1. Higher estrogen levels linked to increased alcohol sensitivity in brain’s ‘reward center’

    November 14, 2017 by Ashley

    From the University of Illinois at Chicago press release:

    The reward center of the brain is much more attuned to the pleasurable effects of alcohol when estrogen levels are elevated, an effect that may underlie the development of addiction in women, according to a study on mice at the University of Illinois at Chicago.

    Led by Amy Lasek, assistant professor of psychiatry in the UIC College of Medicine, researchers found that neurons in a region of the brain called the ventral tegmental area, or VTA (also known as the “reward center”), fired most rapidly in response to alcohol when their estrogen levels were high. This response, according to their findings published online in the journal PLOS ONE, is mediated through receptors on dopamine-emitting neurons in the VTA.

    “When estrogen levels are higher, alcohol is much more rewarding,” said Lasek, who is the corresponding author on the paper and a researcher in the UIC Center for Alcohol Research in Epigenetics. “Women may be more vulnerable to the effects of alcohol or more likely to overindulge during certain stages of their cycle when estrogen levels are higher, or may be more likely to seek out alcohol during those stages.”

    Studies indicate that gender differences in psychiatric disorders, including addiction, are influenced by estrogen, one of the primary female sex hormones. Women are more likely to exhibit greater escalation of abuse of alcohol and other drugs, and are more prone to relapse in response to stress and anxiety.

    The VTA helps evaluate whether something is valuable or good. When neurons in this area of the brain are stimulated, they release dopamine — a powerful neurotransmitter responsible for feelings of wellness — and, in large doses, euphoria. When something good is encountered — for example, chocolate — the neurons in the VTA fire more rapidly, enforcing reward circuitry that encodes the idea that chocolate is enjoyable and something to be sought out. Over time, the VTA neurons fire more quickly at the sight, or even thought of, chocolate, explained Lasek. In addiction, VTA neurons are tuned into drugs of abuse, and fire more quickly in relation to consuming or even thinking about drugs, driving the person to seek them out — often at the expense of their own health, family, friends and jobs.

    Many animal studies have shown that alcohol increases the firing of dopamine-sensitive neurons in the VTA, but little is known about exactly why this occurs.

    Lasek and her colleagues examined the relationship between estrogen, alcohol and the VTA in female mice. They used naturally cycling mice that were allowed to go through their normal estrous cycles, akin to the menstrual cycle in women.

    Mice were evaluated to determine when they entered diestrus — the phase in the estrous cycle when estrogen levels are close to their peak.

    “In mice in diestrus, estrogen levels increase to about 10 times higher than they are in estrus, the phase in which ovulation occurs and estrogen levels drop,” Lasek said.

    VTAs were taken from mice in both estrus and diestrus and kept alive in special chambers. Electrodes recorded the activity of individual dopamine-sensitive neurons in the VTA. Next, the researchers added alcohol to the chamber. Activity increased twice as much in neurons from mice in diestrus compared to the response of neurons from mice in estrus.

    Lasek and her colleagues then blocked estrogen receptors on dopamine-sensitive neurons in VTA in mice in estrus and diestrus. With the blocker present, the response to alcohol in neurons from mice in diestrus was significantly lower compared with neurons where estrogen receptors remained functional. The estrogen receptor blocker reduced the alcohol response to levels seen in mice in estrus. The responses to alcohol in neurons from mice in estrus were unaffected by the estrogen receptor blocker.

    “The increased reward response to alcohol we see when estrogen levels are high is mediated through receptors for estrogen in the VTA,” said Mark Brodie, professor of physiology and biophysics in the UIC College of Medicine and a co-author on the paper.

    Lasek believes that the increased sensitivity to alcohol in the VTA when estrogen levels peak may play a significant role in the development of addiction in women.

    “We already know that binge drinking can lead to lasting changes in the brain, and in women, those changes may be faster and more significant due to the interaction we see between alcohol, the VTA and estrogen,” Lasek said. “Binge drinking can increase the risk of developing alcoholism, so women need to be careful about how much alcohol they drink. They should be aware that they may sometimes inadvertently over-consume alcohol because the area of the brain involved in alcohol reward is responding very strongly.”


