Cannabinoid exposure in rat adolescence reprograms the initial behavioral, molecular, and epigenetic response to cocaine
Authors: Matteo Deidda
Arun Asok
Eric R Kandel
Philippe A Melas
Shao-Shan C Huang
Paola Fadda
Maria Scherma
Rajesh K Soni
Denise B Kandel
Johanna S Qvist
Walter Fratta
Paolo Masia
Ya B Wei
Journal: Proceedings of the National Academy of Sciences of the United States of America (2020)
Discipline: Multidisciplinary
Keywords: THC; adolescence; cannabis; epigenetics; histone acetylation.
Affiliations: Department of Biomedical Sciences, Division of Neuroscience and Clinical Pharmacology, University of Cagliari, 09042 Cagliari, Italy., Department of Neuroscience, Columbia University, New York, NY 10032., Jerome L. Greene Science Center, Mortimer B. Zuckerman Mind Brain Behavior Institute, New York, NY 10027., Center for Genomics and Systems Biology, Department of Biology, New York University, New York, NY 10003., Department of Psychiatry, University of California San Diego, La Jolla, CA 92093., Department of Molecular Medicine and Surgery, Karolinska Institutet, 17176 Stockholm, Sweden., Proteomics Shared Resource, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032., Neuroscience Institute, National Research Council of Italy (CNR), 09042 Cagliari, Italy., Department of Neuroscience, Columbia University, New York, NY 10032;   ., Kavli Institute for Brain Science, Columbia University, New York, NY 10032., Howard Hughes Medical Institute, Chevy Chase, MD 20815., New York State Psychiatric Institute, New York, NY 10032., New York State Psychiatric Institute, New York, NY 10032;   ., Department of Psychiatry, Vagelos College of Physicians and Surgeons and Mailman School of Public Health, Columbia University, New York, NY 10032., Department of Clinical Neuroscience, Karolinska Institutet, 17176 Stockholm, Sweden., Center for Psychiatry Research, Karolinska Institutet, 17176 Stockholm, Sweden., Center for Molecular Medicine, Karolinska University Hospital, 17176 Stockholm, Sweden.

Abstract:  The initial response to an addictive substance can facilitate repeated use: That is, individuals experiencing more positive effects are more likely to use that drug again. Increasing evidence suggests that psychoactive cannabinoid use in adolescence enhances the behavioral effects of cocaine. However, despite the behavioral data, there is no neurobiological evidence demonstrating that cannabinoids can also alter the brain's initial molecular and epigenetic response to cocaine. Here, we utilized a multiomics approach (epigenomics, transcriptomics, proteomics, and phosphoproteomics) to characterize how the rat brain responds to its first encounter with cocaine, with or without preexposure to the synthetic cannabinoid WIN 55,212-2 (WIN). We find that in adolescent (but not in adult) rats, preexposure to WIN results in cross-sensitization to cocaine, which correlates with histone hyperacetylation and decreased levels of HDAC6 in the prefrontal cortex (PFC). In the PFC, we also find that WIN preexposure blunts the typical mRNA response to cocaine and instead results in alternative splicing and chromatin accessibility events, involving genes such as Npas2 Moreover, preexposure to WIN enhances the effects of cocaine on protein phosphorylation, including ERK/MAPK-targets like gephyrin, and modulates the synaptic AMPAR/GluR composition both in the PFC and the nucleus accumbens (NAcc). PFC-NAcc gene network topological analyses, following cocaine exposure, reveal distinct top nodes in the WIN preexposed group, which include PACAP/ADCYAP1. These preclinical data demonstrate that adolescent cannabinoid exposure reprograms the initial behavioral, molecular, and epigenetic response to cocaine. 

Retracted: No

PubPeer comments:
 This article was reviewed on the error bar podcast episode 0: https: theerrorbar.com ?e=0. The review was done in light of newspaper stories about the article. The slightly-edited transcript is copied here: headline: CANNABIS IS A GATEWAY DRUG TO COCAINE tweet: adolescent male rats walk around their cages more when given cocaine, if they had been given a cannabinoid drug the week before. but adult male rats didn t. some brain areas were affected too. nothing here about humans. description: The Daily Mail this week screamed that cannabis really does lead users on to harder drugs like cocaine. the reported study gave rats a synthetic cannabinoid drug twice a day for 11 days, with the dosage doubling every 4 days. a control group of rats instead had only a salt water drug under the same conditions. one week after their last dose, all rats were injected with cocaine. the rats that had been on the cannabinoid drug were found to be more active u2013 about 20-30 minutes after the cocaine, they walked around more than the control rats. this difference was about 10 extra metres walking over a 10 minute period u2013 that s quite a lot for a rat. in the rats brains, lots of different chemicals were looked at, and some of those showed a strong statistical relationship between the brain areas examined and the drug combinations that the animals had received. the prefrontal cortex, which is an important part of the brain, was highlighted in particular. evaluation: first, this is in rats. adolescent rats. adolescent, male rats. it didn t work in adult male rats, just 40 days older. second, it s a single, synthetic cannabinoid drug, not cannabis. cannabis has several thousand different chemical constituents. this study tells us nothing about cannabis. third, this was a one-way relationship u2013 cocaine did not have the same effect on rats responses to the cannabinoid. by The Daily Mail s logic, cocaine is therefore NOT a gateway drug to cannabis. so, is it OK for adolescent boys to inject cocaine? the error bar says no. fourth, there is a LOT of detail in this paper u2013 far too much to wade through, and way out of the error bar s expertise. it s not clear how much of these detailed results were theory-driven, and how much were post-hoc interpretations of a mass of data. fifth, there is quite a strong whiff of cherry-picking of results. while the results in the main paper are rather strong, statistically speaking, several analyses in the appendices, which the main paper clearly relies upon, are much weaker. more problematically, several statistical interactions u2013 a particular kind of statistical relationship u2013 were reported as not significant in the results, but they were interpreted as if they were significant. misinterpreting statistical interactions is a common scientific error. conclusion: one synthetic cannabinoid drug affects young male rats brains and behaviour in some ways, but adult male rats were not affected. how this relates to human drug use is unknown. ,