Laser Light Zaps Away Cocaine Addiction

By stimulating one part of the brain with laser light, researchers at the National Institutes of Health (NIH) and the Ernest Gallo Clinic and Research Center at UC San Francisco (UCSF) have shown that they can wipe away addictive behavior in rats – or conversely turn non-addicted rats into compulsive cocaine seekers.

“When we turn on a laser light in the prelimbic region of the prefrontal cortex, the compulsive cocaine seeking is gone,” said Antonello Bonci, MD, scientific director of the intramural research program at the NIH’s National Institute on Drug Abuse (NIDA), where the work was done. Bonci is also an adjunct professor of neurology at UCSF and an adjunct professor at Johns Hopkins University.

Described this week in the journal Nature, the new study demonstrates the central role the prefrontal cortex plays in compulsive cocaine addiction. It also suggests a new therapy that could be tested immediately in humans, said Billy Chen of NIDA, the lead author of the study.

Any new human therapy would not be based on using lasers, but would most likely rely on electromagnetic stimulation outside the scalp, in particular a technique called transcranial magnetic stimulation (TMS). Clinical trials are now being designed to test whether this approach works, Chen added.

The High Cost of Cocaine Abuse

Cocaine abuse is a major public health problem in the United States today, and it places a heavy toll on society in terms of lost job productivity, lost earnings, cocaine-related crime, incarcerations, investigations, and treatment and prevention programs.

The human toll is even greater, with an estimated 1.4 million Americans addicted to the drug. It is frequently the cause of emergency room visits – 482,188 in 2008 alone – and it is a top cause of heart attacks and strokes for people under 35.

One of the hallmarks of cocaine addiction is compulsive drug taking – the loss of ability to refrain from taking the drug even if it’s destroying one’s life.

What makes the new work so promising, said Bonci, is that Chen and his colleagues were working with an animal model that mimics this sort of compulsive cocaine addiction. The animals, like human addicts, are more likely to make bad decisions and take cocaine even when they are conditioned to expect self-harm associated with it.

Electrophysiological studies involving these rats have shown that they have extremely low activity in the prefrontal cortex – a brain region fundamental for impulse control, decision making and behavioral flexibility. Similar studies that imaged the brains of humans have shown the same pattern of low activity in this region in people who are compulsively addicted to cocaine.

Altering Brain Activity with a Laser

To test whether altering the activity in this brain region could impact addiction, Chen and his colleagues employed a technique called optogenetics to shut the activity on and off using a laser.

First they took light-sensitive proteins called rhodopsins and used genetic engineering to insert them into neurons in the rat’s prefrontal cortex. Activating this region with a laser tuned to the rhodopsins turned the nerve cells on and off.

Turning on these cells wiped out the compulsive behavior, while switching them off turned the non-addicted ones into addicted, researchers found.

What’s exciting, said Bonci, is that there is a way to induce a similar activation of the prelimbic cortex in people through a technique called transcranial magnetic stimulation (TMS), which applies an external electromagnetic field to the brain and has been used as a treatment for symptoms of depression.

Bonci and his colleagues plan to begin clinical trials at NIH in which they will use this technique a few sessions a week to stimulate the prefrontal cortex in people who are addicted to cocaine and see if they can restore activity to that part of the brain and help them avoid taking the drug.

Study stops stress-based drug relapse in rats

All too often, stress turns addiction recovery into relapse, but years of basic brain research have provided scientists with insight that might allow them develop a medicine to help. A new study in the journal Neuron pinpoints the neural basis for stress-related relapse in rat models to an unprecedented degree. The advance could accelerate progress toward a medicine that prevents stress from undermining addiction recovery.

In the paper published March 6, researchers at Brown University and the University of Pennsylvania demonstrated specific steps in the sequence of neural events underlying stress-related drug relapse and showed that they take place within a brain region called the ventral tegmental area (VTA), which helps reinforce behaviors related to fulfilling basic needs. They also showed that a closely related neural process believed to be crucial to stress-related relapse may not be involved after all.

