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

Highlights • We identified a highly conserved enhancer in the CB1 gene that contains a SNP associated with substance abuse in humans.• CRISPR genome editing to delete this enhancer caused a reduction of CB1 gene expression in hippocampus.• Deletion of this enhancer reduced alcohol intake, cannabinoid response and altered anxiety-like behaviour.• These studies provide an important platform for the future exploration of cannabinoid pharmacogenetics.

• Publication year

  2019

• Venue

  Psychoneuroendocrinology

• Publication date

  2019-11-01

• Fields of study

  Biology, Medicine, Psychology

• Identifiers
  DOI 10.1016/j.psyneuen.2019.104407PMID 31445429PMCID 6857436
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• The Cannabinoid Receptor

  2019cited by this paper
• A review of the interactions between Autonomous Vehicles and Vulnerable Road Users

  2019cited by this paper
• Enhancer Logic and Mechanics in Development and Disease.

  2018cited by this paper
• Cannabinoid Receptor 1 Gene by Cannabis Use Interaction on CB1 Receptor Density

  2017cited by this paper
• An analysis of possible off target effects following CAS9/CRISPR targeted deletions of neuropeptide gene enhancers from the mouse genome

  2017cited by this paper
• High-Throughput Approaches to Pinpoint Function within the Noncoding Genome.

  2017cited by this paper
• Cannabinoid Modulation of the Stressed Hippocampus

  2017cited by this paper
• Stratification of Cannabinoid 1 Receptor (CB1R) Agonist Efficacy: Manipulation of CB1R Density through Use of Transgenic Mice Reveals Congruence between In Vivo and In Vitro Assays

  2016influential reference
• Opioid and Cannabinoid System in Food Intake.

  2016cited by this paper
• A cannabinoid receptor 1 polymorphism is protective against major depressive disorder in methadone-maintained outpatients.

  2015cited by this paper
• Use of the Open Field Maze to measure locomotor and anxiety-like behavior in mice.

  2015cited by this paper
• Brain structural and clinical changes after first episode psychosis: Focus on cannabinoid receptor 1 polymorphisms.

  2015cited by this paper
• Mouse Genome Editing Using the CRISPR/Cas System

  2014cited by this paper
• Manipulating the mouse embryo

  2013cited by this paper
• Allele-specific Differences in Activity of a Novel Cannabinoid Receptor 1 (CNR1) Gene Intronic Enhancer in Hypothalamus, Dorsal Root Ganglia, and Hippocampus

  2012cited by this paper
• Associations between Cannabinoid Receptor-1 (CNR1) Variation and Hippocampus and Amygdala Volumes in Heavy Cannabis Users

  2012cited by this paper
• The dynamic nature of type 1 cannabinoid receptor (CB1) gene transcription

  2012cited by this paper
• A review of the interactions between alcohol and the endocannabinoid system: implications for alcohol dependence and future directions for research.

  2012cited by this paper
• Evidence for regulatory diversity and auto-regulation at the TAC1 locus in sensory neurones

  2011cited by this paper
• The Role of Cannabinoids in Modulating Emotional and Non-Emotional Memory Processes in the Hippocampus

  2011cited by this paper
• Long-Range Regulatory Synergy Is Required to Allow Control of the TAC1 Locus by MEK/ERK Signalling in Sensory Neurones

  2010cited by this paper
• CB1 receptor blockade decreases ethanol intake and associated neurochemical changes in fawn-hooded rats.

  2010cited by this paper
• Role of endocannabinoid signaling in anxiety and depression.

  2009cited by this paper
• Endocannabinoids in the treatment of mood disorders: evidence from animal models.

  2009cited by this paper
• Critical role of the endocannabinoid system in the regulation of food intake and energy metabolism, with phylogenetic, developmental, and pathophysiological implications.

  2008cited by this paper
• The incentive salience of alcohol: translating the effects of genetic variant in CNR1.

  2008cited by this paper
• Endocannabinoid receptor 1 gene variations increase risk for obesity and modulate body mass index in European populations.

  2008cited by this paper
• Cannabinoid receptor 1 gene association with nicotine dependence.