  2. Study suggests genetic influences on the brain’s reward, stress systems underlie co-occurring alcohol use disorder, chronic pain

    October 21, 2017 by Ashley

    From the Research Society on Alcoholism press release:

    Alcohol use disorder (AUD) often co-occurs with chronic pain (CP), yet the relationship between the two is complex — involving genetic, neurophysiological, and behavioral elements — and is poorly understood. This review addressed the genetic influences on brain reward and stress systems that neurological research suggests may contribute to the co-occurrence of AUD and CP.

    Candidate gene association studies (CGAS) and genome-wide association studies (GWAS) have provided initial evidence suggesting that a similar dysregulation of reward and stress pathways contribute to AUD and CP, and that genetic influences on these pathways may contribute to both conditions. More specifically, genetic association studies that have looked at AUD and CP independently have identified a number of single-nucleotide polymorphisms (SNPs) — DNA sequence variations — suggestively associated with AUD and CP, with several of these SNPs being located in or near a common set of genes. These common genes are either directly or indirectly related to the reward and stress systems, and are also more broadly involved with the central nervous system (CNS).

    The authors suggested that these results must be interpreted with caution until studies with sufficient statistical power are conducted and replicated. Further, the co-occurrence of AUD and CP reflect a common genetic basis that will likely involve CNS processes other than reward and stress mechanisms in AUD-CP co-occurrence. As the field of molecular genetics continues to advance, if such shared genetic contributions to AUD and CP may be identified, this knowledge can help inform understanding of the underlying mechanisms that contribute to the etiologies of each disorder and their co-occurrence. This would refine and improve the diagnosis and treatment of AUD and CP.


  3. Study suggests having a parent with an alcohol use disorder increases risk for teenage dating violence

    October 18, 2017 by Ashley

    From the University at Buffalo press release:

    Having a parent with an alcohol use disorder increases the risk for dating violence among teenagers, according to a study from the University at Buffalo Research Institute on Addictions.

    In addition, researchers found that the root causes of teen dating violence can be seen as early as infancy.

    “Although teen dating violence is typically viewed as a problem related specifically to adolescent development, our findings indicate that the risk for aggressive behavior and involvement in dating violence are related to stressors experienced much earlier in life,” says Jennifer A. Livingston, PhD, senior research scientist at RIA and lead author of the study.

    Livingston evaluated 144 teenagers who had fathers with an alcohol use disorder and who had been initially recruited for study at 12 months of age. By analyzing data that was collected regularly over the course of their lifespan, Livingston was able to identify factors that led to some of the teenagers to be involved in abusive dating relationships.

    “It appears that family dynamics occurring in the preschool years and in middle childhood are critical in the development of aggression and dating violence in the teenage years,” she says.

    Mothers living with partners who have alcohol use disorder tended to be more depressed and, as a result, were less warm and sensitive in their interactions with their children, beginning in infancy. “This is significant because children with warm and sensitive mothers are better able to regulate their emotions and behavior,” Livingston says. “In addition, there is more marital conflict when there is alcohol addiction.”

    These conditions can interfere with children’s abilities to control their own behavior, resulting in higher levels of aggression in early and middle childhood. Children who are more aggressive in childhood, particularly with their siblings, are more likely to be aggressive with their romantic partners during their teen years.

    “Our findings underscore the critical need for early intervention and prevention with families who are at-risk due to alcohol problems. Mothers with alcoholic partners are especially in need of support,” Livingston says. “Our research suggests the risk for violence can be lessened when parents are able to be more warm and sensitive in their interactions with their children during the toddler years. This in turn can reduce marital conflict and increase the children’s self-control, and ultimately reduce involvement in aggressive behavior.”


  4. What makes alcoholics drink? Research shows it’s more complex than supposed

    September 20, 2017 by Ashley

    From the European College of Neuropsychopharmacology press release:

    What makes alcoholics drink? New research has found that in both men and women with alcohol dependence, the major factor predicting the amount of drinking seems to be a question of immediate mood. They found that suffering from long-term mental health problems did not affect alcohol consumption, with one important exception: men with a history of depression had a different drinking pattern than men without a history of depression; surprisingly those men were drinking less often than men who were not depressed.

    “This work once again shows that alcoholism is not a one-size-fits-all condition,” said lead researcher, Victor Karpyak (Mayo Clinic, MN, USA). “So the answer to the question of why alcoholics drink is probably that there is no single answer; this will probably have implications for how we diagnose and treat alcoholism.”

