Cocaine Treatment and the Stroop Test

Treatment dropouts do poorly on color/word match.

It’s commonly used to demonstrate behavioral inhibition, but it’s also a nifty parlor game. It is called the Stroop Test, and it plays off the fact that people are far better at reading words than they are at intentionally ignoring them. To prove it, John Ridley Stroop’s 1935 Ph.D. thesis showed how difficult it is to interfere with the automatic processing of words. In the basic Stroop test, a list of color names is presented. However, the word green might be printed in red ink, and the word red might be printed in blue ink. The task is to quickly name not the word itself, but the color of the word. As an example, for the word “green” printed in red ink, the correct verbal answer is “red.” Because of a phenomenon called directed attention, this is hilariously difficult to do. The subject must actively inhibit the automatic response—reading the word—in order to do something else.

What’s all this got to do with drug addiction?

Psychologists have known for some time that drug craving focuses attention on drug-related stimuli in the environment, and draws attention away from environmental cues unrelated to drugs. Naturally, researchers began to wonder whether the Stroop test could be brought to bear on the matter of addiction, and employed as a tool with which to predict the likelihood of relapse among the addict population. 

As researchers at the University of Wales have pointed out,  “Decisions about drinking and drug use can be highly automatic, with users being unaware of the factors that influence their decisions.” At the same time, addicts are hyper-aware of addiction-related environmental stimuli, compared to non-addicts. As a result, “the automatic processing of addiction-related stimuli might elicit conditioned responses such as withdrawal… or they might invoke automatic patterns leading to substance use.”

In a recent study of treatment dropouts among 74 cocaine-addicted subjects, published in Neuropsychopharmacology, Dr. Chris Streeter and coworkers at the Boston University School of Medicine and Harvard University provide strong evidence for the use of the Stroop Test as a diagnostic tool in addiction treatment.  Variations on the Stroop Test were better predictors of dropout than addiction severity, depression, and other clinical variables.  Dropouts took 24 per cent longer, on average, to finish the tests than cocaine addicts who stuck with treatment, the researchers reported.  “These finding suggest that the Stroop test can be used to identify cocaine-dependent subjects at risk for treatment dropout,” say the researchers, and that it can serve as another instrument with which to “identify and tailor interventions of at risk individuals in the hope of improving treatment compliance.”

Furthermore, other studies suggest that attentional bias may serve as a useful predictor of opiate relapse and smoking cessation failure as well.

Streeter, C., Terhune, D., Whitfield, T., Gruber, S., Sarid-Segal, O., Silveri, M., Tzilos, G., Afshar, M., Rouse, E., Tian, H., Renshaw, P., Ciraulo, D., & Yurgelun-Todd, D. (2007). Performance on the Stroop Predicts Treatment Compliance in Cocaine-Dependent Individuals Neuropsychopharmacology, 33 (4), 827-836 DOI: 10.1038/sj.npp.1301465

Photo Credit: http://www.edge.org

The Cocaine Conundrum

Effective treatment remains elusive.

For addiction to cocaine, amphetamine, and other stimulants, the treatment picture has been complicated by the lack of any truly significant anti-craving medications. (See post, “No Pill for Stimulant Addiction"). The National Institute on Drug Abuse (NIDA) has yet to approve any medications for the treatment of either cocaine or amphetamine addiction.

Take the case of cocaine. Partly the problem stems from the direct effect cocaine has on dopamine transmission.  The hunt for a pharmaceutical approach to blunt that effect is complicated by the problematic nature of dopamine receptors.  Dopamine antagonist drugs like the antipsychotic drug haloperidol do not always block the stimulant rush. And their side effects, such as lethargy, emotional blunting, and tardive dyskinesia, make them unsuitable for ongoing addiction therapy. Conversely, some drugs that act as dopamine agonists turn out to be addictive in their own right. Many designer drugs are like that.

Because of all this, different approaches may be needed. The direct ride to the pleasure pathway provided by stimulants makes it difficult to tamper selectively with their effects. An antibody that would reduce cocaine consumption and sop up cocaine molecules in the brain, a kind of vaccine against cocaine, is one approach being pursued (See post, “Cocaine Vaccine Hits Snag”).

