Disruption of an enhancer associated with addictive behaviour within the cannabinoid receptor-1 gene suggests a possible role in alcohol intake, cannabinoid response and anxiety-related behaviour

Elizabeth A. Hay, Andrew McEwan, Dana Wilson, Perry Barrett, Giuseppe D'Agostino, Roger G. Pertwee, Alasdair MacKenzie* (Corresponding Author)

*Corresponding author for this work

Research output: Contribution to journalArticle

5 Citations (Scopus)
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Abstract

The cannabinoid-1 receptor (CB1) plays a critical role in a number of biological processes including nutrient intake, addiction and anxiety-related behaviour. Numerous studies have shown that expression of the gene encoding CB1 (CNR1) is highly dynamic with changes in the tissue specific expression of CNR1 associated with brain homeostasis and disease progression. However, little is known of the mechanisms regulating this dynamic expression. To gain a better understanding of the genomic mechanisms modulating the expression of CNR1 in health and disease we characterised the role of a highly conserved regulatory sequence (ECR1) in CNR1 intron 2 that contained a polymorphism in linkage disequilibrium with disease associated SNPs. We used CRISPR/CAS9 technology to disrupt ECR1 within the mouse genome. Disruption of ECR1 significantly reduced CNR1 expression in the hippocampus but not in the hypothalamus. These mice also displayed an altered sex-specific anxiety-related behavioural profile (open field test), reduced ethanol intake and a reduced hypothermic response following CB1 agonism. However, no significant changes in feeding patterns were detected. These data suggest that, whilst not all of the expression of CNR1 is modulated by ECR1, this highly conserved enhancer is required for appropriate physiological responses to a number of stimuli. The combination of comparative genomics and CRISPR/CAS9 disruption used in our study to determine the functional effects of genetic and epigenetic changes on the activity of tissue-specific regulatory elements at the CNR1 locus represent an important first step in gaining a mechanistic understanding of cannabinoid regulatory pharmacogenetics.

Original languageEnglish
Article number104407
Pages (from-to)104407
Number of pages8
JournalPsychoneuroendocrinology
Volume109
Early online date13 Aug 2019
DOIs
Publication statusPublished - Nov 2019

Keywords

  • Cannabinoid-1 receptor
  • CRISPR genome editing
  • gene regulation
  • tissue specific
  • enhancer
  • polymorphisms
  • ethanol intake
  • CB1 agonists
  • Win55
  • 212-2
  • pharmacogenetics
  • Ethanol intake
  • Pharmacogenetics
  • Enhancer
  • NICOTINE
  • Gene regulation
  • Tissue specific
  • ENDOCANNABINOID SYSTEM
  • Anxiety-related behavior
  • Polymorphisms
  • HIPPOCAMPUS
  • Wln55,212-2
  • CB1 RECEPTORS
  • HYPOTHALAMUS

ASJC Scopus subject areas

  • Endocrine and Autonomic Systems
  • Psychiatry and Mental health
  • Biological Psychiatry
  • Endocrinology
  • Endocrinology, Diabetes and Metabolism

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