title: Metabotropic glutamate mGlu2 receptor is necessary for the pharmacological and behavioral effects induced by hallucinogenic 5-HT2A receptor agonists.
abstract: Hallucinogenic drugs, including mescaline, psilocybin and lysergic acid diethylamide (LSD), act at serotonin 5-HT2A receptors (5-HT2ARs). Metabotropic glutamate receptor 2/3 (mGluR2/3) ligands show efficacy in modulating the responses induced by activation of 5-HT2ARs. The formation of a 5-HT2AR-mGluR2 complex suggests a functional interaction that affects the hallucinogen-regulated cellular signaling pathways. Here, we tested the cellular and behavioral effects of hallucinogenic 5-HT2AR agonists in mGluR2 knockout (mGluR2-KO) mice. Mice were intraperitoneally injected with the hallucinogens DOI (2 mg/kg) and LSD (0.24 mg/kg), or vehicle. Head-twitch behavioral response, expression of c-fos, which is induced by all 5-HT2AR agonists, and expression of egr-2, which is hallucinogen-specific, were determined in wild type and mGluR2-KO mice. [(3)H]Ketanserin binding displacement curves by DOI were performed in mouse frontal cortex membrane preparations. Head twitch behavior was abolished in mGluR2-KO mice. The high-affinity binding site of DOI was undetected in mGluR2-KO mice. The hallucinogen DOI induced c-fos in both wild type and mGluR2-KO mice. However, the induction of egr-2 by DOI was eliminated in mGlu2-KO mice. These findings suggest that the 5-HT2AR-mGluR2 complex is necessary for the neuropsychological responses induced by hallucinogens.
authors.affiliation: Department of Psychiatry, Mount Sinai School of Medicine, 1425 Madison Avenue, Box 1229, New York, NY 10029, United States.
authors.forename: José L
authors.initials: JL
authors.lastname: Moreno
authors.forename: Terrell
authors.initials: T
authors.lastname: Holloway
authors.forename: Laura
authors.initials: L
authors.lastname: Albizu
authors.forename: Stuart C
authors.initials: SC
authors.lastname: Sealfon
authors.forename: Javier
authors.initials: J
authors.lastname: González-Maeso
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology*; D051767:Early Growth Response Protein 2 / Q000096:biosynthesis / Q000502:physiology; D005625:Frontal Lobe / Q000187:drug effects / Q000502:physiology; D016762:Genes, fos / Q000502:physiology; D006213:Hallucinogens / Q000378:metabolism* / Q000633:toxicity; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D044402:Receptor, Serotonin, 5-HT2A / Q000172:deficiency / Q000502:physiology*; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*; D012559:Schizophrenia / Q000139:chemically induced / Q000378:metabolism; D058826:Serotonin 5-HT2 Receptor Agonists / Q000378:metabolism* / Q000633:toxicity; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
chemical_list: D051767:Early Growth Response Protein 2; C497327:Egr2 protein, mouse; D006213:Hallucinogens; D044402:Receptor, Serotonin, 5-HT2A; D018094:Receptors, Metabotropic Glutamate; D058826:Serotonin 5-HT2 Receptor Agonists; C108822:metabotropic glutamate receptor 2