But other avenues of attack are being exploited.  Scientists in NIDA’s Intramural Research Program are testing compounds that target certain proteins known as dopamine transporters. Transporters move dopamine molecules in and out of the synaptic gap between neurons in the brain. Interfering with that transportation system is another way of altering dopamine uptake, and it represents one active avenue of approach to the treatment of cocaine addiction.

The researchers tested Benztropine Mesylate (BZT), brand name Cogentin, one of a class of drugs known as anticholinergic suppressants commonly used in the management of Parkinson’s disease. What exactly does benztropine do? It possesses both anticholinergic (acetylcholine-blocking) and antihistaminic effects. It has chemical similarities to atropine, which is used for Parkinson’s and for heart disease.

To begin with, the researchers wanted to establish that benztropine itself is non-addictive. By substituting different BZT analogs for cocaine during self-administration testing on addicted rats, “two of the three BZT analogs that were tested significantly reduced drug self-administration… which indicates that those BZT analogs themselves have low potential for abuse.”

Next, the cocaine-addicted rats were given different BZT analogs before they got their cocaine. “When given before rats had access to cocaine in the self-administration chambers,” the researchers reported in the Journal of Pharmacology and Experimental Therapeutics, “two BZT analogs also significantly reduced the number of times the rats would press a lever to receive cocaine.” Monoamine uptake inhibitors were used as a control. The authors conclude that “these compounds are promising candidates for the development of medications for cocaine addiction.”

Hiranita, T., Soto, P., Newman, A., & Katz, J. (2009). Assessment of Reinforcing Effects of Benztropine Analogs and Their Effects on Cocaine Self-Administration in Rats: Comparisons with Monoamine Uptake Inhibitors Journal of Pharmacology and Experimental Therapeutics, 329 (2), 677-686 DOI: 10.1124/jpet.108.145813

Photo credit: http://www.drugabuse.gov

Cocaine Vaccine Hits Snag

Some addicts risk OD to overcome its effects.

The National Institute on Drug Abuse (NIDA) has increasingly placed its bets on treating cocaine addiction with a vaccine rather than an anti-craving medication. And there is reason for this: No prominent candidates for anti-craving drug treatments have yet emerged from the research on cocaine and methamphetamine addiction.

However, there’s a catch: Some cocaine addicts appear willing to risk overdose in order to defeat a new cocaine vaccine, a recent study has shown.

The study, which appeared in the Archives of General Psychiatry, demonstrated that the TA-CD vaccine could blunt the effects of cocaine in some, but not all, patients. The vaccine works by causing the production of antibodies, which attach themselves to cocaine molecules, making the molecules too big too pass effectively through the blood-brain barrier.

Of 115 addicts involved in the study, only 38 % produced sufficient antibodies to dull the effects of cocaine, Rachel Saslow of the Washington Post  reported. And among the high-antibodies group, only 53 % stayed free of cocaine 50 % of the time. “Immunization did not achieve complete abstinence from cocaine use,” said Thomas Kosten of Baylor college of Medicine, one of the authors of the paper.

Moreover, in some of the study participants for whom antibodies made cocaine a disappointing high, researchers found cocaine levels in the body to be as much as ten times higher than previous levels of usage—an obvious attempt to overcome the vaccine’s effectiveness. There were no overdoses, according to Kosten.

No researcher has claimed this as a complete breakthrough, in light of the fact that even those who responded well in the high-antibody group achieved a substantial reduction in cocaine use during the study period--but not abstinence. At this stage the work appears to be aimed more at dose reduction.

Despite the mixed results, NIDA director Nora Volkow characterized the work as “a promising step toward an effective medical treatment for cocaine addiction,” with the proviso that “larger follow-up studies confirm its safety and efficacy.” In an earlier interview with Addiction Inbox, Volkow also expressed excitement about another possible addiction vaccine: “Currently there are anti-nicotine vaccines in clinical testing, which are designed to capture the nicotine molecules while still in the bloodstream, thus blocking their entry in to the brain and inhibiting their behavioral effects. They appear to be effective in helping subjects who develop a high antibody response sustain abstinence over long periods of time. Even those people with a less robust antibody response to the vaccine, decreased their tobacco use. So this approach appears very promising.”

