Higher sensitivity to the euphoric and rewarding effects of alcohol can predict an use disorder

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A new study out of the University of Chicago Medicine following young adult drinkers for 10 years has found that individuals who reported the highest sensitivity to alcohol’s pleasurable and rewarding effects at the start of the trial were more likely to develop an alcohol use disorder (AUD) over the course of the study.

Moreover, when retested on their responses 10 years later, those who became alcoholics had the highest levels of alcohol stimulation, liking and wanting – and these were heightened compared to their baseline with no signs of tolerance to these pleasurable effects.

The research, published on Jan. 5 in the American Journal of Psychiatry, followed a cohort of 190 young adults in a laboratory-based binge-drinking scenario at three regular intervals over the course of 10 years.

These results indicate that individuals developing an AUD are more likely to be sensitized to the effects of alcohol – that is, they experience a stronger positive response – rather than habituated to the substance with a lower level of response.

In these same individuals, alcohol was less sedating for them from the beginning and this did not change over time.

“Prior longitudinal studies have looked at young drinkers’ response to alcohol and focused primarily on the fatiguing and impairing effects of alcohol,” said lead author Andrea King, Ph.D., professor of psychiatry and behavioral neuroscience at UChicago Medicine.

“The thinking that alcoholics do not like the effects of alcohol over time is based on ad-hoc reports of patients entering treatment. Only by testing the same people over a substantial amount of time to see if alcohol responses change over time were we able to observe this elevated response to alcohol compared with placebo, and in participants who did not know the contents of the drinks, so expectancy effects were minimized.”

The study showed that higher sensitivity to the euphoric and rewarding effects of alcohol can predict who will go on to have an AUD as they progress through their 20s and 30s.

“These pleasurable alcohol effects grow in intensity over time, and do not dissipate, in people progressing in excessive drinking,” said King.

“This tells us that having a higher sensitivity to the rewarding effects of alcohol in the brain puts such individuals at higher risk for developing addiction. It all fits a picture of persistent pleasure-seeking that increases the likelihood of habitual excessive drinking over time.

Alcoholics were thought to need to drink more to finally get their desired effect when they drink, but these well-controlled data do not support that contention.

They get the desirable alcohol effect early in the drinking bout and that seems to fuel wanting more alcohol.”

While it may seem relatively intuitive that individuals who experience alcohol’s pleasurable effects most intensely are at the greatest risk for developing drinking problems, King’s findings run counter to current prominent addiction theories.

“Our results support a theory called incentive-sensitization,” said King. “In response to a standard intoxicating dose of alcohol in the laboratory, ratings of wanting more alcohol increased substantially over the decade among the individuals who developed more severe AUD.

Additionally, the hedonic response – essentially, how much a person liked the effects – remained elevated over this interval and didn’t go down at all. This has traditionally been the crux of the lore of addiction – that addicts don’t like the drug (alcohol) but can’t stop using it.”

The participants were regular light or heavy social drinkers in their mid-20s at the start of the trial from 2004 to 2006. They were brought back for repeated testing of alcohol responses in the laboratory five and 10 years later as they approached middle adulthood. In between testing periods, participants were interviewed at near-annual intervals to track their drinking patterns and symptoms of AUD over time.

King hopes that these results can help improve our understanding of how some individuals have more vulnerability to developing AUD, while others remain social drinkers over their lifespan. She also points out that the results can help to develop better treatments for AUDs and inform earlier interventions for individuals who may be at high risk for developing an addiction.

“I’m already using this information to inform how I talk about addiction with my therapy clients,” King said. “It can be frustrating for them to see other people who can have a couple drinks and just stop there.

They can’t understand why they repeatedly seem unable to do that, too, and I tell them, it may be because your brain responds differently to alcohol that makes it harder to stop drinking once you start. Knowing that information can empower a person to make different decisions.

Even with our current pandemic, a person may drink to cope with stress or reduce negative feelings, but that doesn’t mean that they don’t also experience the buzz, or pleasurable effects from drinking. This is most concerning for at-risk drinkers as those responses may intensify as they progress with heavier drinking.”

