Cannabinoid exposure in rat adolescence reprograms the initial behavioral, molecular, and epigenetic response to cocaine

Proc Natl Acad Sci U S A. 2020 May 5;117(18):9991-10002. doi: 10.1073/pnas.1920866117. Epub 2020 Apr 20.


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.

Keywords: THC; adolescence; cannabis; epigenetics; histone acetylation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Animals
  • Behavior, Addictive / chemically induced
  • Behavior, Addictive / genetics*
  • Behavior, Addictive / pathology
  • Behavior, Animal / drug effects*
  • Benzoxazines / adverse effects
  • Benzoxazines / pharmacology
  • Cannabinoids / adverse effects*
  • Cannabinoids / pharmacology
  • Circadian Rhythm Signaling Peptides and Proteins / genetics
  • Cocaine / adverse effects*
  • Cocaine / pharmacology
  • Epigenesis, Genetic / drug effects
  • Epigenesis, Genetic / genetics
  • Gene Expression Regulation / drug effects
  • Histone Deacetylase 6 / genetics
  • Humans
  • Membrane Proteins / pharmacology
  • Morpholines / adverse effects
  • Morpholines / pharmacology
  • Naphthalenes / adverse effects
  • Naphthalenes / pharmacology
  • Phosphoproteins / drug effects
  • Pituitary Adenylate Cyclase-Activating Polypeptide / genetics
  • Prefrontal Cortex / drug effects
  • Proteome / drug effects
  • Rats
  • Transcriptome / drug effects


  • ADCYAP1 protein, human
  • Adcyap1 protein, rat
  • Benzoxazines
  • Cannabinoids
  • Circadian Rhythm Signaling Peptides and Proteins
  • Membrane Proteins
  • Morpholines
  • Naphthalenes
  • Npas2 protein, rat
  • Phosphoproteins
  • Pituitary Adenylate Cyclase-Activating Polypeptide
  • Proteome
  • gephyrin
  • (3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone
  • HDAC6 protein, rat
  • Histone Deacetylase 6
  • Cocaine