Adolescents are more likely to get hooked on drugs than adults, and two new studies are helping us understand why. Using both animal models and humans, researchers based in the U.S. have attributed these differing susceptibilities to addiction to the activity of a cellular molecule called eIF2α.
When its activity is increased, eIF2α negatively regulates the synthesis of new proteins, a process that previous research has shown is crucial for cocaine-induced change in behavior and the strength of connections between neurons across which information flows, or synapses. In addition, the rate of protein production in the brain is known to decrease with age. To find out how drugs might be affecting this system, the team headed by researchers at the Baylor College of Medicine in Texas began by putting adolescent and adult mice through a behavioral test that assessed their preference for a particular location.
Described in eLife, mice were given either low doses of cocaine while in a given environment or salty water in a different environment. The following day, they were given the opportunity to enter these environments again, and the team assessed the amount of time they spent in each. If the animals experienced a rewarding feeling from the injection, one would expect them to return to the environment in which they were given cocaine, suggesting that cocaine is pleasurable for them.
Indeed, this appeared to be the case, but only for the adolescents. In adults, it took much higher doses of cocaine for them to exhibit a preference for the environment in which they received the drug. To look for differences at the molecular level, the team exposed adult and adolescent brain slices to low doses of cocaine and measured the activity of signaling pathways involved in protein synthesis.
Interestingly, cocaine significantly reduced the activity of eIF2α in the brain of adolescents, but not adults. As a result of this boost to protein synthesis, the connections between dopamine-producing neurons strengthened in the adolescent brains, enhancing the feeling of pleasure that cocaine gives and thus promoting addictive behaviors.
Nicotine also appeared to affect eIF2α activity. Kenishirotie/Shutterstock
Going one step further, the team manipulated eIF2α using both a pharmacological compound and genetic tinkering. This showed that reducing its activity in adults increased their susceptibility to low doses of cocaine, while increasing it in adolescents had the opposite effect. “This is super interesting, since we have a way to convert adolescents into adults, with respect to cocaine-induced changes in brain activity and behavior, and vice versa,” senior author Mauro Costa-Mattioli told IFLScience.
The effects on eIF2α turned out to be region-specific, only affecting an area of the brain’s reward pathway called the ventral tegmental area, but not the areas this projects to. “This suggests that the process of reduced eIF2α activity by cocaine is involved at the induction of the addiction process,” said Costa-Mattioli. The team also found that it wasn’t just cocaine that elicited this response – alcohol, nicotine, and methamphetamine exerted the same effects. “These drugs act on different receptors, but maybe they all converge on this molecule, which is like a conductor of this process,” he added.
In the second study, also published in eLife, the researchers discovered that some people have a variation in the eIF2α gene, which appeared to alter responses to reward stimuli. The researchers scanned the brains of smokers and non-smokers and measured activity in response to a sweet drink reward. The team found that smokers showed less brain activity in response to the reward, but interestingly so did those with the gene variation.
“This study is important, because most of the people who are addicted to drugs start during adolescence,” said Costa-Mattioli. “So I speculate that compounds that can manipulate this system could prevent the transition from recreational to compulsive drug use.”
