title: Chronic treatment with LY341495 decreases 5-HT(2A) receptor binding and hallucinogenic effects of LSD in mice.
abstract: Hallucinogenic drugs, such as lysergic acid diethylamide (LSD), mescaline and psilocybin, alter perception and cognitive processes. All hallucinogenic drugs have in common a high affinity for the serotonin 5-HT(2A) receptor. Metabotropic glutamate 2/3 (mGlu2/3) receptor ligands show efficacy in modulating the cellular and behavioral responses induced by hallucinogenic drugs. Here, we explored the effect of chronic treatment with the mGlu2/3 receptor antagonist 2S-2-amino-2-(1S,2S-2-carboxycyclopropan-1-yl)-3-(xanth-9-yl)-propionic acid (LY341495) on the hallucinogenic-like effects induced by LSD (0.24mg/kg). Mice were chronically (21 days) treated with LY341495 (1.5mg/kg), or vehicle, and experiments were carried out one day after the last injection. Chronic treatment with LY341495 down-regulated [(3)H]ketanserin binding in somatosensory cortex of wild-type, but not mGlu2 knockout (KO), mice. Head-twitch behavior, and expression of c-fos, egr-1 and egr-2, which are responses induced by hallucinogenic 5-HT(2A) agonists, were found to be significantly decreased by chronic treatment with LY341495. These findings suggest that repeated blockade of the mGlu2 receptor by LY341495 results in reduced 5-HT(2A) receptor-dependent hallucinogenic effects of LSD.
authors: Department of Psychiatry, Mount Sinai School of Medicine, 1425 Madison Avenue, Box 1229, New York, NY 10029, United States.
authors: José L
authors: JL
authors: Moreno
authors: Terrell
authors: T
authors: Holloway
authors: Vinayak
authors: V
authors: Rayannavar
authors: Stuart C
authors: SC
authors: Sealfon
authors: Javier
authors: J
authors: González-Maeso
mesh_terms: D000596:Amino Acids / Q000494:pharmacology*; D000818:Animals; D004336:Drug Antagonism; D051766:Early Growth Response Protein 1 / Q000378:metabolism; D051767:Early Growth Response Protein 2 / Q000378:metabolism; D006213:Hallucinogens / Q000378:metabolism / Q000494:pharmacology*; D008238:Lysergic Acid Diethylamide / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D011869:Radioligand Assay; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism*; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D013003:Somatosensory Cortex / Q000378:metabolism; D013239:Stereotyped Behavior / Q000187:drug effects; D014966:Xanthenes / Q000494:pharmacology*
chemical_list: D000596:Amino Acids; D051766:Early Growth Response Protein 1; D051767:Early Growth Response Protein 2; C486109:Egr1 protein, mouse; C497327:Egr2 protein, mouse; D006213:Hallucinogens; C114624:LY 341495; D016760:Proto-Oncogene Proteins c-fos; D044402:Receptor, Serotonin, 5-HT2A; D018094:Receptors, Metabotropic Glutamate; D014966:Xanthenes; C108822:metabotropic glutamate receptor 2; C102718:metabotropic glutamate receptor 3; D008238:Lysergic Acid Diethylamide