NEWLY IDENTIFIED GENES, NEW DRUGS, SPELL HOPE FOR LAWYER ALCOHOLICS

Why can some people take a few sips from one glass of alcohol at a dinner party and call it a night, while others compulsively gulp down four martinis or two bottles of wine at the same event? Scientists say it’s more than differences in one’s upbringing or culture of origin and that it boils down to genetics. The new scientific consensus is that alcoholics break down into subgroups with different genetic mechanisms for their susceptibility to alcohol dependence which warrant different therapies.

It has been clearly established for decades that a key factor in many cases of alcoholism is how the dopamine producing reward system of an individual’s brain responds to ingestion of alcohol. Dopamine is the neurotransmitter which lights up the pleasure center of your brain (the nucleus accumbens). In some people ingesting alcohol produces no measurable increase in the brain secretion of dopamine into the nucleus accumbens. In others ingestion of alcohol triggers a large enough increase of dopamine secretion to produce euphoria, and this euphoria overwhelms the capacity of their frontal lobes to put a brake on their drinking. They can’t stop once they take their first drink. What we are now learning is the genetic reason for this phenomenon.

On May 18, 2010, Dr. Vijay A. Ramchandani and his colleagues at the National Institute on Alcohol Abuse and Alcoholism published a study in Molecular Psychiatry online explaining one genetic basis for susceptibility to alcoholism. His work is focused on gene variants for the construction of the opioid peptide receptors in the ventral striatum of the brain where the nucleus accumbens is located. These receptors must be activated to trigger the flow of dopamine into the nucleus accumbens. The genes that code for construction of these receptors have polymorphisms, which are slight differences in DNA sequences which produce slight differences in genetic expression. These appear to be associated with behavioral differences in humans and animals.

The opioid peptide receptor most studied by experts in alcoholism is the mu-subtype. All primates have different variants of the mu-subtype opioid receptor. Dr. Ramchandani knew that monkeys with a gene variant called the mu-subtype opioid receptor 118G found alcohol ingestion very pleasurable and they drank much more alcohol than other monkey when given the chance. In his experiment, Dr. Ramchandani had people with the common gene variant 118A and people with the less common variant 118G drink alcohol or a placebo beverage and then scanned their brains with a PET scanner (a scanner that uses glucose molecules tagged with a radioactive isotope to pinpoint varying levels of metabolic activity in different parts of the brain).

The study showed that people with the less common 1185 gene variant had a significant increase in dopamine secretion into the nucleus accumbens, while people with the more common 118A variant had no increase in their dopamine secretion level. To confirm causality the researchers developed two lines of mice, one with each gene variant. The mice with variant 118G showed a four-fold peak increase level of dopamine secretion consequent to ingestion of alcohol.

In 1995 the FDA approved the use of the drug Naltrexone for treatment of alcoholism. Naltrexone was originally approved to treat drug addicts because naltrexone molecules bind to the opioid receptors in the brain, block other molecules from binding to them and neutralize the euphoric effect of heroin, morphine, methadone, and cocaine. Studies of naltrexone which led the FDA to approve it showed that Naltrexone reduced the pleasurable effects of ingesting alcohol and reduced cravings in alcoholics who were abstaining from drinking.

Charles P. O’Brien, M.D., Ph.D., director of the Treatment Research Center at the University of Pennsylvania, has been studying why some humans and animals have an exaggerated response in their dopamine system when they consume alcohol. Behaviorally alcoholics are people who experience a very positive reaction to drinking alcohol, something that re-enforces their drinking behavior and makes it hard to abstain. What Dr. O’Brien has found is that only some alcoholics respond favorably to Naltrexone, whereas others can take the drug but continue to have intense enjoyment of alcohol with intense cravings for alcohol when they try to abstain.

While Dr. O’Brien refers to the Asp40 allele in his work, this is the exact same polymorphism as mu-subtype opioid receptor 118G under a different nomenclature. Dr. O’Brien is now running a randomized, prospective clinical trial in patients with alcohol dependence to compare the effects of Naltrexone on those with and without the Asp40 allele. If all, or the vast majority of, Naltrexone responders have the Asp40 allele and the non-responders don’t have it, then doctors can order an inexpensive single-gene test to determine if Naltrexone treatment will be useful.

Whatever the results of Dr. O’Brien’s study may be, some alcoholics don’t respond to Naltrexone. How can they be helped with regard to medication? Right now there are three new research avenues for drugs. The first is trying to find a pill that would overcome the effects of too much CRH (corticotrophin releasing hormone) going from the hypothalamus to the pituitary. Over-secretion of CRH is what drives the adrenal glands to pump out too much stress hormones (adrenalin and cortisol) in highly stressed, anxious people. Individuals with this problem have way more CRH receptors than normals, and the ideal pill would be one that binds with those receptors, blocks the effects of the oversupply of CRH and produces no harmful side effects. So far pharmacologists have not been able to develop such a pill.

The second candidate is a drug that would target substance P. Substance P is a neurotransmitter that is involved in the transmission of pain impulses from the peripheral to the central nervous system and which modulates the body’s immune and inflammatory responses. In some situations Substance P can imitate the effects of CRH in the human brain when a person is stressed. Markus Heilig, Ph.D., and his research group believe that Substance P may be involved in some cases of alcoholism and that blocking the neurokinin 1 receptors for Substance P might reduce their dependence on alcohol.

In 2009 Heilig teamed up scientists at Eli Lilly to test this hypothesis. They created a line of mice that lacked the NK1 receptor for Substance P, and demonstrated that these mice do not develop alcohol dependence or drink as much as normal mice when given increasing amounts of alcohol. Early human clinical trials have begun. In a placebo controlled study on 50 persons Eli Lilly scientists used a PET scanner to show their oral formulation caused 90% blockage of Substance P receptors. When put under stress and given access to alcohol the treated individuals had reduced craving and showed reduced release of CRH using functional MRI. Thus this avenue is research is showing some early promise, but is still a long way off before the FDA approval process can begin.

The third candidate is the drug Varenicline, a smoking cessation drug approved by the FDA marketed by Pfizer under the name Chantix. This drug binds to and partially activates the receptors for nicotine. It lessens the enjoyment of smoking and the craving for a cigarette in people who are abstaining. Approximately 80% of heavy alcohol drinkers with alcohol use disorders also smoke. Selena Bartlett, Ph.D., director of pre-clinical development group at Ernest Gallo Clinic and Research Center at UCSF Medical Center, tested Varenicline on rats and found it helpful in reducing their experimentally-induced alcohol dependence. In July 2009 S.A. McKee (a psychiatrist at Yale University Medical School) published a preliminary study in Biological Psychiatry indicating that using Varenicline for seven days reduced alcohol consumption level and alcohol craving in a group of 50 persons who were heavy-drinking smokers.

The potential promise of Varenicline must be greeted with some caution. First, its application would not be universal, but would apply to those alcoholics who are still smokers. Second, in 2008 the FDA received reports of increased depression, Suicidality and completed suicides in some people using this drug and Pfizer changed its packaging label to reflect this concern. In 2009 the FDA issued an Alert to let health care providers and the public know that Chantix use is associated with these problems but the existence, if any, of a causal mechanism is not yet known. Although it’s a far less serious side effect, Varenicline produces nausea in some people.

Although we have not yet reached the point where psycho-pharmacology can cure alcohol dependence, medical researchers and major drug manufacturers are beginning to make some headway in understanding genetic susceptibility to alcoholism and how to develop medications targeted to reduce that susceptibility.