    The work, presented at the ECNP congress by researchers from the Mayo Clinic*, determined the alcohol consumption of 287 males and 156 females with alcohol dependence over the previous 90 days, using the accepted Time Line Follow Back method and standardized diagnostic assessment for life time presence of psychiatric disorders (PRISM); they were then able to associate this with whether the drinking coincided with a positive or negative emotional state (feeling “up” or “down”), and whether the individual had a history of anxiety, depression (MDD) or substance abuse.

    The results showed that alcohol dependent men tended to drink more alcohol per day than alcohol dependent women. As expected, alcohol consumption in both men and women was associated with feeling either up or down on a particular day, with no significant association with anxiety or substance use disorders. However, men with a history of major depressive disorder had fewer drinking days (p=0.0084), and fewer heavy drinking days (p=0.0214) than men who never a major depressive disorder.

    Victor Karpyak continued: “Research indicates that many people drink to enhance pleasant feelings, while other people drink to suppress negative moods, such as depression or anxiety. However, previous studies did not differentiate between state-dependent mood changes and the presence of clinically diagnosed anxiety or depressive disorders. The lack of such differentiation was likely among the reasons for controversial findings about the usefulness of antidepressants in treatment of alcoholics with comorbid depression.

    This work will need to be replicated and confirmed, but from what we see here, it means that the reasons why alcoholics drink depend on their background as well as the immediate circumstances. There is no single reason. And this means that there is probably no single treatment, so we will have to refine our diagnostic methods and tailor treatment to the individual. It also means that our treatment approach may differ depending on targeting different aspects of alcoholism (craving or consumption) and the alcoholic patient (i.e. man or a woman) with or without depression or anxiety history to allow really effective treatment.”

    Commenting, Professor Wim van den Brink (Professor of Psychiatry and Addiction at the Academic Medical Centre, University of Amsterdam) said:

    “This is indeed a very important issue. Patients with an alcohol use disorder often show a history of other disorders, including mood and anxiety disorders, they also often present with alcohol induced anxiety and mood disorders and finally the may report mood symptoms that do not meet criteria for a mood or anxiety disorder (due to a failure to meet the minimal number of criteria or a duration of less than two weeks). All these different conditions may influence current levels or patterns of drinking.

    The current study seems to show that the current presence of mood/anxiety symptoms is associated with more drinking in both male and female alcoholics, whereas a clinical history of major depression in male alcoholics is associated with lower current dinking levels. Although, the study does not provide a clear reason for this difference, it may have consequences for treatment. For example, antidepressant treatment of males with a history major depression may have no effect on drinking levels. However, these findings may also result from residual confounding, e.g. patients with a history of major depression might also be patients with a late age of onset of their alcohol use disorder and this type of alcohol use disorder is associated with a different pattern of drinking with more daily drinking and less heavy drinking days and less binging. More prospective studies are needed to resolve this important but complex clinical issue.”


  5. Anxiety study shows genes are not fixed: Experience and exposure can change them

    July 14, 2017 by Ashley

    From the Research Society on Alcoholism press release:

    Epigenetics refers to how certain life circumstances can cause genes to be silenced or expressed, become dormant or active, over time. New research shows that adolescent binge drinking can lead to epigenetic reprogramming that predisposes an individual to later psychiatric disorders such as anxiety. These data will be shared at the 40thannual scientific meeting of the Research Society on Alcoholism (RSA) in Denver June 24-28.

    “Adolescence is an important period of growth,” said Subhash C. Pandey, Ph.D., professor and director of the Alcohol Research Center at the University of Illinois at Chicago. “This is when the brain is maturing, and consistent epigenetic programing occurs. This is also a period when binge drinking is prevalent. Adolescent binge drinking can disrupt epigenetic programing in key brain regions by changing certain key molecular targets within the epigenome.”

    Pandey explained that early life exposure to alcohol can have not only long-lasting effects on brain chemistry but also induce a predisposition to psychiatric problems such as alcohol abuse and anxiety disorders. “Anxiety disorder is highly comorbid with alcoholism,” he said, “and adolescent alcohol exposure can lead to the development of high anxiety and alcohol intake in adulthood.” Pandey will elaborate on these findings at the RSA meeting on June 25.

