New Treatments for Alcoholism Show Promise

by Elizabeth Norton Lasley

September, 2008

Drugs and growth factors that target the brain’s “reward pathway” are showing promise as treatment possibilities for alcoholism and are providing insight into how the brain becomes addicted.

The medications may help restore balance to parts of the brain involved in alcoholism. Other new research hints at how alcohol damages the brain. The findings shift the focus away from alcoholism as a moral weakness.

“Interventions that focus on willpower have total abstinence as the goal,” observes Ivan Diamond, vice president for neuroscience at CV Therapeutics in Palo Alto, Calif. “But medically speaking, to reduce the amount of drinking, as well as the harm associated with alcoholism, is a more realistic goal.”

The approaches in the pipeline may work in more specific ways than medications already in use—naltrexone, which blocks the opioid receptors in the brain to prevent the “high” of alcohol; acamprosate, which eases withdrawal symptoms; and disulfuram, which discourages drinking by triggering nausea.

Tweaking the ‘Reward Pathway’

One possibility is topiramate, approved by the Food and Drug Administration to treat epilepsy and migraine. In a clinical trial reported in the Journal of the American Medical Association on October 10, 2007, topiramate reduced “heavy drinking days” while increasing the number of days without a drink.

In a multicenter follow-up study appearing in the June 9 Archives of Internal Medicine, researchers found that topiramate does more than block the urge for alcohol: it leads to physical and psychological improvements. Bankole Johnson, a neuroscientist at the University of Virginia and lead author on both studies, had studied topiramate as a way to rebalance circuits of dopamine-producing neurons, which make up the “reward pathway” and are askew in addiction.

Many approaches for both drug and alcohol addiction target dopamine-producing neurons. In contrast, topiramate acts on dopamine indirectly, by exerting a push-pull effect on two other chemical messengers. It prolongs the effect of gamma-aminobutyric acid (GABA), which tells neurons to slow down their firing rate. It also tones down the actions of glutamate, a neurotransmitter that speeds up neuronal firing.

“The idea was that this dual modulation of dopamine would suppress the reinforcing effects of alcohol,” says Johnson.

In the follow-up study, the investigators worked with 371 alcoholics, roughly half of whom received topiramate while the other half were given a placebo. Patients in the topiramate group reduced their drinking and showed decreases in body mass index and cholesterol levels, plus improvements in liver functioning and blood pressure compared to controls (though blood pressure in both groups remained on the high side). Patients in the placebo group reduced their drinking only slightly compared to those receiving topiramate.

The patients’ mental well-being also improved: those in the treated group slept better and had fewer obsessive thoughts related to drinking. These psychological benefits increased as the study progressed.

“Our research shows that topiramate can effectively treat alcoholism not only by reducing the instances of drinking, but by improving the consequences,” says Johnson.

Efforts to restore balance, or homeostasis, to the reward pathway represent a more nuanced understanding of addiction, says George Koob, a neuropsychopharmacologist at the Scripps Research Institute. “The prevalent notion that addiction equals too much dopamine is an oversimplification,” he says.

Research indicates that dopamine isn’t the whole story. In animal studies, even when dopamine receptors are blocked, some drug-seeking behaviors persist—such as place preference, the urge to reach for the forbidden substance in a place where it has been used before (in human terms, perhaps a bar or favorite restaurant).

Drugs that affect dopamine directly have been ineffective in clinical trials, Koob says. “Therapies like topiramate, that indirectly modulate the dopamine system without clobbering it, are a more promising approach.”

Growth Factors: Not Just for Growing

Another candidate is one of the growth factors (substances that nourish and protect developing brain cells). Glial cellderived neurotrophic factor, or GDNF, has protected dopamine-producing neurons in culture and even coaxed them to regenerate. GDNF is a promising treatment for Parkinson’s disease, which involves the death of dopamine neurons in a brain region called the substantia nigra.

New research shows that GDNF puts the brakes on alcohol consumption when infused into an adjacent area, the ventral tegmental area, which is rich in dopamine-producing neurons and a hotspot of addiction. Dorit Ron and colleagues at the University of California, San Francisco, infused GDNF into the ventral tegmental area of rats that had previously shown a preference for alcohol. The rats were then allowed to press levers dispensing drinks of a 10 percent ethanol solution.

When administered three hours or as little as 10 minutes before the test, GDNF markedly reduced the amount of lever-pressing. Animals receiving the highest dose took only half as many drinks as they did before the infusion.

