The Yin and Yang of Overcoming Cocaine Addiction

Yaoying Ma says that biology, by nature, has a yin and a yang—a push and a pull.

Addiction, particularly relapse, she finds, is no exception.

Ma is a research associate in the lab of Yan Dong, assistant professor of neuroscience in the University of Pittsburgh’s Kenneth P. Dietrich School of Arts and Sciences. She is the lead author of a paper published online today in the journal Neuron that posits that it may be possible to ramp up an intrinsic anti-addiction response as a means to fight cocaine relapse and keep the wolves of relapse at bay.

This paper is the first to establish the existence of a brain circuitry that resists a relapse of cocaine use through a naturally occurring neural remodeling with “silent synapses.”

The work is a follow-up on a recent study conducted by Dong and his colleagues, which was published in Nature Neuroscience last November. The team used rat models to examine the effects of cocaine self-administration and withdrawal on nerve cells in the nucleus accumbens, a small region in the brain that is commonly associated with reward, emotion, motivation, and addiction. Specifically, they investigated the roles of synapses—the structures at the ends of nerve cells that relay signals.

The team reported in its Nature Neuroscience study that when a rat uses cocaine, some immature synapses are generated, which are called “silent synapses” because they are semifunctional and send few signals under normal physiological conditions. After that rat stops using cocaine, these “silent synapses” go through a maturation phase and acquire their full function to send signals. Once they can send signals, the synapses will send craving signals for cocaine if the rat is exposed to cues previously associated with the drug.

The current Neuron paper shows that there’s another side of “silent synapse” remodeling. Silent synapses that are generated in a specific cortical projection to the nucleus accumbens by cocaine exposure become “unsilenced” after cocaine withdrawal, resulting in a profound remodeling of this cortical projection. Additional experiments show that silent synapse-based remodeling of this cortical projection decreases cocaine craving. Importantly, this anti-relapse circuitry remodeling is induced by cocaine exposure itself, suggesting that our body has its own way to fight addiction.

Dong, the paper’s senior author, says that the pro-relapse response is predominant after cocaine exposure. But since the anti-relapse response exists inside the brain, it could possibly be clinically tweaked to achieve therapeutic benefits.

Ma notes that this finding “may provide insight into ways to manipulate this yin-yang balance and hopefully provide new neurobiological targets for interventions designed to decrease relapse.”

“The story won’t stop here,” Ma adds. “Our ongoing study is exploring some unusual but simple ways to beef up the endogenous anti-relapse mechanism.”

(Image: PA)

Novel compound halts cocaine addiction and relapse behaviors

A novel compound that targets an important brain receptor has a dramatic effect against a host of cocaine addiction behaviors, including relapse behavior, a University at Buffalo animal study has found.

The research provides strong evidence that this may be a novel lead compound for treating cocaine addiction, for which no effective medications exist.

The UB research was published as an online preview article in Neuropsychopharmacology last week.

In the study, the compound, RO5263397, severely blunted a broad range of cocaine addiction behaviors.

“This is the first systematic study to convincingly show that RO5263397 has the potential to treat cocaine addiction,” said Jun-Xu Li, MD, PhD, senior author and assistant professor of pharmacology and toxicology in the UB School of Medicine and Biomedical Sciences.

“Our research shows that trace amine associated receptor 1 – TAAR 1—holds great promise as a novel drug target for the development of novel medications for cocaine addiction,” he said.

TAAR 1 is a novel receptor in the brain that is activated by minute amounts of brain chemicals called trace amines.

The findings are especially important, Li added, since despite many years of research, there are no effective medications for treating cocaine addiction.

The compound targets TAAR 1, which is expressed in key drug reward and addiction regions of the brain.

“Because TAAR 1 anatomically and neurochemically is closely related to dopamine – one of the key molecules in the brain that contributes to cocaine addiction – and is thought to be a ‘brake’ on dopamine activity, drugs that stimulate TAAR 1 may be able to counteract cocaine addiction,” Li explained.

The UB research tested this hypothesis by using a newly developed TAAR 1 agonist RO5263397, a drug that stimulates TAAR 1 receptors, in animal models of human cocaine abuse. 

One of the ways that researchers test the rewarding effects of cocaine in animals is called conditioned place preference. In this type of test, the animal’s persistence in returning to, or staying at, a physical location where the drug was given, is interpreted as indicating that the drug has rewarding effects.

In the UB study, RO5263397 dramatically blocked cocaine’s rewarding effects.  

“When we give the rats RO5263397, they no longer perceive cocaine rewarding, suggesting that the primary effect that drives cocaine addiction in humans has been blunted,” said Li.

The compound also markedly blunted cocaine relapse in the animals.

“Cocaine users often stay clean for some time, but may relapse when they re-experience cocaine or hang out in the old cocaine use environments,” said Li. “We found that RO5263397 markedly blocked the effect of cocaine or cocaine-related cues for priming relapse behavior.

