The working hypothesis to explain the progression from mild (fatty liver) to more severe forms of alcoholic liver disease (e.g., fibrosis, cirrhosis, alcoholic hepatitis and hepatocellular carcinoma) has been that alcohol requires a secondary initiator or trigger for this progression, or that alcohol is secondary to some other initiating event. Hepatitis C virus (HCV) infection has been a strong candidate for this role. A recent study provides mechanistic details for this pathway and identifies FOXO3 (forkhead box transcription factor) as potential target for therapeutic intervention in alcoholic liver disease.
To test whether FOXO3 is protective for alcoholic liver injury, researchers fed alcohol to FOXO3(-/-) mice. After 3 weeks, one third of these mice developed severe hepatic steatosis, neutrophilic infiltration, and >10-fold alanine aminotransferase (ALT) elevations. In cell culture, either alcohol or HCV infection alone increased FOXO3 transcriptional activity and expression of target genes, but the combination of HCV and alcohol together caused loss of nuclear FOXO3 and decreased its transcriptional activity.
This was accompanied by increased phosphorylation of FOXO3. Mice expressing HCV structural proteins on a background of reduced expression of superoxide dismutase 2 (SOD2; Sod2(+/-)) also had increased liver sensitivity to alcohol, with elevated ALT, steatosis, and lobular inflammation. Elevated ALT was associated with an alcohol-induced decrease in SOD2 and redistribution of FOXO3 to the cytosol.
These results demonstrate that FOXO3 functions as a protective factor preventing alcoholic liver injury. The combination of HCV and alcohol, but not either condition alone, inactivates FOXO3, causing a decrease in expression of its target genes and an increase in liver injury. Modulation of the FOXO3 pathway is a potential therapeutic approach for HCV-alcohol-induced liver injury.
Alcohol, tobacco, and marijuana are the substances American adolescents use the most. A recent study led by researchers at the National Institute on Alcohol Abuse and Alcoholism examined how adolescents’ substance use patterns are associated with substance use disorders in young adulthood. Their findings, published in Drug and Alcohol Dependence in March 2014, show that adolescents who drink alcohol and also smoke cigarettes and marijuana are more likely to suffer from alcohol and other substance use disorders as young adults than adolescents who delay trying these substances.
The researchers used data from Waves I (1994–1995) and IV (2008) of the National Longitudinal Study of Adolescent Health (Add Health), the largest, most comprehensive survey of adolescents in the United States, to estimate the prevalence of various patterns of early adolescent use of alcohol, cigarettes, and marijuana, individually and in combination. They also examined the differences in these patterns based on age, gender, and race/ethnicity among users of all three substances. Then, they examined the effects of these patterns on subsequent young adult substance use behaviors and DSM-IV substance use disorders.
Researchers found that multiple substance use is highly prevalent among U.S. adolescents, with 34.1% reporting early use of alcohol and marijuana, or alcohol, marijuana and cigarettes. They also found that early use of multiple substances is associated with higher rates of substance use dependence in young adults. According to their analyses, about one-fourth of young adults ages 24 to 32 who had used alcohol, marijuana, and cigarettes before age 16 met the DSM-IV criteria for a substance use disorder. By contrast, only about 16% of young adults who had used these same substances after age 16 met the criteria for a substance use disorder.
The researchers also examined the associations between the use of multiple substances in early adolescence with a range of subsequent young adult substance use behaviors. They found that adolescents who used alcohol, cigarettes, and marijuana prior to age 16 were twice as likely to meet the criteria for marijuana dependence and three times as likely to be dependent on other illicit drugs.
The authors conclude that prevention programs should aim to encourage kids to delay use of all three problematic substances – alcohol, cigarettes, and marijuana – rather than targeting each substance separately.
Recent research from the National Institute on Alcohol Abuse and Alcoholism (NIAAA) sheds new light on habitual behaviors, specifically the circuits in the brain that allow mice to break from routine actions. Such shifting between old habits and new behavior aimed at accomplishing a particular goal are critical to flexible decision-making in everyday life. It also has important implications for mental health and substance abuse interventions. The inability to shift between routine behavior and new goal-directed actions may underlie disorders such as addiction and obsessive compulsive disorder.
“While habits are important to efficient-decision making, we encounter situations in which it is necessary to ‘break habits’ and re-evaluate actions based on their consequences,” said the study’s first author, Dr. Christina Gremel of the NIAAA Laboratory for Integrative Neuroscience. “These findings give us insight into the neural basis of such adaptability.”
In the study, published in Nature Communications, researchers set out to identify the neural circuitry involved in the shift between habit and goal-directed behavior. Previous studies indicate the involvement of two neighboring regions in the forebrain – the dorsal medial striatum is necessary for goal-directed actions, while the dorsal lateral striatum is needed for habitual actions.
