A Slew of Studies Provides Addiction Insight

by Jim Schnabel

December 9, 2008

Probably the best known effect of addiction on the brain is its subversion of the “mesolimbic” reward-and-motivation circuitry—a mesh of connections that include midbrain dopamine-supplying neurons and the region known as the striatum. At this year’s Society for Neuroscience meeting, researchers acknowledged that the mesolimbic reward circuit is only one area influenced by addiction; also affected are the insular cortex, or insula, and the prefrontal cortex, which normally mediate self-awareness and help to restrain impulsive behavior.

“People seem to have overlooked the functionality” of the insula, said Antoine Bechara, a neuroscientist at the University of Southern California. He noted that damage to the insula, typically from a stroke, is associated with a condition known as anosognosia. Patients with anosognosia deny—sometimes for years—that they have suffered any mishap, even if a stroke has rendered them immobile on one side.

Such a lack of awareness can have a surprising benefit vis-à-vis addiction. Bechara and colleagues recently studied a group of people who had found it remarkably easy to quit smoking after suffering stroke-related insula damage. One went from chain-smoking more than two packs of unfiltered cigarettes a day, before his stroke, to not smoking at all afterward. His mind, he told Bechara, had “forgotten the urge to smoke.”

Could drugs or surgical techniques be used to dial down insula activity and thus reduce an addict’s awareness of his body’s craving for drugs? Bechara considers it a possibility, noting that the insula-damaged patients he studied did not appear to have lost more basic, survival-related urges, such as hunger and thirst.

In a healthy adult brain, the compulsions that flow from the activities of the insula and related limbic regions are normally held in check by the more recently evolved prefrontal cortex, which gauges the long-term consequences of behaviors. Bechara and his colleagues studied groups of smokers and binge drinkers and found evidence from standard behavioral tests that both had prefrontal impairments, making them more impulsive and less concerned about the long-term consequences of their decisions.

Bechara believes that at least some of this impairment is caused by the addiction process itself: “The insula is sensitized to an extent that there is an intensified awareness of the craving and seeking of drugs, but at the same time there is this hijacking of the prefrontal cortex.”

Other researchers presented findings consistent with Bechara’s. Hugh Garavan of Trinity College, Dublin, reported that in standard behavioral tests designed to measure self-awareness, cocaine users—during a period of abstinence—showed a reduced awareness of errors, which correlated with reductions in the functional magnetic resonance imaging (fMRI) response of prefrontal regions known to be related to self-awareness, including the anterior cingulate cortex.

When the users took cocaine, their responses became normal again. Garavan therefore suspects that the observed blunting of self-awareness in abstinent users was largely an effect of drug use over time. This effect is not necessarily limited to hard drugs, Garavan believes. “We’ve seen similar patterns of reduced activity in nicotine and cannabis users,” he said.

Yale University researcher Jane Taylor reported on experiments in monkeys suggesting that cocaine use brought about changes in the orbitofrontal cortex, a prefrontal region also involved in planning and impulse inhibition. The evidence came not only from behavioral tests but also from sensitive biochemical assays showing lower levels of proteins that regulate synapses in the orbitofrontal cortex.

Genetic and developmental factors, as well as brain injuries, can also lead to a weakened prefrontal system, which makes people particularly prone to drug-taking and addiction, evidence suggests. Daina Economidou, a neuroscientist at Cambridge University, reported that rats with inherent “high impulsivity”—as gauged by their pre-drug-taking responses in lever-pressing tests—were significantly more likely to relapse into cocaine-seeking behavior after a period of cocaine use followed by forced abstinence. (Following the meeting, researchers at Columbia reported that in a group of more than 500 adult smokers, those with hyperactivity/impulsivity associated with attention-deficit/hyperactivity disorder, or ADHD, had a harder time quitting.)

The power of subliminal cues

Anna Rose Childress of the University of Pennsylvania School of Medicine pointed out that in some cases, prefrontal, impulse-inhibiting regions may be left out of the loop altogether. In an experiment, Childress and her colleagues exposed a group of crack cocaine users to drug-related images, for example of a crack pipe, too briefly for conscious perception. Functional MRI scans showed corresponding bursts of activity in limbic regions such as the amygdala and ventral striatum, while impulse-moderating regions such as the prefrontal cortex remained relatively quiet, as if unable to process the information. Those addicts with the strongest fMRI responses to the subliminal imagery also expressed the strongest feelings about the same images a day later when allowed to perceive them over longer intervals, i.e., consciously.

Childress suspects that the “instant, volcanic cravings” addicts often describe arise not only from prefrontal deficiencies but from subliminal, drug-related cues in ordinary life that ignite the limbic structures without sufficiently activating prefrontal areas. “We think this limbic vulnerability might be every bit as important as conscious desire in maintaining addiction,” she said.

Drugs for forgetting drugs

If researchers could blunt the limbic reaction to subliminal drug cues or prompt a more normal response from prefrontal regions, they might be able to reduce the emotional force of drug cravings. Childress reported on a small trial in her cocaine-addicted subjects, which suggested that baclofen, a muscle-relaxant drug, may do both.

Similarly, Economidou gave her high-impulsivity rats atomoxetine, an ADHD drug that boosts levels of the neurotransmitter norepinephrine and apparently enhances executive control processes. She and her colleagues found that it markedly reduced the rats’ cocaine-seeking relapse rate.

More than a dozen other research groups at the meeting reported promising tests of compounds meant to block addiction memories and thereby reduce drug-seeking behavior. But all of these tests were small-scale, mostly in rodents, and together they targeted a wide variety of brain receptors. There was no sign of movement toward a single effective strategy for extinguishing “the memory of addiction.”

An expanding problem

Nevertheless, the hundreds of lectures and poster presentations on addiction research demonstrated that the field is expanding into realms of behavior well beyond illicit drug use.

Several presentations concerned gambling addictions. A group from Seoul National University’s College of Medicine presented a poster describing “increased orbitofrontal and striatal glucose metabolism in adults with Internet game overuse.” Researchers from the Institute Pasteur in Paris reported that wheel-running mice showed signs of “exercise addiction”—like that seen in some humans—by exhibiting greater withdrawal symptoms, after morphine exposure, than relatively sedentary mice.

Paul Johnson of the Scripps Research Institute’s Florida facility reported on a set of obesity experiments in rats. Those with access to a high-fat diet, including bacon and cheesecake, did not become markedly overweight if their access was restricted to an hour a day. But those with essentially unlimited access quickly became as super-sized as their meals. Moreover, their sensitivity to the feeling of reward, as measured by a standard self-stimulating technique with implanted electrodes, decreased markedly—suggesting that, as with addictive drugs, they had to consume ever-greater quantities just to feel normal.

“We’ve known that there could be similarities between drug addiction and obesity,” said Johnson. “But empirical evidence has been lacking.”