miRNA stunts drug addiction

The brain appears to contain molecular elements that can protect it from drug addiction -- specifically, small non-coding RNAs that inhibit the development of addiction in rats exposed to cocaine, according to a study published this week in Nature. Image: Wikimedia commons, AnetodeSpecifically, one particular microRNA (miRNA) "seems to actively decrease the motivation of the animal to take the drug," said behavioral neuroscientist and study author linkurl:Paul Kenny;http://www.scripps.edu/flor

Written byJef Akst

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Image: Wikimedia commons,
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Specifically, one particular microRNA (miRNA) "seems to actively decrease the motivation of the animal to take the drug," said behavioral neuroscientist and study author linkurl:Paul Kenny;http://www.scripps.edu/florida/research/faculty.php?rec_id=8368 of The Scripps Research Institute in Florida. "This is the first molecular adaptation that leads to decreased drug intake" in animals that have prolonged and repeated exposure to a drug, said neuroscientist linkurl:Marina Picciotto;http://www.med.yale.edu/mdphd/administration/picciotto.htm of Yale University, who was not involved in the research. "This is a mechanism that has presumably evolved to keep the intracellular signaling pretty normal even in the face of stressors that change [the environmental conditions] pretty dramatically," such as drug abuse, added Picciotto, who wrote an accompanying News and Views article. Addictive drugs, such as cocaine, trigger a number of molecular changes in the brain that can alter one's sensitivity to the drug's effects and influence the development of behaviors exhibited by addicted users. Now, Kenny and his colleagues have identified a new player in the emergence of addictions -- miRNAs that appear to actually decrease the drug user's motivation to get high. Permanently implanting catheters in the jugular veins of rats, the researchers created a scenario that mimicked voluntary drug use, in which the rats could simply press a lever to get an injection of cocaine. The researchers then compared expression levels of different miRNAs in rats with access to the drug for 0, 1 or 6 hours each day, and found that animals with prolonged access to cocaine (6 hours per day) had higher levels of miR-212 and the closely related miR-132 in the dorsal striatum, the part of the brain known to regulate the development of compulsive drug use. The researchers did not see the same pattern in rats that were given the drug regardless of whether or not they pressed the lever. Using a lentiviral vector, the team explored the effects of overexpressing miR-212 in the same brain region. The increased levels of miR-212 did not change how much of the drug rats with restricted access to cocaine (1 or less hour per day) chose to consume, but, interestingly, it did appear to affect the amount consumed by rats given more access (6 hours, enough to become addicted) -- however, not in the way Kenny and his team expected. They had anticipated that "addicted" rats with more miR-212 would choose to consume more cocaine, but the opposite was true -- rats with high miR-212 requested less and less cocaine. Furthermore, those rats did not continue to seek the drug when it was no longer available, as the control rats did, indicating that higher levels of miR-212 may have eliminated the compulsive drug-seeking behavior. "The effects were actually really striking," Kenny said. "The more cocaine they got, the less they appeared to like it, which is the complete opposite to what you normally see." Delving into the mechanism of miR-212's action, the researchers demonstrated that miR-212 helps regulate the activity of CREB, a transcription factor known to play a role in decreasing the rewarding properties of cocaine. CREB, in turn, appeared to increase the expression of miR-212. Interestingly, the expression of CREB is stimulated by cocaine intake, suggesting a self-limiting mechanism of drug use. "The idea that initial signaling through CREB is what starts the expression of miR-212 is very interesting and very exciting," Picciotto said. "It really shows that this is something that the brain does to try to protect itself." Importantly, miR-212's effects on cocaine intake may have implications for the development of addiction treatments, Picciotto said. "Why not target [the] activity [of one of miR-212's targets] and see if you can mimic [its effects to] decrease the escalation of drug intake in these animals?" J.A. Hollander, et al., "Striatal microRNA controls cocaine intake through CREB signalling," Nature 466:197-202, 2010.
**__Related stories:__***linkurl:Triggering Addiction;http://www.the-scientist.com/article/display/55237/
[December 2008]*linkurl:Needling into addiction;http://www.the-scientist.com/article/display/54223/
[February 2008]*linkurl:How pharmacogenomics might help addiction treatment;http://www.the-scientist.com/article/display/53244/
[June 2007]*linkurl:Addictive Research;http://www.the-scientist.com/article/display/53236/
[June 2007]

Meet the Author

Jef Akst

Jef (an unusual nickname for Jennifer) got her master’s degree from Indiana University in April 2009 studying the mating behavior of seahorses. After four years of diving off the Gulf Coast of Tampa and performing behavioral experiments at the Tennessee Aquarium in Chattanooga, she left research to pursue a career in science writing. As The Scientist's managing editor, Jef edited features and oversaw the production of the TS Digest and quarterly print magazine. In 2022, her feature on uterus transplantation earned first place in the trade category of the Awards for Excellence in Health Care Journalism. She is a member of the National Association of Science Writers.

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