In the present study, researchers found that the orbital frontal cortex, a region associated with obsessive compulsive disorder, is critical to shifting to goal-directed actions.
To uncover this finding, researchers developed an instrumental feeding task in which mice would shift between habitual and goal-directed behavior. Use of this newly-developed procedure allowed the researchers to probe the brain mechanisms involved when the animals shifted action strategies.
The researchers found that using light to activate individual neurons in the orbital frontal cortex, a process known as optogenetics, increased goal-directed actions in the mice. Inhibiting these neurons using a chemical and genetic approach interfered with the shift to goal-directed behavior, leaving the mice acting out of habit.
“Our findings indicate that shifts in activity of the orbital frontal cortex and the striatum mediate the shifting between goal-directed and habitual actions,” said the study’s senior author, Rui Costa, Ph.D., of the Champalimaud Foundation, in Portugal and a guest researcher at NIAAA. “Interestingly, these neural circuits appear to work in parallel, enabling both automatic and goal-directed actions to be learned.”
In a study conducted in mice and rats, scientists in NIAAA’s Laboratory for Integrative Neuroscience examined the cellular basis for learning and memory in the dorsolateral striatum, a part of the brain involved in habit learning. A particular receptor in the dorsolateral striatum, the cannabinoid type 1 receptor (CB1), is critical for habit learning.
“We know that CB1 in this brain region is involved in habit learning, but we have very little idea about how CB1 acts to sculpt this neural circuitry to ultimately result in the expression of habits,” said first author Brian Mathur, Ph.D.He explained that direct and indirect pathways originating in the striatum are composed of medium-sized spiny neurons (MSNs) have opposing effects on movement.The relative activation of the direct pathway over the indirect pathway, known as a“go signal,” is believed to encode for reinforcement of an action. A Change in a neural pathway associated with learning a behavior is called neuroplasticity.
The researchers examined the role of CB1 in a form of neuroplasticity known as long-term depression of synaptic transmission (LTD). LTD refers to the long-lasting decrease in the strength of signal transmission at a synapse, where signals pass from one neuron to another. A synapse that has undergone LTD is less able to influence the activity of the postsynaptic neuron.“We hypothesized that because CB1 is necessary for this long lasting form of the cellular substrate for learning and memory known as LTD, that this neuroplasticity allows for ‘go signal’ generation,” continued Mathur.
Using a novel combination of brain slice electrophysiology and optogenetics, a technique allowing for the activation of specific neural circuits with light, the investigators were able to determine the specific contribution of different inputs onto direct and indirect pathway MSNs to LTD. They found that MSNs express two forms of CB1-dependent LTD depending upon whether the MSN membrane voltage is in an excited “up state” or a more refractory “down state” These two different forms of LTD are each mediated by a separate signaling molecule capable of activating CB1: 2-AG and anandamide. The down state, anandamide-mediated form of LTD occurred only at inhibitory synapses onto direct pathway MSNs, offering a mechanism for go signal generation.
“This is a big step forward in understanding the possible molecular and circuit dynamics underlying habit formation,” said Mathur. The research team hopes their research will help uncover novel therapeutic strategies for the treatment of alcohol use disorders. A report of the study was published online in Nature Neuroscience on July 28, 2013.
New research supported by NIAAA suggests that a drug currently used to prevent the rejection of transplanted organs could someday help lessen the alcohol cravings that often lead to relapse among people with drinking problems. Alcohol-related memories, or cues—such as the smell of alcohol—can trigger cue-induced alcohol craving. Previous research has found that the mammalian target of rapamycin complex 1 (mTORC1), a group of proteins found in cells throughout the body, is involved in memory processes in the brain, and also plays an important role in alcohol-seeking behavior. In a study published online in Nature Neuroscience, researchers from the University of California San Francisco examined whether inhibiting mTORC1 could disrupt memories of alcohol cues—and thus diminish alcohol relapses in rats that had been trained to binge drink. After a period of alcohol abstinence, researchers exposed the rats to a small amount of alcohol to provide an odor and taste cue to the animals. The researchers then administered a dose of rapamycin, an mTORC1 inhibitor. Compared with a control group that did not receive rapamycin, rats that received the rapamycin sought and consumed less alcohol for the duration of the experiment. Researchers found that by disrupting memories of alcohol cues, rats were less likely to relapse to drinking than those whose memories were intact.
The researchers note memory disruption has shown success in humans who are addicted to heroin and suggest that it may prove helpful in developing new relapse-prevention strategies in alcoholics as well.