry, points to a clear and workable method to disrupt unwanted memories while leaving the rest intact.
“Our memories make us who we are, but some of these memories can make life very difficult,” said Courtney Miller, a TSRI assistant professor who led the research. “Not unlike in the movie Eternal Sunshine of the Spotless Mind, we’re looking for strategies to selectively eliminate evidence of past experiences related to drug abuse or a traumatic event. Our study shows we can do just that in mice — wipe out deeply engrained drug-related memories without harming other memories.”
Changing the Structure of Memory
To produce a memory, a lot has to happen, including the alteration of the structure of nerve cells via changes in the dendritic spines—small bulb-like structures that receive electrochemical signals from other neurons. Normally, these structural changes occur via actin, the protein that makes up the infrastructure of all cells.
In the new study, the scientists inhibited actin polymerization—the creation of large chainlike molecules—by blocking a molecular motor called myosin II in the brains of mice and rats during the maintenance phase of methamphetamine-related memory formation.
Behavioral tests showed the animals immediately and persistently lost memories associated with methamphetamine—with no other memories affected.
In the tests, animals were trained to associate the rewarding effects of methamphetamine with a rich context of visual, tactile and scent cues. When injected with the inhibitor many days later in their home environment, they later showed a complete lack of interest when they encountered drug-associated cues. At the same time, the response to other memories, such as food rewards, was unaffected.
While the scientists are not yet sure why powerful methamphetamine-related memories are also so fragile, they think the provocative findings could be related to the role of dopamine, a neurotransmitter involved in reward and pleasure centers in the brain and known to modify dendritic spines. Previous studies had shown dopamine is released during both learning and drug withdrawal. Miller adds, “We are focused on understanding what makes these memories different. The hope is that our strategies may be applicable to other harmful memories, such as those that perpetuate smoking or PTSD.”
(Source: scripps.edu)
New Findings Could Help Improve Development of Drugs for Addiction
Scientists from the Florida campus of The Scripps Research Institute have described findings that could enable the development of more effective drugs for addiction with fewer side effects.
The study, published in the August 2, 2013 issue of the Journal of Biological Chemistry, showed in a combination of cell and animal studies that one active compound maintains a strong bias towards a single biological pathway, providing insight into what future drugs could look like.
The compound examined in the study, known as 6’- guanidinonaltrindole (6’-GNTI), targets the kappa opioid receptor (KOR). Located on nerve cells, KOR plays a role in the release of dopamine, a neurotransmitter that plays a key role in drug addiction. Drugs of abuse often cause the brain to release large amounts of dopamine, flooding the brain’s reward system and reinforcing the addictive cycle.
“There are a number of drug discovery efforts ongoing for KOR,” said Laura Bohn, a TSRI associate professor, who led the study. “The ultimate question is how this receptor should be acted upon to achieve the best therapeutic effects. Our study identifies a marker that shows how things normally happen in live neurons—a critically important secondary test to evaluate potential compounds.”
While KOR has become the focus for drug discovery efforts aimed at treating addiction and mood disorders, KOR can react to signals that originate independently from multiple biological pathways, so current drug candidates targeting KOR often produce unwanted side effects. Compounds that activate KOR can decrease the rewarding effects of abused drugs, but also induce sedation and depression.
The new findings, from studies of nerve cells in the striatum (an area of the brain involved in motor activity and higher brain function), reveal a point on the KOR signaling pathway that may prove to be an important indicator of whether drug candidates can produce effects similar to the natural biological effects.
“Standard screening assays can catch differences but those differences may not play out in live tissue,” Bohn noted. “Essentially, we have shown an important link between cell-based screening assays and what occurs naturally in animal models.”
(Source: scripps.edu)
Missing Enzyme Linked to Drug Addiction
A missing brain enzyme increases concentrations of a protein related to pain-killer addiction, according to an animal study. The results were presented at The Endocrine Society’s 95th Annual Meeting in San Francisco.
Opioids are pain-killing drugs, derived from the opium plant, which block signals of pain between nerves in the body. They are manufactured in prescription medications like morphine and codeine, and also are found in some illegal drugs, like heroin. Both legal and illegal opioids can be highly addictive.
In addition to the synthetic opioids, natural opioids are produced by the body. Most people have heard of the so-called feel-good endorphins, which are opioid-like proteins produced by various organs in the body in response to certain activities, like exercise.
Drug addiction occurs, in part, because opioid-containing drugs alter the brain’s biochemical balance of naturally produced opioids. Nationwide, drug abuse of opioid-containing prescription drugs is skyrocketing, and researchers are trying to identify the risk factors that differentiate people who get addicted from those who do not.
In this particular animal model, researchers eliminated an enzyme called prohormone convertase 2, or PC2, which normally converts pre-hormonal substances into active hormones in certain parts of the brain. Previous research by this team demonstrated that PC2 levels increase after long-term morphine treatment, according to study lead author Theodore C. Friedman, MD, PhD, chairman of the internal medicine department at Charles R. Drew University of Medicine and Science in Los Angeles.
“This raises the possibility that PC2-derived peptides may be involved in some of the addiction parameters related to morphine,” Friedman said.
For this study, Friedman and his co-researchers analyzed the effects of morphine on the brain after knocking out the PC2 enzyme in mice. Morphine normally binds to a protein on cells known as the mu opioid receptor, or MOR. They found that MOR concentrations were higher in mice lacking PC2, compared to other mice.
To analyze the effects of PC2 elimination, the researchers examined MOR levels in specific parts of the brain that are related to pain relief, as well as to behaviors associated with reward and addiction. They measured these levels using a scientific test called immunohistochemistry, which uses specific antibodies to identify the cells in which proteins are expressed.
“In this study, we found that PC2 knockout mice have higher levels of MOR in brain regions related to drug addiction,” Friedman said. “We conclude that PC2 regulates endogenous opioids involved in the addiction response and in its absence, up-regulation of MOR expression occurs in key brain areas related to drug addiction.”
(Source: newswise.com)