Progress Report 2009: Substance Abuse
The 2009 Progress Report on Brain Research


by Elizabeth Norton Lasley

January, 2009

For several decades, research has been suggesting that substance abuse is a disorder with neurobiological underpinnings. Several medications are already available to treat alcoholism, and more are in the pipeline. Findings in 2008 show that different types of addiction may have genetic roots. One line of research shows that an alcoholic patient’s response to treatment may hinge on variations in a key receptor. Another effort reveals distinct pathways of alcoholism, brought about by separate neural circuits. In the future, treatments will be targeted to the type of addiction a patient has, pinpointing the approach that will be most successful for each individual.

Although progress in 2008 centers on the roots of alcoholism, the implications could shed new light on understanding addictions in general. In fact, studies of alcoholism and other types of addiction are occasionally, sometimes surprisingly, intertwined.

Homing In on the Opioid Receptor

Much of the scientific knowledge of substance abuse centers on the opiate drugs. These include opium itself—an extract of the poppy plant known since ancient times for its superior pain-relieving qualities—and its derivatives, including heroin, morphine, and codeine. The opiates have a downside, however: the potential to cause addiction. In the first half of the twentieth century, researchers directed their efforts toward finding a drug that rivaled the painkilling power of the opiates but did not carry the addictive potential. To date, they have found none.

Despite these efforts, interest in treating addictions lagged during that half-century. According to Ting Kai Li, director of the National Institute on Alcohol Abuse and Alcoholism (NIAAA), not only addiction but behavioral research in general was slow to be regarded as a subfield of neuroscience. Behavior was widely considered voluntary—a choice, for good or bad—and not the result of brain processes.

“It’s true that drinking or drug use may start out as voluntary behavior,” Li observed, “but for some people what’s voluntary may become habitual and, finally, compulsive.”

The question of what happens in the brain to cause addiction became a priority when the government declared a “war on drugs” in the 1970s. To find answers, the NIAAA and the National Institute on Drug Abuse (NIDA) were founded in the early 1970s.

One of the first milestones in addiction research resulted from this initiative. Scientists had already developed several successful opiate antagonists—structurally similar compounds that (presumably) latched onto the same receptor as opium, either blocking or reversing its actions. These included naloxone, a rapid-acting compound used to treat overdoses, and a longer-acting version called naltrexone. But the future of addiction research was limited by the fact that the receptor itself was still undiscovered. “They were working in the dark,” said Charles O’Brien, director of the University of Pennsylvania’s Center for Studies in Addiction. The first opiate receptor was officially identified in a 1973 NIDA-sponsored study by Solomon Snyder and Candace Pert at Johns Hopkins University.1

Chemical Messengers in Addiction

Scientists had found no apparent reason for the human brain to contain receptors for a plant extract. The brain did have its own repertoire of chemicals—about a dozen had been identified by the mid-1970s. But many researchers suspected that the opioid receptor interacted with an unknown brain chemical, which opium resembled sufficiently to bind to the same receptor.

This view was confirmed in 1975, when two researchers from Scotland, John Hughes and Hans Kosterlitz of Scotland confirmed this view in 1975, isolating the chemical structure of an endogenous, opiatelike neurotransmitter they called enkephalin.2 The word “endorphin” (short for “endogenous morphine”) was already in general use and became the better-known term for the brain’s naturally occurring painkillers. These findings raised hopes—both in the scientific community and among legislators—that addiction could be treated medically. Studies over the next three decades culminated in a 2008 finding showing that an alcoholic patient’s response to the opiate antagonist, naltrexone, may be linked to the patient’s genetic makeup.

A Surprise Connection

A bit of context will illustrate the significance of this finding. In 1980, the scientific community was jolted by a study of rhesus monkeys showing that naltrexone helped quash the desire for alcohol. At the time, little was known about alcohol’s effects on the brain; the prevailing dogma held that opioid receptors were not involved. “As is always the case with basic research, something turned up that no one would have dreamed of,” said O’Brien. Other studies upheld the finding, however—including many studies of naltrexone in human alcoholics conducted by O’Brien and colleagues—and in 1995 naltrexone won FDA approval as a treatment for alcoholism.

In 2003, O’Brien led a study that linked naltrexone response with a specific genetic variant of the mu-opioid receptor.3 This receptor type is widespread throughout the body, including the reward areas of the brain, and is thought to play a role in the adaptive changes that accompany chronic drug or alcohol use. Specifically, O’Brien’s team examined the DNA from participants in several published studies. Individuals with the genetic variant were less likely to relapse into drug use after treatment.

