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New study sheds light on brain changes facilitating cocaine addiction

LA JOLLA, Calif. – Dec. 18, 2017 – An international team of scientists that included investigators at The Scripps Research Institute (TSRI) has uncovered a phenomenon in the brain that may fuel the shift from moderate cocaine use to compulsive cocaine use and addiction. The research explains how an imbalance in the activity of different populations of brain cells can increase the urge to take drugs.

The new experiments in rats revealed how serotonin transmission from two distinct brain regions is differentially involved in controlling moderate versus compulsive cocaine use. Serotonin is a major chemical messenger of the brain whose main sources of production are located in the dorsal raphe nucleus (DRN) and medial raphe nucleus (MRN).

The results of the study suggest that when cocaine use ramps up, serotonin transmission from the DRN “overrides” serotonin transmission from the MRN. This takeover by the DRN appears to change the levels of a stress hormone called corticotropin-releasing factor (CRF) and drive the compulsive aspect of drug taking.

This finding, published recently in the journal Biological Psychiatry, also gave researchers a clue to why some people are more likely to become addicted to psychostimulants, such as cocaine.  These individuals carry a gene polymorphism that lowers the expression of the serotonin transporter (SERT)—the protein responsible for eliminating serotonin from synapses. In the new study, the researchers found that rats missing SERT not only consume more cocaine but are also more sensitive to the CRF-level changes triggered by cocaine.

“The study shows that reduced SERT expression exacerbates the behavioral and neurochemical effects of cocaine use in a brain region-specific manner,” says TSRI Associate Professor Candice Contet, Ph.D., who was co-first author of the study with Michel M.M. Verheij of Radboud University Nijmegen Medical Centre.

The study was led by senior authors Professor George Koob, Ph.D., then at TSRI and now at the National Institutes of Health; and Judith R. Homberg of Radboud University Nijmegen Medical Centre.

Distinct sources of serotonin control different stages of cocaine use

Researchers already knew that low levels of SERT expression increase anxiety and cocaine intake in both humans and rats, but the specific roles of the DRN and MRN were unknown.

Using a tool called virally mediated RNA interference, researchers were able to silence SERT expression in the DRN or MRN to dissect how serotonin transmission from those two regions impacts cocaine consumption. They found that reducing SERT expression only in the MRN prompted rats to increase cocaine intake under conditions that produce stable, moderate intake, but the silencing had no effect under conditions that produce escalating, compulsive intake. In contrast, reducing expression of SERT in the DRN increased compulsive cocaine use, without affecting moderate cocaine use.

This suggested that the DRN begins to override the influence of the MRN when cocaine consumption increases. This could be a critical step in the transition to cocaine addiction.

In both groups of rats, reduced SERT expression appeared to drive changes in CRF levels—albeit in different brain regions: the paraventricular nucleus of the hypothalamus in the MRN-targeted rats and the central amygdala in DRN-targeted rats. Strikingly, these changes mimicked the effects produced by moderate and compulsive cocaine use, respectively.

“The study shows the importance of maintaining the right balance of serotonin activity between the MRN and DRN,” says Contet. Researchers believe future studies could look at ways to target the MRN in early stages of drug use and the DRN in later stages to better target the circuits that drive addiction and perhaps even halt the shift from moderate use to addiction.

In addition to Contet, Verheij, Koob and Homberg, authors of the study “Median and dorsal raphe serotonergic neurons control moderate versus compulsive cocaine intake” were Peter Karel, Judith Latour, Rick H.A. van der Doelen, Bram Geenen, Josephus A. van Hulten, Francisca Meyer and Tamas Kozicz of Radboud University Nijmegen Medical Centre; and Olivier George of The Scripps Research Institute.

The study was supported by the National Institutes of Health’s (NIH) National Institute on Alcohol Abuse and Alcoholism (grants AA006420, AA024198 and AA021491); a joint research grant from the Netherlands Organisation for Health Research and Development (ZonMW) and the NIH National Institute on Drug Abuse (NIDA; grant 31180005); a NIDA INVEST fellowship; a European College of Neuropsychopharmacology Research Grant for Young Scientists; the Netherlands Organisation for Scientific Research (grant 819.02.022); an Era-Net NEURON grant “RESPOND”; and VIDI grant 864.10.003.

About The Scripps Research Institute

The Scripps Research Institute (TSRI) is one of the world's largest independent, not-for-profit organizations focusing on research in the biomedical sciences. TSRI is internationally recognized for its contributions to science and health, including its role in laying the foundation for new treatments for cancer, rheumatoid arthritis, hemophilia, and other diseases. An institution that evolved from the Scripps Metabolic Clinic founded by philanthropist Ellen Browning Scripps in 1924, the institute now employs more than 2,500 people on its campuses in La Jolla, CA, and Jupiter, FL, where its renowned scientists—including two Nobel laureates and 20 members of the National Academies of Science, Engineering or Medicine—work toward their next discoveries. The institute's graduate program, which awards PhD degrees in biology and chemistry, ranks among the top ten of its kind in the nation. In October 2016, TSRI announced a strategic affiliation with the California Institute for Biomedical Research (Calibr), representing a renewed commitment to the discovery and development of new medicines to address unmet medical needs. For more information, see www.scripps.edu.

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Study co-author Candice Contet, Ph.D., associate professor at TSRI (High-res image)


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