    “More specifically, our data indicate that the enzymes histone deacetylases and demethylases — which are responsible for the regulation of histone acetylation and methylation — are altered in adulthood due to previous adolescent alcohol exposure. This alteration causes specific genes involved in regulating synaptic events to become suppressed, leading to high anxiety and high alcohol drinking behavior.” In other words, adolescent alcohol exposure can change the architecture where certain genes reside, and thus modify how the genes perform.

    “In short,” said Pandey, “epigenetic reprogramming in the brain due to early life experiences or exposure to alcohol can lead to the changes in gene functions and predispose an individual to adult psychopathology.”


  6. Drinking makes you older at the cellular level

    by Ashley

    From the Research Society on Alcoholism press release:

    The more alcohol that people drink, the more their cells appear to age. In a new study that will be shared at the 40th annual scientific meeting of the Research Society on Alcoholism (RSA) in Denver June 24-28, researchers found that alcoholic patients had shortened telomere lengths, placing them at greater risk for age-related illnesses, such as cardiovascular disease, diabetes, cancer and dementia..

    Telomeres, the protein caps on the ends of human chromosomes, are markers of aging and overall health,” said Naruhisa Yamaki, M.D., a clinical fellow at the Kobe University Graduate School of Medicine. Yamaki explained that every time a cell replicates, a tiny bit of telomere is lost, so they get shorter with age. But some groups may have shorter telomeres for reasons other than aging.

    “Our study showed that alcoholic patients have a shortened telomere length, which means that heavy drinking causes biological aging at a cellular level,” he said. “It is alcohol rather than acetaldehyde that is associated with a shortened telomere length.” Yamaki will present this research at the RSA meeting on June 25.

    Yamaki and his co-authors recruited 255 study participants from alcoholism treatment services at Kurihama National Hospital in Yokosuka, Japan: 134 alcoholic patients and 121 age-matched controls or non-alcoholics, ranging in age from 41 to 85 years old. DNA samples, as well as drinking histories and habits, were collected from all participants.

    “We also found an association between telomere shortening and thiamine deficiency (TD),” said Yamaki. “TD is known to cause neuron impairments such as Wernicke-Korsakoff Syndrome. Although how exactly TD can cause neural impairments is unclear, it is well known that oxidation stress cause telomere shortening and, thus, it is possible that oxidation stress may also cause neuron death.”

    Yamaki added that it’s important for the public to understand that heavy drinking causes telomere shortening because “awareness of this fact provides important information necessary for people to live healthier.”

    Yamaki will present these findings during the RSA 2017 meeting on Sunday, June 25 at 3:15 during “A Multifaceted View of Alcoholism in Older Adults” at the Hyatt Regency Denver.


  7. Study suggests alcohol use frequency may lead to cognitive impairments

    July 1, 2017 by Ashley

    From the Columbia University’s Mailman School of Public Health press release:

    Impairments in processing and using information that help with decision-making and planning simple tasks such as grocery shopping are linked with one’s frequency of alcohol or drug use according to a new study. Researchers at Columbia University’s Mailman School of Public Health and Columbia University Medical Center found that cognitive impairments are not a problem limited to addiction patients in treatment, but constitute a broader problem among substance users in the U.S. general population. Results are published online in the journal Addiction.

    This is the first study to find associations between deficits in attention and executive functioning with frequency of binge drinking and use of marijuana, cocaine, opioids, sedatives and tranquilizers, and stimulants in the general population ages 18 and older.

    “Regardless if cognitive impairments precede substance use or vice versa, poorer cognitive functioning negatively impacts daily life and may cause lack of insight into one’s substance use as a source of problems, impeding treatment utilization or decreasing the likelihood of effective treatment,” said senior author Deborah Hasin, PhD, Columbia Mailman School of Public Health professor of Epidemiology and in the Department of Psychiatry at Columbia University Medical Center.

    The researchers analyzed data from 36,085 respondents to the 2012-2013 National Epidemiologic Survey on Alcohol and Related Conditions-III, a representative sample of the U.S. adult population, to create two cognitive scales based on dimensionality and reliability.