O’Brien’s findings were confirmed in 2008, in a multicenter study of more than 900 patients, reported by Raymond Anton of the University of South Carolina and colleagues.4 The paper appeared in the February issue of Archives of General Psychiatry (a journal that rejected the original 1980 naltrexone study, as O’Brien noted in an accompanying commentary).

PR09_CH01_Volpi_spotlight

A) Alcohol is thought to stimulate the release of endogenous opioids, which may produce the euphoric feelings associated with alcohol consumption. B) Endogenous opioids are released into the synapse and C) stimulate activity at opiate receptors, which produces a signal in the target neuron. D) Exogenous opiates such as morphine also stimulate opiate receptors. E) Naltrexone is thought to block opioids from activating opiate receptors. (Joseph Volpicelli / NIH National Institute on Alcohol Abuse and Alcoholism) 

Just how alcohol works at the opioid receptor remains a mystery, but it seems to produce its high by stimulating endorphins, which, in turn, drive up dopamine levels in the brain’s reward pathway—a relay that’s effectively blocked by naltrexone. When experimental animals accustomed to alcohol are first given naltrexone, the endorphin-induced buildup of dopamine in the reward pathway is curtailed. Human subjects, too, report less of an alcoholic buzz when given naltrexone.

“Naltrexone responders” seem to share certain traits. Their cravings for alcohol are especially intense, and they have a strong family history of alcoholism. They begin drinking young and can outdrink everyone else. On a biochemical level, their endorphin response is more marked than that of nonresponders.

In the 2008 study, alcoholic patients with the genetic variant who received naltrexone were able to go for more days without a drink, had fewer days where they drank heavily, and were better able to abstain from alcohol or drink only moderately for the last eight weeks of the sixteen-week study. On the other hand, among patients without the variant, those given naltrexone showed no more improvement than did the placebo-treated group.

“These findings put us on the verge of an important therapeutic development,” said O’Brien. “Right now an alcoholic is someone who drinks too much. But we may soon be able to identify subsets of patients who respond very differently to treatment depending on the mechanisms of their addiction.”

Li of the NIAAA agreed. He points out that currently, according to the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV), the standard handbook for mental health professionals, an alcoholic is someone who meets three of seven criteria, a list that includes loss of control when drinking, tolerance, and withdrawal syndrome. “If you have only two of the seven factors you’re not an alcoholic. If you have three—any three—you are,” Li said. In the future, alcoholism may be classified and quantified, using both the patient’s genetic profile and personal characteristics to come up with the best possible treatment.

Only two other drugs have been approved to treat alcoholism. Acamprosate has shown modest success in easing withdrawal symptoms; though it is widely used in Europe, U.S. studies have questioned its efficacy. The earliest treatment, disulfuram (Antabuse), blocks the metabolism of alcohol, leading to the buildup of a toxic compound. The results are unpleasant: flushing, palpitations, nausea, and vomiting. Li, who has worked with alcoholic patients using disulfuram, found the approach effective if the drinker was strongly motivated, or compelled by law (after a drunk driving conviction, for example) to take it. But the unpleasant effects are easily avoided by simply not taking the drug. Disulfuram remains a deterrent, not a cure.

Genetic Profiles of Addiction

Other 2008 findings support the possibility that future treatments could be genomically based. In the April 23 BMC Medical Genetics, as part of a larger study of substance abuse among American Indians, Cindy Ehlers and colleagues at The Scripps Research Institute reported a connection between mu-opioid receptor variants and the effects of alcohol.5

Participants from eight reservations gave blood samples and completed diagnostic interviews describing their response to alcohol. Subjects who had more-intense or unpleasant feelings after two or three drinks—such as clumsiness, dizziness, nausea, or discomfort— were likely to have at least one of seven individual variants of the mu-opioid receptor. Because they reported more-unpleasant experiences with alcohol than did those without the variants, these participants were less likely to drink, suggesting that the genetic configuration of the receptor conferred resistance to alcohol.

A study of former heroin addicts showed an “epigenetic” alteration of the mu-opioid receptor, possibly increasing susceptibility to addiction. This type of alteration, which affects the gene’s function but not the DNA sequence (and so is not a “mutation” in the strict sense of the term), may be either genetically inherited or drug-induced. Studies of humans and animals show that substances of abuse, including alcohol, nicotine, and cocaine, can affect a biochemical alteration process called DNA methylation. In the July 23 Neuropsychopharmacology, David Nielsen and colleagues at Rockefeller University looked at a specific site in the promoter region, which controls gene expression, and found significantly higher alteration of the mu-opioid receptor gene in former heroin addicts as compared with controls.6

Two drugs already in use may reduce methylation—azacitidine, used to treat a group of blood diseases, and valproic acid, an anticonvulsant used to treat epilepsy and bipolar disorder—and may be a therapeutic option for addiction. Because DNA methylation may be influenced through many routes, including inheritance, environmental events, and drug exposure, the potential benefits of such an approach extend beyond just patients with a specific genetic configuration.