Equally striking, GDNF treatment prevented animals from relapsing. In rats addicted to alcohol, as in humans, one drink after a period “on the wagon” is likely to set off a binge. When rats were “primed” with a drink containing ethanol after a period of withdrawal, those given GDNF 10 minutes before the subsequent test showed no increase in leverpressing—whereas the untreated animals returned to their previous high levels of consumption. These findings appear in the June 10 Proceedings of the National Academy of Sciences.

“Relapse is one of the biggest problems in treating alcohol dependence,” Ron says. “To our knowledge, our results are the first evidence of a rapidaction growth factor on both drug use and relapse.”

Although GDNF infusion is not a treatment option for humans, Diamond is intrigued by the idea that separate pathways in the brain regulate drinking behavior. “The question now is, do these pathways come together? Or are there separate circuits, separate components of alcoholism, different types of alcohol addiction?”

Growth Factors and Plasticity

The idea of a heretofore unknown role for a growth factor makes sense to Moses Chao, who heads the molecular neurobiology department at New York University’s Skirball Institute. “The field originally focused on the ability of growth factors to help neurons survive.

But it’s very clear that growth factors in the adult brain play roles in the neural circuits that underlie behavior,” Chao says.

Many growth factors support the brain’s ability to remodel itself, a process known as plasticity. When an experience is repeated—as in memorizing dates or practicing the violin—the neurons in the relevant part of the brain produce more synapses, or points of contact through which they exchange signals.

Drug exposure counts as a repeated experience, and it alters synaptic plasticity for the worse. Dopamine-producing neurons in the ventral tegmental area are especially likely to remodel themselves in ways that lead to addiction and drug tolerance.

Chao says the striking effects of GDNF in this area, as reported by Ron and colleagues, may indicate an effect on plasticity that wards off alcohol addiction. “The specific effects of GDNF on synaptic transmission haven’t yet been tested,” says Chao. “But I wouldn’t be surprised if it produces changes in synaptic plasticity.”

Insulin and the Brain

While GDNF seems to help ward off alcohol addiction, chronic alcohol consumption impairs the brain’s ability to respond to another growth factor: insulin-like growth factor, or IGF.

Insulin is best known as a hormone produced by the pancreas. Diabetes results when the pancreas produces insufficient insulin or when the body becomes resistant to insulin’s effects.

In the brain, insulin and IGF play roles in energy metabolism, neuronal survival and plasticity, all of which help to maintain the brain’s cognitive and motor functioning.

Chronic alcohol abuse can undermine of these processes, and a new study suggest that it does so, in part, by causing resistance to both insulin and IGF.

In the September 2008 Alcoholism: Clinical and Experimental Research, Suzanne de la Monte of Brown University teams up with researchers at the University of Sydney, Australia, to study brain tissue taken postmortem from six male alcoholics and six controls.

The brains of the alcoholics showed a pattern of damage often seen after chronic alcohol abuse. Neuronal loss in the cerebellum, a movement-control center, could explain the balance problems that many alcoholics experience, de la Monte says. These brains also showed impaired functioning in the anterior cingulate, a frontal area involved in cognitive processes such as paying attention, which could account for the memory problems common in alcoholism.

Brain tissue taken from the alcoholic patients showed marked reductions, in both regions, of the genes needed for the brain to respond to insulin and IGF, suggesting that alcoholism had led to insulin resistance and that the insulin resistance contributed to the damage.

Tissue analysis also linked the neuronal death in the cerebellum with alcohol-induced damage to the brain cell membrane, called “oxidative” stress.

“It’s likely that sustained oxidative stress caused by chronic alcohol abuse may leave the brain more vulnerable to ‘second hits,’ such as stroke or head injury from falling, which would not cause permanent injury in an otherwise normal brain,” says de la Monte.

The study reaffirms the dangers of chronic alcoholism. But it also offers a ray of hope: de la Monte says treatments that increase insulin sensitivity may help protect alcoholic patients against this type of damage.

Taken together, the topiramate, BDNF and IGF research begins to clarify the complex picture of alcohol addiction.

Diamond adds that although health consequences of chronic alcoholism—such as brain degeneration and liver disease—are severe, many studies show that moderate drinking confers health benefits, especially to the heart. For example, alcohol is the only substance known to raise levels of the high-density lipoprotein, the “good cholesterol.”

“If we can switch off the intense craving that produces addiction, as well as preventing the serious health consequences, we could help alcoholics become capable of moderate drinking,” Diamond says. This goal may be more achievable, and ultimately more beneficial, to society, he concludes.