Moreover, this new understanding allowed the researchers to prevent relapse to drug seeking in the animal model. When they treated rats that had recovered from cocaine addiction with a chemical that blocks the “kappa opioid receptors” that stress activates in the VTA, the rats did not relapse to cocaine use under stress. Untreated rats who had also recovered from addiction did relapse after the same stress.

The chemical that helped the rats, “nor-BNI,” may be one that would someday be tried in humans, said study senior author Julie Kauer, professor of biology in Brown’s Department of Molecular Pharmacology, Physiology, and Biotechnology. By deepening scientists’ understanding of the stress-related relapse mechanism, she and her co-authors hope to identify multiple possible targets for eventual patient treatments.

“If we understand how kappa opioid receptor antagonists are interfering with the reinstatement of drug seeking we can target that process,” Kauer said. “We’re at the point of coming to understand the processes and possible therapeutic targets. Remarkably, this has worked.”

The neural crux of relapse

Exactly how stress acts in the brain to trigger relapse is a complicated sequence that is still not fully understood, but the new study focuses on and elucidates three key players at the crux of the phenomenon in the VTA: GABA-releasing neurons, dopamine-releasing neurons, and the kappa opioid receptors that affect their connections.

Fulfilling natural needs such as hunger or thirst results in a rewarding release of dopamine from the VTA’s dopamine neurons, Kauer said. Unfortunately, so does using drugs of abuse.

In normal brain function, GABA applies the brakes on the rewarding dopamine release, slowing it back to a normal level. It achieves this by forging and then strengthening the connections, called synapses, with the dopamine neuron. The strengthening process is called long-term potentiation (LTP).

In the first of their experiments, the team at Brown, including lead author Nicholas Graziane, showed that stress interrupts the LTP process, hindering GABA’s ability to slam the brakes on dopamine release.

Previous research implicated kappa opioid receptors as one of many neural entities that could have a role in stress-related relapse. Kauer, Graziane, and co-author Abigail Polter investigated that directly by blocking the receptors in some rats with a treatment of nor-BNI in the VTA and leaving others untreated. Then they subjected the rats to a standardized five-minute stress exercise. After 24 hours they looked at the cells in the VTA and found that LTP was hindered in the untreated rats but still present and underway in the rats whose receptors had been blocked with nor-BNI.

With the role of stress and the receptors in the GABA-dopamine dynamic both confirmed and then mitigated, the question remained: Could this knowledge be used to prevent relapse?

To answer that, Penn co-authors Lisa Briand and Christopher Pierce performed the experiment demonstrating that nor-BNI delivered directly to the VTA prevented stressed rats from relapsing to cocaine seeking, while untreated rats subjected to the same stress did relapse.

“Our results indicate that the kappa receptors within the VTA critically control stress-induced drug seeking in animals,” the authors wrote in Neuron.

Along the way, the team also discovered evidence that another stress-affected synapse in the VTA – one that excites dopamine release rather than inhibits it – does not play a role in the stress-related relapse as many researchers have thought. The nor-BNI treatment that prevented stress-related relapse, for example, did not affect those synapses.

Kauer emphasized that her lab’s findings of therapeutic potential are the product of more than a decade of essential basic research on the importance of how changes in synapses relate to behaviors including addiction.

“If we can figure out how not only stress, but the whole system works, then we’ll potentially have a way to tune it down in a person who needs that,” she said.

UCSB Study of Cocaine Addiction Reveals Targets for Treatment

Scientists at UC Santa Barbara are researching cocaine addiction, part of a widespread problem, which, along with other addictions, costs billions of dollars in damage to individuals, families, and society. Laboratory studies at UCSB have revealed that the diminished brain function and learning impairment that result from cocaine addiction can be treated –– and that learning can be restored.