Based on this research, King sees the potential for a sort of “personalized medicine” approach for treating AUDs, describing how sharing an individual’s “thumbprint” response to alcohol can make a difference in how they think about their consumption.

“This could be an opportunity for early intervention, comparable to how someone may get their cholesterol tested and then may be more motivated to change their diet, exercise more or start a medication to rein it in,” King said.

“Similarly, knowing one’s acute response to alcohol and how it may indicate a person’s future risk for drinking problems, one may decide to change their drinking on their own or seek help to avoid the progression to addiction.”


Addiction is a complex brain disease that manifests both behaviorally as well as physiologically.4,5 Addiction is characterized as the compulsive seeking of rewarding stimulation despite reduction in euphoric effects and other negative consequences that may accompany this compulsive seeking for the individual.4–7

While addiction is not a disease that is part of the Diagnostic and Statistical Manual, version 5 (DSM-5), many of the defining traits associated with addiction are covered by the diagnostic criteria for Substance Use Disorders (SUD). Addiction is often used in correspondence with severe SUDs, but making a precise diagnosis of the severity of an SUD can be difficult even with the clearly defined diagnostic criteria set forth by the (DSM-5).

The difficulty establishing a precise diagnosis is that diagnostic criteria are based on symptom counts, and it has been shown that while two individuals may check off the same number of diagnostic criteria for an SUD they can drastically differ on the severity of their addiction depending on which criteria they endorse.8 With the numerous biological and societal factors that go into each individual case of addiction or SUD, studying their basic underlying features of these diseases is critical to improve our understanding of them.

With increased prevalence of mental health issues and drug availability SUDs are highly prevalent diseases that cause devastating effects to both the individual and society. In 2018, the Substance Abuse and Mental Health Services Administration (SAMHSA) conducted a national survey that estimated 164.8 million (60.2%) Americans had used alcohol, nicotine, or illicit drugs within the past month, and 20.3 million people ages twelve and up are currently suffering from an

SUD related to their use of alcohol or illicit drugs.9 The National Institute on Drug Abuse (NIDA) estimated that this use of drugs and alcohol costs Americans more than $700 billion and contributes to 570,000 deaths per year. 4,10 Collectively, these data illustrate that as a result of increased access to drugs and alcohol SUDs are becoming drastically more prevalent diseases with devastating effects on the individual and society.

Neurocircuitry of Addiction

Repeated exposure to drugs of abuse, used by people with SUDs, lead to compulsive behavior through their pharmacological effects on dopaminergic neurons in the reward pathway common to all mammals.5 The regions of the brain most commonly associated with addiction and SUDs are the prefrontal cortex (PFC), extended amygdala, and the ventral and dorsal striatum, which include components of the mesolimbic pathway (reward pathway).

Due to evolutionary importance these reward pathways have been highly conserved across many different species12–14. These pathways likely evolved to increase Darwinian fitness through incentive salience (motivation) and hedonic pleasure (liking), but because drugs of abuse activate habit formation pathways, the motivation for drugs can persist even after the liking subsides. 5,7,15

The NAc is an ancient forebrain structure which may have originally developed to increase Darwinian fitness through incentive salience for rewarding stimuli such as food and sex.15 Today highly refined drugs of abuse hijack this system with over stimulation of dopaminergic neurons falsely signifying large benefits to our survival.15

The excessive release of dopamine from the terminals of VTA neurons within the NAC leads to motivational arousal in the individual that creates a drive to procure the drug again. Along with innervating the NAc, the VTA also innervates regions of the PFC that in conjunction with the amygdala make environmental and emotional cues respectively to guide further decision about the motivation to procure the drug.5,16

As drug use continues, these cues and associations get stronger and incentive salience for the drugs continues to escalate as more cues become associated with their use. In addition to the increasing motivation for drug use, dopamine neurons in the substantia nigra (SN) translate the recurring reward signals into habitual actions that become increasingly insensitive to the reduction of hedonic response to continued drug use and instead use the reinforcement associated with prior experiences17,18.