  2008cited by this paper
• The role of the hippocampus in mediating emotional responses to nicotine and cannabinoids: a possible neural substrate for functional interactions

  2007cited by this paper
• SR147778, a CB1 cannabinoid receptor antagonist, suppresses ethanol preference in chronically alcoholized Wistar rats.

  2006cited by this paper
• Human cannabinoid receptor 1: 5′ exons, candidate regulatory regions, polymorphisms, haplotypes and association with polysubstance abuse

  2004cited by this paper
• Role of Endocannabinoids and Cannabinoid CB1 Receptors in Alcohol‐Related Behaviors

  2004cited by this paper
• Cannabinoid CB1 receptor knockout mice exhibit markedly reduced voluntary alcohol consumption and lack alcohol‐induced dopamine release in the nucleus accumbens

  2003cited by this paper
• The endogenous cannabinoid system affects energy balance via central orexigenic drive and peripheral lipogenesis.

  2003cited by this paper
• CB1 receptors in the preoptic anterior hypothalamus regulate WIN 55212-2 [(4,5-dihydro-2-methyl-4(4-morpholinylmethyl)-1-(1-naphthalenyl-carbonyl)-6H-pyrrolo[3,2,1ij]quinolin-6-one]-induced hypothermia.

  2002influential reference
• International Union of Pharmacology. XXVII. Classification of Cannabinoid Receptors

  2002cited by this paper
• A detailed ethological analysis of the mouse open field test: effects of diazepam, chlordiazepoxide and an extremely low frequency pulsed magnetic field.

  2001cited by this paper
• Functional expression of cell surface cannabinoid CB(1) receptors on presynaptic inhibitory terminals in cultured rat hippocampal neurons.

  2000cited by this paper
• Unresponsiveness to cannabinoids and reduced addictive effects of opiates in CB1 receptor knockout mice.

  1999cited by this paper
• Exploratory behavior models of anxiety in mice.

  1985influential reference

• An ancient polymorphic regulatory region within the BDNF gene associated with obesity modulates anxiety-like behaviour in mice and humans

  2024cites this paper
• Early life adversity: Epigenetic regulation underlying drug addiction susceptibility.

  2023cites this paper
• Biomarkers of the Endocannabinoid System in Substance Use Disorders

  2022cites this paper
• Molecular Insights into Epigenetics and Cannabinoid Receptors

  2022cites this paper
• Context-dependant enhancers as a reservoir of functional polymorphisms and epigenetic markers linked to alcohol use disorders and comorbidities

  2022cites this paper
• The IntelliCage System: A Review of Its Utility as a Novel Behavioral Platform for a Rodent Model of Substance Use Disorder

  2021cites this paper
• An ancient polymorphic regulatory region within the BDNF gene associated with obesity modulates anxiety-like behaviour in mice and humans

  2021influential citation
• Confirmation of a Causal Taar1 Allelic Variant in Addiction-Relevant Methamphetamine Behaviors

  2021cites this paper
• FURTHER EVIDENCE OF ANXIETY- AND DEPRESSION-LIKE BEHAVIOR FOR TOTAL GENETIC ABLATION OF CANNABINOID RECEPTOR TYPE 1.

  2020cites this paper
• The Epigenetics of the Endocannabinoid System

  2020cites this paper
• CRISPR disruption and UK Biobank analysis of a highly conserved polymorphic enhancer suggests a role in male anxiety and ethanol intake

  2020cites this paper
• Perspective: Quality Versus Quantity; Is It Important to Assess the Role of Enhancers in Complex Disease from an In Vivo Perspective?

  2020influential citation
• Neuronal and synaptic morphological alterations in the hippocampus of cannabinoid receptor type 1 knockout mice

  2020cites this paper
• Endocannabinoid System Components as Potential Biomarkers in Psychiatry

  2020cites this paper
• Disease‐associated polymorphisms within the conserved ECR1 enhancer differentially regulate the tissue‐specific activity of the cannabinoid‐1 receptor gene promoter; implications for cannabinoid pharmacogenetics

  2019cites this paper
• CRISPR disruption and UK Biobank analysis of a highly conserved polymorphic enhancer suggests its role in anxiety and male alcohol intake

  2019cites this paper