Karen Szumlinski, a professor in the Department of Psychological & Brain Sciences at UCSB, and her colleagues Osnat Ben-Shahar and Tod Kippin, have worked in the field of addiction for many years. Senior author of a paper on this topic published recently in The Journal of Neuroscience, Szumlinski is particularly interested in the part of the brain called the prefrontal cortex, where the process of “executive function” –– or decision-making –– is located. This area is involved in directing one’s behavior in an appropriate manner, and in controlling behavior.

With her research team, Szumlinski discovered that a drug that stimulates a certain type of glutamate receptor –– when aimed at the prefrontal cortex –– could restore learning impairment in rats with simulated cocaine addiction.

"Needless to say, this (the prefrontal cortex) is one of the last parts of the brain to develop, and, of relevance to our students, continues to develop through about age 25 to 28," said Szumlinski.

Szumlinski explained that in the prefrontal cortex there seems to be “hypo-frontality,” or reduced functioning, in drug addicts, as well as in patients with a range of neuropsychiatric diseases, including schizophrenia, depression, and attention deficit disorder.

Szumlinski calls the prefrontal cortex a late-developing brain area that is critical for making proper decisions, and inhibiting behavior. “You damage this brain region and you lose the ability to self-regulate, you make impulsive decisions like engaging in risky sexual behavior or drug-taking, you basically go off the deep end in terms of function,” she said. “So we were very much interested in how drugs of abuse impact the prefrontal cortex, given that human drug addicts show deficits in this brain area when you put them into a scanner. They show hypo-activity.” She said this hypo-activity, or hypo-frontality, might relate to a neurotransmitter that scientists know is involved in exciting the brain.

A key question, according to Szumlinski, is this: “Was that hypo-frontality there in the first place, and that’s why they became an addict; or did the drugs change their prefrontal cortext, to cause it to become hypo-functioning and thus they’re not able to control their drug use? You can’t parse that out in humans. So that’s why we turn then to animal models of the disorder, and we do have this rat model that we use in the paper.”

Szumlinski pointed out a key difficulty in the development of treatments for addiction: There is little money targeted to the study of this disease. Hence, in addition to studying the brain mechanisms that are involved, she is joining forces with researchers who study other neurological diseases that are well-funded, to help find cures. She hopes that government approval of new drugs for these other diseases would eventually make the drugs available for clinical trials to study their effects on cocaine addiction.

(Image: iStock)

Researchers Find That Diabetes Drug Could Be Effective in Treating Addiction

Vanderbilt researchers are reporting today that a drug currently used to treat type 2 diabetes could be just as effective in treating addiction to drugs, including cocaine.

The findings, published online as a Letter To The Editor in the journal Molecular Psychiatry, could have far-reaching implications for patients worldwide who suffer from addiction.

“What we have demonstrated is that a brain mechanism already known to be therapeutic for the treatment of diabetes also appears to be implicated in at least certain types of drug addiction,” said Gregg Stanwood, Ph.D., assistant professor of Pharmacology and an investigator within the Vanderbilt Kennedy Center and Vanderbilt Brain Institute.

“We found that this drug called Exendin-4 that is already used for the medical management of diabetes, reduces the rewarding effects of cocaine in animals. We suspect that this is a general mechanism that will translate to additional drugs of abuse, especially other stimulants like amphetamine and methamphetamine.”

Co-author Aurelio Galli, Ph.D., professor of Molecular Physiology and Biophysics and Vanderbilt Brain Institute investigator, said Exendin-4 is already FDA-approved for diabetes (Byetta and Bydureon), so this target isn’t just “druggable” – it’s already “drugged.”

“I think the power of this research is that it is so easily translatable to humans because it is already FDA approved,” said Galli, also co-director of the Neuroscience Program in Substance Abuse (N-PISA) at Vanderbilt University. “This is the first indication that it will work on psychostimulants. So our studies offer immediate translational opportunities to improve outcomes in human abusers.”