“Also, when we measured how hard the animals are willing to work to get an injection of cocaine, RO5263397 reduced the animals’ motivation to get cocaine,” said Li. “This compound makes rats less willing to work for cocaine, which led to decreased cocaine use.”

The UB researchers plan to continue studying RO5263397, especially its effectiveness and mechanisms in curbing relapse to cocaine addiction.

(Image: Shutterstock)

New study shows promise for first effective medicine to treat cocaine dependence

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."

*Editor’s Notes:

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.

New Insight Into How Brain ‘Learns’ Cocaine Addiction

A team of researchers says it has solved the longstanding puzzle of why a key protein linked to learning is also needed to become addicted to cocaine. Results of the study, published in the Aug. 1 issue of the journal Cell, describe how the learning-related protein works with other proteins to forge new pathways in the brain in response to a drug-induced rush of the “pleasure” molecule dopamine. By adding important detail to the process of addiction, the researchers, led by a group at Johns Hopkins, say the work may point the way to new treatments.

“The broad question was why and how cocaine strengthened certain circuits in the brain long term, effectively re-wiring the brain for addiction,” says Paul Worley, M.D., a professor in the Solomon H. Snyder Department of Neuroscience at the Johns Hopkins University School of Medicine. “What we found in this study was how two very different types of systems in the brain work together to make that happen.” Cocaine addiction, experts say, is among the strongest of addictions.

Worley did not come to the problem as an addiction researcher, but as an expert in a group of genes known as immediate early genes, which rapidly ramp up production in neurons when the brain is exposed to new information. In 2001, he said, a European group led by François Conquet of GlaxoSmithKline reported that deleting mGluR5, a protein complex that responds to the common brain-signaling molecule glutamate, made mice unresponsive to cocaine. “That finding came out of the blue,” says Worley, who knew mGluR proteins for their interactions with immediate early genes. “I never would have thought this type of protein was linked to dopamine and addiction, because the functions for it that we knew about up to that point were completely unrelated. That’s what scientists love: when you’re pretty sure something is right, but you don’t have a clue why.”

The finding set Worley’s research group on a long search for an explanation. Eventually, in addition to studying the effects of altering genes for the relevant proteins in mice, they partnered with experts in measuring the brain’s electrical signals and in a biophysical technique that detects when chemical bonds are rotated within protein molecules. Using different types of experiments, they pieced together a complex story of how dopamine released in response to cocaine works together with mGluR5 and immediate early genes to switch cells into synapse-strengthening mode.

“The process we identified explains how cocaine exposure can co-opt normal mechanisms of learning to induce addiction,” Worley says. Knowing the details of the mechanism may help researchers identify targets for potential drugs to treat addiction, he adds.

(Image: Milos Jokic)

Team Points to Brain’s ‘Dark Side’ as Key to Cocaine Addiction

Scientists at The Scripps Research Institute (TSRI) have found evidence that an emotion-related brain region called the central amygdala—whose activity promotes feelings of malaise and unhappiness—plays a major role in sustaining cocaine addiction.

In experiments with rats, the TSRI researchers found signs that cocaine-induced changes in this brain system contribute to anxiety-like behavior and other unpleasant symptoms of drug withdrawal—symptoms that typically drive an addict to keep using. When the researchers blocked specific brain receptors called kappa opioid receptors in this key anxiety-mediating brain region, the rats’ signs of addiction abated.

“These receptors appear to be a good target for therapy,” said Marisa Roberto, associate professor in TSRI’s addiction research group, the Committee on the Neurobiology of Addictive Disorders. Roberto was the principal investigator for the study, which appears in the journal Biological Psychiatry.

Carrot or Stick?

In addition to its clinical implications, the finding represents an alternative to the pleasure-seeking, “positive” motivational circuitry that is traditionally emphasized in addiction.

While changes in these pleasure-seeking brain networks may dominate the early period of drug use, scientists have been finding evidence of changes in the “negative” motivational circuitry as well—changes that move a person to take a drug not for its euphoric effects but for its (temporary) alleviation of the anxiety-ridden dysphoria of drug withdrawal. George F. Koob, chair of TSRI’s Committee on the Neurobiology of Addictive Disorders, has argued that these “dark side” brain changes mark the transition to a more persistent drug dependency.

In a series of recent studies, TSRI researchers including Roberto and Koob have highlighted the role of one of these dark-side actors: the receptor for the stress hormone CRF. Found abundantly in the central amygdala, CRF receptors become persistently overactive there as drug use increases, and that overactivity helps account for the negative symptoms of drug withdrawal.

The central amygdala also contains a high concentration of a class of neurotransmitters called dynorphins, which bind to kappa opioid receptors. Much like the CRF system, the dynorphin/kappa opioid system mediates negative, dysphoric feelings—and there have been hints from previous studies that CRF doesn’t work alone in producing such feelings during addiction.

“Our hypothesis was that the dynorphin/kappa opioid receptor system in the central amygdala also becomes overactive with excessive cocaine use,” said Marsida Kallupi, first author of the paper, who was a postdoctoral research associate in Roberto’s laboratory at the time of the study.

