Cannabinoid Modulation of Eukaryotic Initiation Factors (elF2_ and elF2B1) and Behavioral Cross-Sensitization to Cocaine in Adolescent Rats

Cell Reports. 2018 Mar 13;22(11):2909-2923. doi: 10.1016/j.celrep.2018.02.065. PMID: 29539420.
Authored By:
Melas PA, Qvist JS, Deidda M, Upreti C, Wei YB, Sanna F, Fratta W, Scherma M, Fadda P, Kandel DB, Kandel ER.
Reduced eukaryotic Initiation Factor 2 (eIF2)α phosphorylation (p-eIF2α) enhances protein synthesis, memory formation, and addiction-like behaviors. However, p-eIF2α has not been examined with regard to psychoactive cannabinoids and cross-sensitization. Here, we find that a cannabinoid receptor agonist (WIN 55,212-2 mesylate [WIN]) reduced p-eIF2α in vitro by upregulating GADD34 (PPP1R15A), the recruiter of protein phosphatase 1 (PP1). The induction of GADD34 was linked to ERK/CREB signaling and to CREB-binding protein (CBP)-mediated histone hyperacetylation at the Gadd34 locus. In vitro, WIN also upregulated eIF2B1, an eIF2 activator subunit. We next found that WIN administration in vivo reduced p-eIF2α in the nucleus accumbens of adolescent, but not adult, rats. By contrast, WIN increased dorsal striatal levels of eIF2B1 and ΔFosB among both adolescents and adults. In addition, we found cross-sensitization between WIN and cocaine only among adolescents. These findings show that cannabinoids can modulate eukaryotic initiation factors, and they suggest a possible link between p-eIF2α and the gateway drug properties of psychoactive cannabinoids.
Published in:
Cell Reports

More Publications

April 18, 2024

Nature Genetics

Genome-wide association analyses identify 95 risk loci and provide insights into the neurobiology of post-traumatic stress disorder

March 5, 2024

Translational Psychiatry

Potential causal association between gut microbiome and posttraumatic stress disorder

January 29, 2024

Scientific Reports

Differential recruitment of brain circuits during fear extinction in non-stressed compared to stress resilient animals

December 29, 2023

Journal of Law and the Biosciences

Defusing the legal and ethical minefield of epigenetic applications in the military, defense, and security context

August 1, 2023

Journal of Psychopharmacology

Improving Translational Relevance in Preclinical Psychopharmacology (iTRIPP)

July 29, 2023

Frontiers in Neurology

Models and methods: a perspective of the impact of six IMI translational data-centric initiatives for Alzheimer’s disease and other neuropsychiatric disorders