PR09_CH01_Sequence_spotlight

The computer-analyzed output from a gene sequencing procedure shows changes in the genetic structure of the mu-opioid receptor gene in former heroin addicts undergoing methadone treatment. (David Nielsen, Ph.D. / Rockefeller University)

The Other Side of Alcoholism

Research in 2008 sheds light on another broad category of patients— the ones who do not respond to naltrexone. These patients, who may represent the majority of alcoholics, don’t get more of an alcoholic buzz than most people; in fact, getting drunk is not their goal. Typically they indulge only moderately until later in life, when they escalate their drinking in response to stress, anxiety, grief, or health problems. For these users, heightened dopamine effects in the reward pathway are not the explanation. Instead, alcohol begins as a coping tool but soon disrupts the very circuitry with which the brain responds to stress. In what neuroscientist George Koob of The Scripps Research Institute describes as the “dark side” of substance abuse, these drinkers suffer more intensely from the discomfort of withdrawal. Quitting becomes a stressor in itself, which only the forbidden substance can relieve.

This line of research shares its beginnings with the 1975 discovery of endorphins. Endorphins belong to a class of chemical messengers called neuropeptides—short chains of amino acids, the building blocks of proteins. Many researchers suspected not only that the brain produced neuropeptides but that some of them acted as hormones— secreted by a part of the brain called the hypothalamus into the bloodstream, then acting on the pituitary gland to touch off a variety of hormonal responses.

One such neuropeptide, corticotropin releasing hormone (CRH), was discovered in 1983 by Wylie Vale of the Salk Institute.7 When secreted from the hypothalamus into the bloodstream, CRH acts on the pituitary gland to mobilize components of the body’s stress response, such as the endocrine and immune systems. This discovery helped reveal many of the biological underpinnings of stress and stress-related illness. But CRF also acts within the brain itself, in areas that play a role in both stress and addiction.

Koob and others have shown that the brains of rodents accustomed to alcohol have overly active stress pathways. In particular, the effects of CRH are exaggerated in a region called the amygdala, a nexus of both fear and memory. A 2008 study published in Biological Psychiatry by Markus Heilig, a former student of Koob’s who is now at the NIAAA, found evidence of a link between stress, alcohol, and CRH activity.8 The investigators found that in rats that are accustomed to alcohol but are currently “on the wagon,” a subsequent stressor makes the rats more likely to drink alcohol when it becomes available; the animals also have heightened fear responses and increased levels of CRH receptors in the amygdala.

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Markus Heilig and colleagues found that mice accustomed to alcohol are more likely to drink it when their stress pathways are stimulated. (Markus Heilig, M.D., Ph.D. / National Institute on Alcohol Abuse and Alcoholism)

The same may be true of humans, according to another 2008 paper, again in Biological Psychiatry. A team of researchers in Germany and England found that adolescents with certain variants of a CRH receptor resorted to heavy drinking after a stressful life event, such as difficulty with family, school, living conditions, or legal troubles.9 The study is the first in humans to link a CRH gene with stress and alcohol abuse.

“The CRH work provides compelling evidence that a genetic variant can predict who is likely to be the second type of alcoholic—the ones who don’t drink to feel good but because they feel even worse when they stop,” said Koob. Unlike the naltrexone responders, however, these alcoholics do not have a treatment currently available. Experimental chemicals that block CRH receptors are not feasible options for humans.

A related pathway, however, holds promise as a possible therapeutic target. The stress-induced increase of CRH activity in the brains of alcoholics has been shown to trigger changes in another neurotransmitter, called substance P. The receptor for this chemical messenger, called the neurokinin (NK-1) receptor, has a known antagonist already in use in clinical trials. In the March 14 Science, another team led by Heilig showed that in recently detoxified “anxious alcoholics” a drug that attached to the NK-1 receptor (thus blocking the effects of substance P) blunted the patients’ cravings for alcohol, including those brought on by stress.10 Imaging studies showed that the effects of alcohol in key emotional centers of the brain were reduced among the study subjects compared with untreated alcoholics. NK-1 antagonists have been safely used in an effort, albeit unsuccessful, to relieve symptoms of depression and may become an important treatment for stress-induced alcoholism.