An earlier study by Margaret Haney and others at Columbian University Medical Center, published in Biological Psychiatry, had similar results: “The TA-CD vaccine substantially decreased smoked cocaine's intoxicating effects in those generating sufficient antibody.”

In both studies, roughly a quarter of participants made almost no antibodies at all in response to a vaccine injection.

A multi-site clinical trial of the vaccine, headed up by Kosten at Baylor, will begin sometime this spring.

Haney of Columbia told the Washington Post that people “have a mistaken view of how a vaccine might work, thinking of it as magic, where what it’s doing, at best, is blunting the effects. They get very excited, and it’s heartbreaking.” An earlier Addiction Inbox post on cocaine vaccination brought several emails from people asking where they could obtain the vaccine.

DrugMonkey at scienceblogs.com dissected the complicated study, particularly the different levels of antibodies generated in study participants, calling the vaccine “quite obviously not a silver bullet at present.” Furthermore: “Even for the high-responders the outcome was far from overwhelming, a 10 percentage improvement from 35% to 45% cocaine-free urines.” 

Given how intractable to treatment addiction to stimulants has proven, any promising results at all are cause for cautious optimism. DrugMonkey writes: “We need new approaches and this immunopharmacotherapy stuff has potential.”

Photo Credit: http://addictions.about.com/b/2009/10/10/new-cocaine-vaccine.htm

Who are Cocaine’s Primary Victims?

The answer may surprise you.



They are not necessarily the poor, the desperate, or the weak-willed. A National Institute of Drug Abuse (NIDA) study by Dr. Michael Nader and coworkers at Wake Forest University demonstrates that they are likely to be people with innately low levels of dopamine receptor availability. This flaw, possibly genetic, renders them more sensitive to the rewarding effects of cocaine. Put simply: Individuals with less dopamine naturally available in the brain may have an inherited predisposition for cocaine addiction. [Brains Scans at right: Dopamine receptor availability in yellow falls markedly after 6 and 12 months of cocaine self-administration.]



Dopamine D2 receptors, a crucial part of the brain’s primary reward system, are normally occupied by dopamine molecules—although at any given moment, many of the receptors are empty and remain available until a stimulus like cocaine increases dopamine levels and the empty receptors help mop up the excess. Dr. Nader believes that lower D2 receptor availability could be a precursor of addiction to drugs like cocaine. “Perhaps an individual with low availability gets a greater kick from cocaine because the drug-induced dopamine release stimulates a greater percentage of their receptors,” Dr. Nader told staff writer Lori Whitten in a recent edition of NIDA Notes. “Another possibility is that the drug prompts some individuals’ brain cells to release dopamine in particularly high quantities that are sufficient to fill the great majority of vacant D2 receptors, and this augments the high.”



An obvious question hangs over studies of this kind: Are the D2 receptor differences innate, or do they represent changes induced by drug use? To answer this question, Dr. Nader’s team worked with rhesus monkeys in order to take D2 density measurements with PET scans before the animals had ever been exposed to cocaine. Sure enough, the monkeys with the lowest baseline level of D2 receptor availability went on to self-administer cocaine at much higher rates than their D2-normal compatriots. Offering food to the low-dopamine animals did not prove to be a substitute of cocaine, so the effect does not appear to increase all kinds of reward.



There is no doubt that the use of cocaine itself does lead to a rapid reduction of available dopamine receptors, as the brain seeks to achieve a new equilibrium in the face of regular dosings of dopamine-active chemicals. In five monkeys that self-administered cocaine for a year, three of the monkeys showed a strong recovery of receptor availability after only a month of abstinence. However, two of the monkeys showed slower recovery of previous D2 receptor levels. Dr. Cora Lee Wetherington, a neuroscience researcher at NIDA, said that the research thus posed the question of whether people whose dopamine receptor levels recover more slowly during abstinence might prove to be those most likely to relapse.



Medications that increase D2 receptor availability without themselves being highly rewarding represent another promising avenue for treatment. The drugs most likely to help, Dr. Nader thinks, are drugs that act indirectly on dopamine levels through alterations of serotonin and GABA levels in the brain. In addition, researchers are pursuing environmental enrichment experiments in animals and human subjects. Some studies have shown that enriching the environment results in greater D2 receptor levels, Dr. Nader says.



Photo Credit: NIDA



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