New Studies May Explain Adolescents' Increased Susceptibility to Addiction
The recent findings identify promising targets for the development of addiction treatments.
Adolescence is a time of increased susceptibility to drug addiction, but experts have been uncertain about why this is so. New findings involving mice and humans shed light on potential mechanisms for this heightened vulnerability and offer clues about future addiction treatments.
In 2 related studies published in March 2016 in eLife, researchers at multiple US universities investigated the role of eIF2α−a protein that regulates the generation of new proteins−in the development of addiction. The research was funded by the National Institutes of Health (the National Institute of Mental Health, the National Institute of Neurological Disorders and Stroke, and the National Institute on Drug Abuse), the Howard Hughes Medical Institute, and the US Department of Veterans Affairs.
One of the ways in which addictive drugs cause changes in brain function is by strengthening synaptic connections between neurons, making communication between them easier. This effect relies on translation, which is the production of new proteins via protein synthesis. The researchers hypothesized that adolescents' greater addiction susceptibility may be due to their increased capacity for protein production compared with adults, which could facilitate changes in synaptic strength.
The administration of a low dose of cocaine to adolescent mice decreased the phosphorylation of eIF2α (p-eIF2α) in the ventral tegmental area, a key area of the brain's reward system. Additionally, the cocaine “potentiated synaptic inputs to [ventral tegmental area] dopaminergic neurons and induced drug-reinforced behavior.” These effects were not observed in adult mice. However, when researchers reduced the p-eIF2α-mediated translational control in the adult mice, their vulnerability to the effects observed in the adolescent mice increased. Similar effects were found when the mice were treated with methamphetamine, nicotine, and ethanol.
“Conversely, like adults, adolescent mice with increased p-eIF2α became more resistant to cocaine's effects,” they wrote. “Accordingly, metabotropic glutamate receptor-mediated long-term depression (mGluR-LTD)—whose disruption is postulated to increase vulnerability to drug addiction—was impaired in both adolescent mice and adult mice with reduced p-eIF2α mediated translation.” The researchers concluded that the “reduced eIF2α activity accounts for why adolescents are particularly vulnerable to the synaptic and behavioral effects of cocaine.”
Results of the companion study show that, similar to the effects observed with cocaine, adolescent mice were more vulnerable to nicotine-induced changes in synaptic strength due to reduced eIF2α activity. Again, as observed in the related study, such changes were equally likely to occur in adult mice when researchers reduced their eIF2α activity. Additionally, functional magnetic resonance imaging revealed that “brain activity of human smokers was significantly reduced when given a natural reward,” and further investigation showed “a variation in the gene encoding the eIF2α protein that affects how smokers respond to a reward, suggesting that this variant is linked to the likelihood that a person will be addicted to nicotine,” according to the paper.
Taken together, the findings highlight potential mechanisms underlying addiction vulnerability, as well as identify promising targets for the development of novel addiction treatments.
- Huang W, Placzek AN, Di Prisco, et al. Translational control by eIF2α phosphorylation regulates vulnerability to the synaptic and behavioral effects of cocaine. eLife. 2016;5:e12052.
- Placzek AN, Molfese DL, Khatiwada S, et al. Translational control of nicotine-evoked synaptic potentiation in mice and neuronal responses in human smokers by eIF2α. eLife. 2016;5:e12056.