Cannabinoid Modulation of Eukaryotic Initiation Factors (eIF2α and eIF2B1) and Behavioral Cross-Sensitization to Cocaine in Adolescent Rats
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
Affiliations
Philippe A. Melas
Department of Neuroscience, College of Physicians and Surgeons of Columbia University, New York, NY 10032, USA; Department of Clinical Neuroscience, Karolinska Institutet, 17176 Stockholm, Sweden; Center for Molecular Medicine, L8:00, Karolinska University Hospital, 17176 Stockholm, Sweden
Johanna S. Qvist
Department of Neuroscience, College of Physicians and Surgeons of Columbia University, New York, NY 10032, USA
Matteo Deidda
Department of Biomedical Sciences, Division of Neuroscience and Clinical Pharmacology, University of Cagliari, 09042 Cagliari, Italy
Chirag Upreti
Department of Neuroscience, College of Physicians and Surgeons of Columbia University, New York, NY 10032, USA
Ya Bin Wei
Center for Molecular Medicine, L8:00, Karolinska University Hospital, 17176 Stockholm, Sweden; Department of Psychiatry, University of California, San Diego, La Jolla, CA 92093, USA; Department of Molecular Medicine and Surgery, Karolinska Institutet, 17176 Stockholm, Sweden
Fabrizio Sanna
Department of Biomedical Sciences, Division of Neuroscience and Clinical Pharmacology, University of Cagliari, 09042 Cagliari, Italy
Walter Fratta
Department of Biomedical Sciences, Division of Neuroscience and Clinical Pharmacology, University of Cagliari, 09042 Cagliari, Italy; Centre of Excellence Neurobiology of Dependence, University of Cagliari, 09042 Cagliari, Italy
Maria Scherma
Department of Biomedical Sciences, Division of Neuroscience and Clinical Pharmacology, University of Cagliari, 09042 Cagliari, Italy
Paola Fadda
Department of Biomedical Sciences, Division of Neuroscience and Clinical Pharmacology, University of Cagliari, 09042 Cagliari, Italy; Centre of Excellence Neurobiology of Dependence, University of Cagliari, 09042 Cagliari, Italy
Denise B. Kandel
Department of Psychiatry, College of Physicians and Surgeons of Columbia University, New York, NY 10032, USA; Department of Sociomedical Sciences, Mailman School of Public Health, Columbia University, New York, NY 10032, USA; New York State Psychiatric Institute, New York, NY 10032, USA
Eric R. Kandel
Department of Neuroscience, College of Physicians and Surgeons of Columbia University, New York, NY 10032, USA; Department of Psychiatry, College of Physicians and Surgeons of Columbia University, New York, NY 10032, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA; Zuckerman Mind Brain Behavior Institute, New York, NY 10027, USA; Kavli Institute for Brain Science, New York, NY 10032, USA; Corresponding author
Summary: 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. : 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. Keywords: drug use, addiction, cannabis, marijuana, cocaine, epigenetics, eIF2a, CREB, GADD34, gateway drugs