Such overactivity would be expected to arise as the brain struggles to maintain “reward homeostasis”—a middle-of-the-road balance between pleasure and displeasure—despite frequent drug-induced swerves toward euphoria. “Dynorphin possibly acts to balance the euphoric effects produced by other opioid systems during recreational drug use,” said Scott Edwards, who is a research associate in the Koob laboratory and a co-author of the study.

Reducing Signs of Addiction

When the TSRI researchers gave rats extended access to cocaine, the rats escalated their daily intake as many human users would. Sensitive electrophysiological measurements revealed signs of a persistent functional overactivity of the GABAergic system in the rats’ central amygdalae—which corresponds to an anxiety-like state in the animals. Probing with compounds that activate or block kappa opioid receptors, the scientists found signs that these receptors, like CRF receptors, do indeed help drive the central amygdala into overactivity during excessive cocaine use.

When the researchers blocked the kappa opioid receptors, central amygdala overactivity was greatly reduced. The same kappa opioid receptor-blocking treatment (antagonist) also reduced two standard signs of addiction in cocaine-using rats—the escalating hyperactive behavior each time the drug is taken and the anxiety-like behavior during withdrawal.

These results give Roberto and her colleagues hope that a similar treatment might help human cocaine addicts feel less compelled to keep using. Kappa opioid receptor blockers are already being developed for the treatment of depression and anxiety.

Blocking negative-motivational factors such as the kappa opioid and CRF systems also has the potential advantage that it spares the positive motivational pathways—the targets of older addiction therapies such as naltrexone. “We need to keep our positive motivational pathways intact so that they can signal the many normal rewarding events in our lives,” said Roberto. By contrast, she suspects, our negative motivational pathways involving CRF and kappa opioid receptors become abnormally active only in disease states such as addiction, and thus may be blocked more safely.

Researchers identify pathway that may protect against cocaine addiction

A study by researchers at the National Institutes of Health gives insight into changes in the reward circuitry of the brain that may provide resistance against cocaine addiction. Scientists found that strengthening signaling along a neural pathway that runs through the nucleus accumbens — a region of the brain involved in motivation, pleasure, and addiction — can reduce cocaine-seeking behavior in mice.

Research suggests that about 1 in 5 people who use cocaine will become addicted, but it remains unclear why certain people are more vulnerable to drug addiction than others.

“A key step in understanding addiction and advancing treatment is to identify the differences in brain connectivity between subjects that compulsively take cocaine and those who do not,” said Ken Warren, Ph.D., acting director of the National Institute on Alcohol Abuse and Alcoholism (NIAAA). Researchers at NIAAA, part of NIH, conducted the study.

“Until now, most efforts have focused on finding traits associated with vulnerability to develop compulsive cocaine use. However, identifying mechanisms that promote resilience may prove to have more therapeutic value,” said the paper’s senior author, Veronica Alvarez, Ph.D., acting chief of the Section on Neuronal Structure in the NIAAA Laboratory for Integrative Neuroscience. The study is available on the Nature Neuroscience website ahead of print.

In the study, mice were conditioned to receive an intravenous dose of cocaine each time they poked their nose into a hole in their enclosure. Cocaine was then made unavailable for periods of time during the day. Some of the mice would stop seeking the drug once it was removed while others would obsessively continue to poke the hole in an effort to obtain the drug.

Mice that quickly stopped seeking the drug were found to have stronger connections along the indirect pathway — a neural tract that forms indirect projections into the midbrain and contains cells called medium spiny neurons expressing dopamine D2 receptors (D2-MSNs). A parallel pathway — known as the direct pathway — forms direct projections into the midbrain neurons and contains medium spiny neurons expressing D1 receptors (D1-MSNs). These two pathways are thought to work together in complementary but sometimes opposing ways to affect behavior.

"We were very surprised by the results of the study because we were originally looking for vulnerability factors for developing compulsive drug use,” said Dr. Alvarez. “Instead, we found changes that only happened in subjects that show a resilience to becoming compulsive drug users. Resilient mice had a strong inhibitory circuit that allowed them to exert better control over their drug intake."

To test this observation, researchers used lasers to activate individual neurons, and found that stimulating D2-MSNs in the nucleus accumbens decreased cocaine seeking in the mice. Blocking D2-MSN signaling with a chemical process increased motivation to obtain cocaine.

“This research advances our understanding of how the recruitment, activation and the interaction among brain circuits can either restrain or increase motivation to take drugs,” said David Shurtleff, Ph.D. acting deputy director of the National Institute on Drug Abuse.

Previous studies have shown that people with lower levels of dopamine D2 receptors in the striatum, a brain region associated with reward and working memory, are more likely to develop compulsive behaviors toward stimulant drugs.

Dopamine is a key neurotransmitter involved in reward-based learning and addiction. Cocaine disrupts communication between neurons at the synapse, the small junction between nerve cells, by blocking the reabsorption of dopamine into the transmitting neuron. As a result, dopamine continues to stimulate the receiving neuron, causing feelings of alertness and euphoria.