Often at this point the euphoric feelings that originally were associated with drug use have subsided and further administration of drugs merely reduces the depressive feelings caused by changes to normal dopamine levels in the reward pathway so the individual can return to an emotional and physiological baseline 7,15.

This dysregulation of the reduced hedonic response in the NAc and increased incentive salience, driven by positively reinforcing cues stored in the PFC and amygdala, can lead to emergence of the compulsive drug taking habits which underlie addiction and SUDS.5,7,11,12,17

With the multitude of neural processes and brain regions working in unison there are many mechanisms by which genetic and biological variations can alter their function. The slight alterations to different brain regions and neural processes can manifest themselves in many different behavioral and physiological manners leading to many mechanisms of addiction vulnerability in different people.

SUDs Comorbidity with Mental Health Disorders

Results from the 2018 Substance Abuse and Mental Health Service Administration (SAMHSA) survey show a high rate of comorbidity between SUDs and people that suffer from mental illness.9 This study estimated that currently 9.2 million people are suffering from both mental illness and an SUD. This estimate represents about twenty percent of all people suffering from mental illnesses.9

The high rates of comorbidity between mental illness and SUDs are indicative of potential genetic, neurobiological, and behavioral traits underlying both of these complex diseases. Some believe these diseases are connected through the self-medication hypothesis, which posits that people take drugs as negative reinforcers that relieve symptoms of mental illness.

However, self-administration of drugs also alters natural levels of neurotransmitters such as dopamine or GABA19,20 in regions of the brain, leading to or exacerbating mental health problems. Although the interplay of the disorders and trajectory between 21,22 are not fully elucidated, it is clear that SUDs and mental health disorders are two strongly intertwined diseases.

Using the connections between SUDs and many mental illnesses, studies have shown that many predisposing drug-naïve behaviors, personality traits, and co-occurring psychological conditions connected to mood disorders such as anxiety, depression, impulsivity, and sensation/novelty seeking are associated with the risk for and are also consequences of many aspects of SUDs. 23–26

These connections between SUDs and mental illnesses can make it a vicious cycle of one disease predisposing individuals to the other disease leading to a vicious cycle that is hard to break. Although these traits and behaviors may be putting individuals at greater risk, many other factors must be taken into account when determining the overall risk of an individual developing an SUD.

These factors may include socioeconomic status, family/ peer structure, age, sex, genetic vulnerability, and other extrinsic influences.1,27,28 Finding the genetic and biological factors that underlie substance use and many of the traits associated with mental illness2,3 can provide biomarkers for screenings and potential therapeutic targets for treating these diseases.

Role of Genetics in Addiction

Many factors play a role in determining whether an individual will develop an SUD and become addicted to that substance. An individual who lives in an environment where there is no access to drugs is highly unlikely to develop an addiction to a drug, but few such places exist.

Beyond environmental access to drugs and predisposing behaviors associated with drug use, not all individuals who initiate drug use become addicted to the substances they use implying that there must be some underlying biological or genetic vulnerability to addiction. Many studies in humans have shown that on average the heritability of substance addiction is around 50% 12,27,29,30 with hallucinogen use being the least heritable 39% and cocaine use being the most heritable 72% according to data from twin studies.1

Although genetic vulnerability to addiction and substance use is relatively high across many substances it can be challenging to identify and examine the effects of any particular candidate gene. Due to their highly heterogeneous nature and numerous confounding gene × environment interactions, it is therefore a daunting task to identify genes that underlie the vulnerability to SUDs and addictions.

Historically, researchers have undertaken complex hypothesis driven studies to examine the role of a particular gene in often a specific substance use paradigm, leading to long, expensive studies that slowly advance our knowledge of the genetic factors playing a role in addiction based on already well-studied mechanisms. Much focus has gone into studying genetic components underlying substance-specific effects because these genetic components can play crucial roles in development of treatments for drug-specific SUDs. In addition to studying these substance-specific gene additional focus is being put on identifying and characterizing substance-non-specific genes which may underlie generalized substance use. These genes that affect use of multiple substances are important as well because they could play a role in

developing more generalized substance-use treatments.31 Additionally, it has been shown that genes predisposing for addiction risk traits like high intake or preference drinking differ from the genes involved in transition from substance use to addiction.32 Distinguishing the genetic factors that underlie addiction risk factors like high initial intake from those that underlie susceptibility to transition into addiction is a challenging task further slowing the pace for discovery.

