Cannabinoid Modulation of Eukaryotic Initiation Factors (eIF2α and eIF2B1) and Behavioral Cross-Sensitization to Cocaine in Adolescent Rats

Publication date: 13 March 2018
Source:Cell Reports, Volume 22, Issue 11
Author(s): Philippe A. Melas, Johanna S. Qvist, Matteo Deidda, Chirag Upreti, Ya Bin Wei, Fabrizio Sanna, Walter Fratta, Maria Scherma, Paola Fadda, Denise B. Kandel, Eric R. Kandel
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.

Graphical abstract

Teaser

Melas et al. show that psychoactive cannabinoids modulate levels of two eukaryotic initiation factors (eIF2α and eIF2B1) known to be involved in protein synthesis, memory formation, and drug sensitivity. Cannabinoid modulation of eIF2α in vivo is only observed in adolescent animals, and is associated with cross-sensitization to cocaine.


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