    “Our study shows the validity of two scales for assessing how cognitive impairments are associated with many substance disorders including alcohol, cannabis, cocaine and one’s ability to function well in important interpersonal or occupational areas,” said Efrat Aharonovich, PhD, Department of Psychiatry, Columbia University Medical Center, and first author. “Our validation of the cognitive scales will facilitate further investigations of the relationships of cognitive functioning to the use of multiple substances, substance use disorders and treatment utilization, advancing our knowledge of substance use, a major public health problem.”

    Poorer attention was linked with frequent and infrequent binge drinking and use of drugs, in particular, stimulants. A lower score on executive functioning scale was associated with frequent binge drinking and drug use, cocaine in particular.

    Binge drinking was defined as four or more drinks in a day for women and at least 5 drinks in a day for men. About half the sample was female, 45 years of age or older, with an income of $20,000 or less. Slightly more than two-thirds were Non-Hispanic White; and 60 percent completed at least some college. Prevalence of substance use ranged from 33 percent for binge drinking to 1 percent for cocaine.

    “While abstinence or reduced substance use may partially improve cognition, future research should determine whether factors shown to protect against cognitive impairments in aging adults, such as a healthy diet, and physical and intellectual activities, also protect against cognitive impairments in populations with difficulties in reducing substance use,” said Dr. Hasin.


  8. Drinking during adolescence can alter brain cell nerve growth

    June 24, 2017 by Ashley

    From the Research Society on Alcoholism press release:

    The developmental period from adolescence to adulthood is accompanied by a greater vulnerability to addictions — including alcohol use disorders — than is seen in other periods of life. This increased risk may be due to genetic predisposition, poor impulse control, or heightened sensitivity of the still-developing brain to drug-related toxicity. This report describes a study in mice of the neurobehavioral impact of chronic, intermittent alcohol-vapor exposure during adolescence, in an effort to model periodic heavy drinking and compare it with similar drinking behavior during adulthood.

    Researchers conducted two parallel tests in adult male mice following their exposure to alcohol vapors during adolescence (4-6 weeks old) or adulthood (8-10 weeks old). First, they tested the adult mice for changes in the density and structure of dendritic spines (nerve endings) in the infralimbic cortex (IL), prelimbic cortex (PL) and basolateral amygdala (BLA) regions of the brain. Second, they tested the adult mice for alcohol drinking, sensitivity to alcohol intoxication, blood-alcohol clearance, and measures of response to food reward.

    Chronic exposure to alcohol vapors during adolescence produced significant, persistent, and strong regional-specific alterations in neuronal dendritic spine density in IL and BLA neurons, accompanied by a limited set of behavioral alterations. Comparable effects were not seen in the mice exposed to alcohol only during adulthood. Together, these data demonstrate that specific key brain circuits are vulnerable to alcohol’s effects during adolescence, with lasting and potentially detrimental consequences for behavior.


  9. New study may pave way for treating alcohol addiction by reducing motivation to drink

    June 11, 2017 by Ashley

    From the Elsevier press release:

    A new study in Biological Psychiatry may pave the way for treating alcohol addiction by reducing motivation to drink, rather than by altering the effects of alcohol itself. Led by Drs. Kasia Radwanska and Leszek Kaczmarek of the Nencki Institute, Warsaw, Poland, the study reports a new mechanism behind alcohol seeking behavior.

    When people think about drugs to treat alcoholism, their first thought is usually a drug that stimulates or blocks a receptor for a chemical messenger. However, the new study highlights a process that changes brain activity by altering the network of proteins that surrounds nerve cells. This network of proteins, called the extracellular matrix, provides active support for the development and activity of nerve cells. The functions of the matrix are regulated, in part, by enzymes that break down matrix proteins; one of these enzymes is matrix metalloproteinase-9 (MMP-9).

    In the study, while mice had free access to alcohol to establish addiction-like behavior, those missing the enzyme MMP-9 (MMP-9 KO) drank just as much as normal mice. However, first author Dr. Marzena Stefaniuk and colleagues found that MMP-9 KO mice were less motivated to obtain alcohol when its access was restricted, and less persistent to seek alcohol during withdrawal — behaviors normally characteristic of addiction. The researchers were able to restore the impaired motivation by replacing MMP-9 in the central amygdala, a part of the brain’s emotional center that has also been implicated in alcohol dependence.