In contrast, discovery approaches including Genome Wide Association Studies (GWAS) allow for the discovery of previously unknown genes in addiction. While GWA studies do not have the precise control over factors such as environment and experimental conditions, these studies can work directly with vast quantities of human data and therefore, genetic candidates are known to be involved in human disease, in contrast to findings from animal models, which need to be evaluated from a comparative perspective.

Now, using the mass amount of data compiled in the human, GWAS researchers can use results from addiction phenotypes and biomarkers to identify genetic loci, individual genes, and sometimes even single nucleotide polymorphisms (SNPs) that can explain some of the heritability for addiction. 27,28 While GWAS are a promising start, data from hundreds of thousands to millions of individuals is required to explore the genetics underlying addiction in humans, making the studies of many drugs and many populations cost- prohibitive.

Many of the factors that limit genetic discovery in human studies, including environmental factors, genetic background, medical history, and sample size are easily controlled when using animal models. The use of animal models, such as mice, can serve as a powerful research tool for studying many of the genetic and biological mechanisms underlying complex disease phenotypes.33–35 Animal models, in combination with advancing genetic engineering technologies, have been used to evaluate and characterize hypothesized gene disease associations from human

studies and provide therapeutic targets through the use of behavioral assays proven to have translational applications.35 Additionally, advancing high-diversity mouse populations such as the Diversity Outbred (DO) and Collaborative Cross (CC) stocks greatly increase the power to identify genetic factors and biological mechanisms underlying complex diseases when used in a systems genetics approach.33

Using these ever advancing animal models and technologies also allow for the discovery of high order interactions such as gene × sex intaractions34 and gene × environment interactions36 which most human studies are underpowered to detect. Undoubtedly, complementary findings from both human and animal models will be required to identify and characterize genetic risk factors underlying our susceptibility to addictions and SUDs.

Current Treatments and Potential for Pharmacotherapeutic Treatments

Sadly, of the nearly twenty million people with SUDs, SAMSHA estimated that in 2018 90-97% of people who needed treatment received no treatment of any type including medical, psychiatric, or support groups.10,37 Among the small percentage of people who do seek treatment, there is a 40-60% relapse rate across all SUDs which is comparable to the relapse rates of many other well established chronic diseases.4,38

Due to the highly heterogeneous causes of SUDs and addictions, lack of precise diagnostic criteria for assessing true severity of the disease39, and inadequate training of medical professionals in the field of substance use40 it is not surprising that there are extremely high rates of relapse.

Current treatments for addictions and SUDs are limited and often consist of a combination of behavior therapy, counseling, and medications depending on what substance an individual is using. Research for new pharmacotherapeutic treatments is ongoing, but currently the FDA has only approved medications for the treatment of alcohol, nicotine, and opioid use.5 New techniques

with promising results for the treatment of addictions and SUDs are being developed at increasing rates as the cost of these diseases continues to rise. One of these promising techniques include: transdiagnostic treatments, which look to treat the underlying conditions shared across behavioral and substance related addictions41. One promising pharmacological treatment is the development of the drug Topiramate that shows efficacy across SUDs.5,42

One area of interest is the identification of genes and biological mechanisms that could lead to the discovery of novel therapeutic agents. These novel biomarkers could allow medical professionals to assess a person’s vulnerability to SUDs, identify which pharmacotherapeutic techniques could be the most beneficial to an afflicted individual43, or even help determine the vulnerability to relapse44. Through the discovery of novel addiction genes and biological mechanisms, there is the potential to accelerate the rate at which we can produce improved therapeutic treatments, both general and individualized.

reference link : https://digitalcommons.library.umaine.edu/cgi/viewcontent.cgi?article=4249&context=etd


More information: “Subjective Responses to Alcohol in the Development and Maintenance of AUD,” American Journal of Psychiatry (2021). ajp.psychiatryonline.org/doi/a … pi.ajp.2020.20030247

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