Researchers have discovered one reason why adolescents are more prone to drug addiction than adults, with findings that could lead to new treatments for addictive disorders.
In two studies with mice and humans to be published together in the journal eLife, the investigators from Baylor College of Medicine, US, have found that the ability to produce (or synthesize) new proteins, regulated by the molecule eIF2, accounts for adolescents’ hypersensitivity to both cocaine and nicotine.
“In humans, adolescence, namely the period between the early teenage years and early twenties, is a time of heightened susceptibility to the effects of addictive drugs, but previous studies have struggled to explain why. Our studies support the idea that regulation of protein synthesis by eIF2 might be the underlying cause,” says senior author Mauro Costa-Mattioli.
In the first study, the team injected adolescent and adult mice with saline or a low dose of cocaine. Their results showed that in adolescents, but not adults, cocaine reduces the activity of eIF2α. This leads to an increase in the strength of the connections, or synapses, between dopamine-storing neurons in a part of the midbrain that is rich with these cells.
“This greater communication between dopamine-rich neurons gives a greater sense of pleasure from taking the drug and encourages behaviors related to addiction,” says lead author Wei Huang.
“Only higher doses of cocaine led to similar responses in adult mice, proving that adolescents have a lower threshold for the effects of cocaine on these neurons.”
With the combined use of genetics and pharmacology, the investigators altered the production of proteins controlled by eIF2α in adult mice, essentially converting them into adolescents by making them more susceptible to cocaine-induced changes in synaptic strength and behavior. Conversely, adolescent mice with increased eIF2α activity in the brain became more resistant to the effects of cocaine, as seen in adults.
“It’s truly remarkable that by manipulating the processes surrounding eIF2α in this way, we can rejuvenate brain activity. This could hold significant promise for developing new treatments for drug addiction and related disorders,” says Costa-Mattioli.
For the second paper, the team carried out similar experiments in mice with different doses of nicotine instead of cocaine, showing that the same effects are also true for this drug.
In the study, they also identified a variation in the gene encoding eIF2α and found that such variation affects how human smokers’ brains respond to reward, as determined by changes seen in functional magnetic resonance imaging.
“Our findings are clinically relevant as they identify a novel addiction target in rodents, along with parallel supporting evidence from brain imaging studies in human addicts,” explains Andon Placzek, lead author of the nicotine study.
“In the US, the indirect financial costs of smoking and the costs of enforcing the drug control system are estimated at more than $300 billion and $100 billion per year, respectively. To help bring down both these and the human costs of addiction, our new insights could help educate adolescents about the risks of recreational drug use and experimentation, discouraging these behaviors as a result. They could also help discover a new way to fight addiction in both adolescents and adults, for example by altering the activity of eIF2α in the brain.”
About this addiction research
Others who contributed to these studies include: David L Molfese and Ramiro Salas (Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine), Gonzalo Viana Di Prisco and Russell Ray (Department of Neuroscience, Baylor College of Medicine), Kresimir Krnjevic (McGill University), Christopher L Amos (Center for Genomic Medicine, Dartmouth College), John Dani (Department of Neuroscience, Perelman School of Medicine), Peter Walter and Carmela Sidrauski (Howard Hughes Medical Institute, University of California, San Francisco).
Source: Emily Packer – eLife Image Credit: Image is in the public domain. Original Research: Full open access research for “Translational control by eIF2α phosphorylation regulates vulnerability to the synaptic and behavioral effects of cocaine” by Wei Huang, Andon N Placzek, Gonzalo Viana Di Prisco, Sanjeev Khatiwada, Carmela Sidrauski, Krešimir Krnjević, Peter Walter, John A Dani, and Mauro Costa-Mattioli in eLife. Published online March 1 2016 doi:10.7554/eLife.12052
Full open access research for “Translational control of nicotine-evoked synaptic potentiation in mice and neuronal responses in human smokers by eIF2α” by Andon N Placzek, David L Molfese, Sanjeev Khatiwada, Gonzalo Viana Di Prisco, Wei Huang, Carmela Sidrauski, Krešimir Krnjević, Christopher L Amos, Russell Ray, John A Dani, Peter Walter, Ramiro Salas, and Mauro Costa-Mattioli in eLife. Published online March 1 2016 doi:10.7554/eLife.12056
Translational control by eIF2α phosphorylation regulates vulnerability to the synaptic and behavioral effects of cocaine
Adolescents are especially prone to drug addiction, but the underlying biological basis of their increased vulnerability remains unknown. We reveal that translational control by phosphorylation of the translation initiation factor eIF2α (p-eIF2α) accounts for adolescent hypersensitivity to cocaine. In adolescent (but not adult) mice, a low dose of cocaine reduced p-eIF2α in the ventral tegmental area (VTA), potentiated synaptic inputs to VTA dopaminergic neurons, and induced drug-reinforced behavior. Like adolescents, adult mice with reduced p-eIF2α-mediated translational control were more susceptible to cocaine-induced synaptic potentiation and behavior. Conversely, like adults, adolescent mice with increased p-eIF2α became more resistant to cocaine’s effects. 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. Thus, during addiction, cocaine hijacks translational control by p-eIF2α, initiating synaptic potentiation and addiction-related behaviors. These insights may hold promise for new treatments for addiction.
“Translational control by eIF2α phosphorylation regulates vulnerability to the synaptic and behavioral effects of cocaine” by Wei Huang, Andon N Placzek, Gonzalo Viana Di Prisco, Sanjeev Khatiwada, Carmela Sidrauski, Krešimir Krnjević, Peter Walter, John A Dani, and Mauro Costa-Mattioli in eLife. Published online March 1 2016 doi:10.7554/eLife.12052
Translational control of nicotine-evoked synaptic potentiation in mice and neuronal responses in human smokers by eIF2α
Adolescents are particularly vulnerable to nicotine, the principal addictive component driving tobacco smoking. In a companion study, we found that reduced activity of the translation initiation factor eIF2α underlies the hypersensitivity of adolescent mice to the effects of cocaine. Here we report that nicotine potentiates excitatory synaptic transmission in ventral tegmental area dopaminergic neurons more readily in adolescent mice compared to adults. Adult mice with genetic or pharmacological reduction in p-eIF2α-mediated translation are more susceptible to nicotine’s synaptic effects, like adolescents. When we investigated the influence of allelic variability of the Eif2s1 gene (encoding eIF2α) on reward-related neuronal responses in human smokers, we found that a single nucleotide polymorphism in the Eif2s1 gene modulates mesolimbic neuronal reward responses in human smokers. These findings suggest that p-eIF2α regulates synaptic actions of nicotine in both mice and humans, and that reduced p-eIF2α may enhance susceptibility to nicotine (and other drugs of abuse) during adolescence.
“Translational control of nicotine-evoked synaptic potentiation in mice and neuronal responses in human smokers by eIF2α” by Andon N Placzek, David L Molfese, Sanjeev Khatiwada, Gonzalo Viana Di Prisco, Wei Huang, Carmela Sidrauski, Krešimir Krnjević, Christopher L Amos, Russell Ray, John A Dani, Peter Walter, Ramiro Salas, and Mauro Costa-Mattioli in eLife. Published online March 1 2016 doi:10.7554/eLife.12056