    “Interestingly, in human alcoholics, the MMP-9 gene polymorphism that leads to a higher MMP-9 production correlates with greater motivation to drink alcohol,” said Dr. Kaczmarek, referring to their analysis of 167 alcohol-addicted males compared with 199 control males, also included in the new study. Using a clinical assessment of alcoholism behavior, the researchers found that addicted people with a T allele in the MMP-9 gene continued to drink alcohol despite the negative consequences more frequently than patients with a C allele. The findings further support the role of MMP-9 in motivation for alcohol.

    “Matrix metalloproteinases play critical roles in brain function and disease that have only recently received intensive study,” said Dr. John Krystal, Editor of Biological Psychiatry. “The exciting study by Stefaniuk and colleagues implicates them in alcohol use disorders, but they are likely to play roles quite broadly in psychiatric disorders. It will be important to determine whether these proteins may be targeted therapeutically.”

    In previous studies, MMP-9 has been demonstrated to be mandatory in the central amygdala for formation of appetitive memory traces via synaptic plasticity — the structural and physiological alteration of synapses, the connections that facilitate communication between neurons. Indeed, the loss of MMP-9 in mice impaired structural and physiological alcohol-related alterations in the central amygdala, leading the authors to suggest MMP-9-dependent synaptic plasticity in this brain region as a new mechanism behind alcohol craving.

    “In aggregate, these findings point to MMP-9 as a novel therapeutic target in fighting alcohol addiction,” said Kaczmarek.


  10. Resetting balance in reward centers may help treat alcohol addiction

    June 9, 2017 by Ashley

    From the Elsevier press release:

    The human brain functions on a delicate balance of reinforcing positive behaviors and suppressing negative ones, which takes place in the dorsal striatum, a brain region critical for goal-directed behavior and implicated in drug and alcohol addiction.

    According to a new study in Biological Psychiatry, two pathways in the dorsal striatum that regulate this process — the “Go” pathway, which hits the gas for rewarding behaviors, and the “No-Go” pathway, which hits the brakes — have opposite effects to control alcohol drinking behavior. Led by Dr. Jun Wang of Texas A&M Health Science Center, the study reports that alcohol-induced alterations in the signaling of these two pathways reinforce alcohol consumption, possibly leading to alcohol abuse or addiction.

    Co-first authors Dr. Yifeng Cheng, Dr. Cathy Huang, and Dr. Tengfei Ma and colleagues trained mice to become heavy drinkers by repeated cycles of consumption and withdrawal of 20% alcohol — slightly higher than the average alcohol content in a glass of wine — and measured the effects on the balance of this delicate control of reward behavior.

    “To the best of our knowledge, this article demonstrated, for the first time, that excessive alcohol consumption suppresses activity of the No-Go pathway,” said Wang. By recording the activity of cells, the researchers found substantially increased GABA signaling, the primary inhibitory neurotransmitter of the brain, which quieted the No-Go pathway. Excessive alcohol consumption had the opposite effect in the Go pathway. These cells had increased glutamate signaling, the primary excitatory neurotransmitter in the brain, ramping up the Go signal.

    The findings reveal detailed information on the mechanisms underlying control of alcohol consumption. “Both of these effects serve to reinforce alcohol consumption, leading to pathological excessive use of alcohol,” wrote the authors.

    Through manipulation of cells specific to each pathway to mimic either increased glutamatergic or GABAergic activity, Cheng and colleagues confirmed that inhibition of cells in the No-Go pathway and excitation of cells in the Go pathway promotes alcohol consumption. The findings indicate that either of these alterations is sufficient to drive alcohol drinking behavior.

    The researchers dug deeper into the mechanism and found that activation of dopamine D2 receptors, the type that mediate the No-Go pathway, also reduced GABAergic activity and alcohol consumption. The regulation in GABAergic activity was mediated by a downstream target of D2 receptors called GSK3?, which altered the expression of GABA receptors in the cells.

    “These findings identified potential therapeutic targets,” said Wang, referring to GSK3? and GABA signaling in the No-Go pathway, which the researchers hope will aid development of new ways to treat alcohol abuse.

    The study may have even broader implications, according to Dr. John Krystal, Editor of Biological Psychiatry. “The balance between signaling in the [Go] and [No-Go] pathways is likely to be a critical factor influencing motivated behavior, generally. This balance might be targeted to treat alcoholism, but also other addictions, mood disorders, and perhaps OCD,” he said.