Can Brain Modulation Confer Resilience to Addiction?

Resilience is an individual’s ability to be protected from the development of an illness, including addiction. To an extent, it can be thought of as the opposite of vulnerability, or the increased risk of developing a disease. Identifying the factors that influence resilience and vulnerability could lead to strategies to prevent the development of addiction, and may even lead to new treatment approaches for substance use disorders.

In Europe, a large study is being conducted by the IMAGEN consortium to study resilience and vulnerability in mental health, with a focus on addiction. Over two thousand 14-year-old children have been enrolled and have received brain scans, genetic testing and behavioral assessments (Schumann Molecular Psychiatry, 15(12), 1128-1139). A recent publication from this group showed that they could predict with about 70% accuracy which children would become binge drinkers by age 16 (Whelan et al Nature. 2014 512(7513):185-9). The factors conferring risk or resilience to the development of binge drinking studied by the IMAGEN group were divided into the categories of history, genetics, personality and brain.

With respect to the history category, children who drank alcohol at 14, smoked tobacco or experienced early romantic/sexual relationships were more likely to be binge drinking at 16. However, others factors that are often considered to confer greater risk proved inconclusive from the early results. This included disruptive family events like a family history of alcohol problems and more developed pubertal status, which predicted current, but not future binge drinking.

In the genetics category, members of the IMAGEN consortium conducted an analysis of 15 genotypes that have previously been implicated in alcohol dependence, which affect a range of functions, from alcohol metabolism to neurotransmitter levels (Rietschel et al, Genetics of Alcohol Dependence. Ann. NY Acad. Sci. 1282, 39–70 (2013)). However, none were predictive of drinking in adolescents.

In the category of personality, increased novelty-seeking behavior (seeking out, and feeling rewarded by, new experiences) and impulsivity at age 14 were predictive of heavy alcohol use at age 16. On the other hand, conscientiousness, which can be defined as motivation to achieve a desired goal, was lower in those who developed binge drinking at age 16.

As for the category of brain, future binge drinkers had reduced gray matter but increased brain activity in response to a reward in the prefrontal cortex (pre-central and superior frontal gyrus). Broadly, the function of these brain regions is to assess reward outcome and to exert inhibitory control over impulsive acts. Similar results showing altered function of some brain regions as an important factor in the context of resilience have been demonstrated in the literature. In particular, there are several interesting animal studies that focus on the role of the prefrontal cortex and the activation of pathways in the striatum.

Chen, et al. (Nature, 2013 Apr 18;496(7445):359-62) showed that the excitability of the neurons in the prefrontal cortex is markedly reduced in rats with “addiction” (the ones that self-administer drug in a compulsive way), and that stimulating the prefrontal cortex (prelimbic region) decreases compulsive drug-seeking in these animals. The ability of the prefrontal cortex to exert this inhibitory control over impulsive acts is largely related to its ability to modulate the reward-driven activity of the striatum.

The prefrontal cortex sends connections to the striatum, and controls information processing within the striatum. Thus, while the striatum is involved in responding to rewards, it is the prefrontal cortex that controls the final output, like the leash on a dog. There are two main output pathways of the striatum, called the direct and indirect pathways. The direct pathway acts as a “go” signal for reward-driven behavior whereas the indirect pathway acts as a “no-go” signal or the “brake” on behavior.

There are important differences in the neurobiology of the neurons that make up these pathways. For example, the direct pathway mostly expresses dopamine type 1 receptors, whereas the indirect pathway neurons express dopamine type 2 receptors. Human imaging studies in addiction consistently show a decrease in the levels of the type 2 dopamine receptor in the striatum, suggesting that the indirect pathway, or brake, is somehow altered in substance use disorders.

Both pathways can be modulated and controlled by input from the prefrontal cortex, which contain the neurotransmitter glutamate. A recent animal study showed that mimicking an enhancement of activity of glutamate projections onto the direct or the indirect pathways could confer vulnerability or resilience to cocaine consumption in rodents (Bock et al., Nat Neurosci. 2013 May;16(5):632-8). All rodents in the study were exposed to cocaine, but some showed less addiction-like behavior even after exposure – which were considered as the resilient animals. Cocaine increased glutamate transmission to the direct (“go”) pathway in all animals, but the resilient animals also had greater glutamate transmission to the indirect (“brake”) pathway, whereas the animals that continued to seek cocaine did not.

The authors then manipulated the activity of the direct and indirect pathways. They showed that reducing the activity of the indirect pathway (“brake”) increased drug self-administration and that mimicking increased “brake” (indirect pathway) activity rendered the animals more “resistant” to the development of addiction, inhibiting their cocaine intake.

These results suggest that, under cocaine exposure, naturally resilient animals have greater activity in the indirect pathway, which acts as a brake on addictive behavior, even in animals that have experienced exposure to drugs of abuse. More importantly, this study shows that increasing signaling within the indirect pathway can rescue animals with “addiction,” and make them resilient to the rewarding effects of cocaine.

In summary, the human imaging study shows that predictors of binge drinking in adolescents include risky behaviors, such as novelty seeking and impulsivity, early use of drugs/alcohol, and alterations in the prefrontal cortex. A good predictor of resilience is motivation to obtain goals. Previous research has shown that these behaviors are modulated by the prefrontal cortex and the striatum, and that the connections between them act as an accelerator or brake for impulsive versus motivated behavior (as described before). The study by Chen, et al now shows that the “brake” can be activated in previously “addicted” animals to make them more resilient to cocaine. Thus, while we usually think of vulnerability and resilience to addiction as being lifelong “traits,” this data suggests that these factors may be modifiable by changing brain function. But, because the research methods from rodent studies are invasive, the challenge then becomes how these types of manipulation can be applied to humans. New methods and ideas for performing this in humans are being developed, and will be the topic of another article.