Research points to brain's 'dark side' as key to cocaine addiction

June 12, 2013

(Medical Xpress)—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 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 called kappa 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 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 , 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 , has argued that these "dark side" mark the transition to a more persistent .

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.

Explore further: Two-drug combination has potential to fight cocaine addiction: study

More information: "Kappa Opioid Receptor-Mediated Dysregulation of GABAergic Transmission in the Central Amygdala in Cocaine Addiction," Biological Psychiatry.

Related Stories

Two-drug combination has potential to fight cocaine addiction: study

August 8, 2012
A fine-tuned combination of two existing pharmaceutical drugs has shown promise as a potential new therapy for people addicted to cocaine—a therapy that would reduce their craving for the drug and blunt their symptoms ...

Research pinpoints, prevents stress-induced drug relapse in rats

March 6, 2013
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 ...

Heroin vaccine blocks relapse in preclinical study

May 6, 2013
Scientists at The Scripps Research Institute (TSRI) have reported successful preclinical tests of a new vaccine against heroin. The vaccine targets heroin and its psychoactive breakdown products in the bloodstream, preventing ...

A path to lower-risk painkillers

June 10, 2013
For patients managing cancer and other chronic health issues, painkillers such as morphine and Vicodin are often essential for pain relief. The body's natural tendency to develop tolerance to these medications, however, often ...

Study provides clues for designing new anti-addiction medications

March 22, 2012
Scientists are now one step closer to developing anti-addiction medications, thanks to new research that provides a better understanding of the properties of the only member of the opioid receptor family whose activation ...

Collaborative preclinical efficacy studies suggest a new target for drug addiction treatment

March 14, 2012
In preclinical studies, researchers at SRI International and Astraea Therapeutics have recently evaluated the role of a new drug receptor target that shows promise for the treatment of drug addiction.

Recommended for you

Study examines effects of stopping psychiatric medication

July 20, 2017
Despite numerous obstacles and severe withdrawal effects, long-term users of psychiatric drugs can stop taking them if they choose, and mental health care professionals could be more helpful to such individuals, according ...

Study finds gene variant increases risk for depression

July 20, 2017
A University of Central Florida study has found that a gene variant, thought to be carried by nearly 25 percent of the population, increases the odds of developing depression.

In making decisions, are you an ant or a grasshopper?

July 20, 2017
In one of Aesop's famous fables, we are introduced to the grasshopper and the ant, whose decisions about how to spend their time affect their lives and future. The jovial grasshopper has a blast all summer singing and playing, ...

Perceiving oneself as less physically active than peers is linked to a shorter lifespan

July 20, 2017
Would you say that you are physically more active, less active, or about equally active as other people your age?

New study suggests that reduced insurance coverage for mental health treatment increases costs for the seriously ill

July 19, 2017
Higher out-of-pocket costs for mental health care could have the unintended consequence of increasing the use of acute and involuntary mental health care among those suffering from the most debilitating disorders, a Harvard ...

Old antibiotic could form new depression treatment

July 19, 2017
An antibiotic used mostly to treat acne has been found to improve the quality of life for people with major depression, in a world-first clinical trial conducted at Deakin University.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.