Addiction, Then and Now

The first written records of the pleasures of alcohol date to 4,000 B.C., when recipes for fermented beverages appear in writings from China, Egypt, and Sumeria. Ancient Greek and Roman gods were sometimes depicted carrying poppy plants, the original source of opium. Modern, synthetic forms of opiates used for the relief of severe pain seldom result in compulsive drug-seeking behavior. But recreational use of opiates has long been known to be both destructive and addictive. In 1821, Thomas De Quincey published an essay called “Confessions of an English Opium Eater,” in which the drug’s pain-relieving effects paled in comparison to the euphoria it produced. De Quincey’s essay sparked a fad of opium use by celebrities of the day, including the poets Elizabeth Barrett Browning and Samuel Taylor Coleridge (the poem “Kubla Khan” was written under the drug’s influence); both quickly became addicts. Injected morphine, a highly purified opium extract, was first widely used for pain relief during the Civil War; so many soldiers came home addicted that morphine addiction became known as “the soldier’s disease.”

By illuminating the pathways of addiction in the brain, research continues to dispel the long-perceived link between substance abuse and pleasure-seeking (even in Roman times, the poet Seneca defined drunkenness as “nothing but voluntary madness”). Experts agree that recent findings in addiction research signal a change of fortune in what has traditionally been a challenging field in which to make progress, and may have profound implications for the future. For example, the naltrexone research may extend beyond alcoholism.

“The fact that an opioid receptor can predict which alcoholic patients will respond to treatment with an opiate receptor antagonist suggests a shared fundamental mechanism in substance abuse,” said Li. Koob added that recent advances extend beyond addiction research. “Whatever we discover about how emotional systems are disrupted by addiction will carry over into other areas of research, including anxiety, depression, post-traumatic stress disorder, and possibly schizophrenia.”

Notes

1. Pert CB and Snyder SH. Opiate receptor: Demonstration in human tissue. Science 1973 179(77):1011–1014.

2. Hughes J, Smith TW, Kosterlitz HW, Fothergill LA, Moran BA, and Morris HR. Identification of two related pentapeptides from the brain with potent opiate agonist activity. Nature 1975 258(5536):577–579.

3. Oslin DW, Berrettini W, Kranzler HR, Pettinati H, Gelertner J, Volpicelli JR, and O’Brien CP. A functional polymorphism of the mu-opioid receptor gene is associated with naltrexone response in alcohol-dependent patients. Neuropsychopharmacology 2003 28(8):1546–1552.

4. Anton RF, Oroszi G, O’Malley S, Couper D, Swift R, Pettinati H, and Goldman D. An evaluation of mu-opioid receptor (OPRM1) as a predictor of naltrexone response in the treatment of alcohol dependence. Archives of General Psychiatry 2008 65(2):135–144.

5. Ehlers CL, Lind PA, and Wilhelmsen KC. Association between single nucleotide polymorphisms in the mu-opioid receptor gene (OPRM1) and self-reported response to alcohol in American Indians. BMC Medical Genetics 2008 9:35.

6. Nielsen DA, Yuferov V, Hamon S, Jackson C, Ho A, Ott J, and Kreek MJ. Increased OPRM1 DNA methylation in lymphocytes of methadone-maintained former heroin addicts. Neuropsychopharmacology 2008, online publication July 23, 2008; doi:10.1038/npp.2008.108.

7. Vale W., Speiss J, Rivier C, and Rivier J. Characterization of a 41-residue ovine hypothalamic peptide that stimulates secretion of corticotropin and beta-endorphin. Science 1981 213(4514):1394–1397.

8. Sommer WH, Rimondini R, Hansson AC, Hipskind PA, Gehlert DR, Barr CS, and Heilig MA. Upregulation of voluntary alcohol intake, behavioral sensitivity to stress, and amygdala Crhr1 expression following a history of dependence. Biological Psychiatry 2008 63(2):139–145.

9. Blomeyer D, Treutlein J, Esser G, Schmidt MH, Schumann G, and Laucht M. Interaction between Crhr1 gene and stressful life events predicts adolescent heavy alcohol use. Biological Psychiatry 2008 63(2):146–151.

10. George DT, Gilman J, Hersh J, Thorsell A, Herion D, Geyer C, Peng X, Kielbasa W, Rawlings R, Brandt JE, Gehlert DR, Tauscher J, Hunt SP, Hommer D, and Heilig M. Neurokinin 1 receptor antagonism as a possible therapy for alcoholism. Science 2008 319(5869):1536–1539.