Objective 1.1: Characterize the genetic, neurobiological, environmental, social, and developmental factors that mediate risk and resilience for drug use and addiction
Like most behavioral health disorders, SUDs are polygenic disorders with a complex pattern of inheritance that results from the combined effects of multiple genes and their interaction with the environment.40 There are likely to be many regions of the genome that contribute to SUD risk, and their individual effects may vary across developmental stages. Understanding the confluence of biological, behavioral, environmental, social, and developmental factors that mediate risk and resilience will provide a foundation of knowledge necessary for designing new prevention and treatment strategies that are tailored towards an individual’s unique risk profile.
Understanding the gene x environment x development interactions that contribute to the risk for SUD phenotypes using GWAS will require methods to overcome statistical challenges due to multiple comparisons. One of the primary challenges to understanding how these factors contribute to the various stages of SUDs (e.g., escalation, relapse, etc.) is to determine how to detect relatively small genetic effects that contribute to the overall heritability of SUDs and then examine how these genetic effects operate within changing environments and across human development. Though GWAS has been one of the most productive methods for identifying genetic variants associated with disease, the reduced costs and high throughput of genome sequencing will make it increasingly feasible to apply this technique to SUD research. The development of advanced analytical and computational tools will be essential to take advantage of this rich information.
In addition, mice with defined genetic backgrounds (e.g., inbred strains, recombinant inbred strains, strains carrying defined naturally occurring and induced genetic variations, etc.) provide a way to test gene x environment and gene x development interactions under controlled experimental conditions.
- Conduct human molecular genetics studies, including large-sample GWAS and genome sequencing, to identify genetic variants that contribute or provide resilience to SUDs
- Integrate GWAS and sequencing efforts with behavioral phenotype identification, environmental effects (including social contexts), postmortem molecular changes, and epigenomic characterization across human development
- Expand efforts to characterize epigenetic modifications associated with SUDs
- Functionally validate and characterize SUD-related gene variants in animal models and identify opportunities for clinical translation
The Neuroscience of Addiction
We have learned an enormous amount in the last decade about the effects of drugs on the brain and the biological processes involved in developing SUDs. The process involves major changes to multiple interconnecting circuits in the brain.
First, drugs of abuse affect, or in some cases directly mimic, the actions of signaling chemicals in the brain (neurotransmitters), including raising the level of the neurotransmitter dopamine in reward circuits (the nucleus accumbens and dorsal striatum). This produces feelings of euphoria. However, with repeated drug use, these circuits adapt to the dopamine surges by reducing their sensitivity. A person then needs more of the drug to get the initial effect (tolerance) and to avoid withdrawal symptoms (dependence).5
When someone develops an addiction, not only these reward circuits but also circuitry involved in stress, learning, and self-control become altered. "Anti-reward" circuits involving the amygdala and other brain areas that control our emotional responses cause an addicted person to feel severe stress when not using the drug; the person then needs the drug to feel physically well. In addition, the brain learns to associate the drug with many other aspects of the person’s daily life and routine. Frequent reminders of the drug (triggers) reinforce constant preoccupation and craving. And, crucially, parts of the prefrontal cortex needed for decision-making and exerting self-control also become desensitized to dopamine.46 This makes it very difficult for the person to stop or limit drug use even if he or she is aware of negative consequences and has a strong, sincere desire to quit.
As a result of these changes, people with an addiction do not feel motivated by ordinary rewarding behaviors, need the drug just to feel temporarily normal, and experience powerful urges to seek and use the drug despite knowing that it is harming them and causing disastrous effects in their lives. This compromised self-control is one of the most painful aspects of addiction. It is also the hardest for nonaddicted people to understand, leading to persistent stigma against people with SUDs.
The good news is that it is possible for brain circuit function to be repaired and for the brain to readapt to the absence of drugs. However, like all healing processes in the body, it takes time. SUDs are chronic, relapsing disorders; successful recovery often involves months to years of treatment. In many cases, such as opioid addiction, medications can be an important part of treatment to reduce withdrawal symptoms and reduce the chance of relapse.47 Future research will capitalize on our growing understanding of the neurobiology of addiction by creating new and better methods for prevention and treatment, including new medications and other nondrug therapeutics.