title: D-serine deficiency attenuates the behavioral and cellular effects induced by the hallucinogenic 5-HT(2A) receptor agonist DOI.
abstract: Both the serotonin and glutamate systems have been implicated in the pathophysiology of schizophrenia, as well as in the mechanism of action of antipsychotic drugs. Psychedelic drugs act through the serotonin 2A receptor (5-HT2AR), and elicit a head-twitch response (HTR) in mice, which directly correlates to 5-HT2AR activation and is absent in 5-HT2AR knockout mice. The precise mechanism of this response remains unclear, but both an intrinsic cortico-cortical pathway and a thalamo-cortical pathway involving glutamate release have been proposed. Here, we used a genetic model of NMDAR hypofunction, the serine racemase knockout (SRKO) mouse, to explore the role of glutamatergic transmission in regulating 5-HT2AR-mediated cellular and behavioral responses. SRKO mice treated with the 5-HT2AR agonist (±)-2,5-dimethoxy-4-iodoamphetamine (DOI) showed a clearly diminished HTR and lower induction of c-fos mRNA. These altered functional responses in SRKO mice were not associated with changes in cortical or hippocampal 5-HT levels or in 5-HT2AR and metabotropic glutamate-2 receptor (mGluR2) mRNA and protein expression. Together, these findings suggest that D-serine-dependent NMDAR activity is involved in mediating the cellular and behavioral effects of 5-HT2AR activation.
authors.affiliation: Neurobiology Research Unit, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark; Laboratory for Psychiatric and Molecular Neuroscience, McLean Hospital, Belmont, MA, USA; Department of Psychiatry, Harvard Medical School, Boston, MA, USA.
authors.forename: Martin A
authors.initials: MA
authors.lastname: Santini
authors.affiliation: Laboratory for Psychiatric and Molecular Neuroscience, McLean Hospital, Belmont, MA, USA; Department of Psychiatry, Harvard Medical School, Boston, MA, USA.
authors.forename: Darrick T
authors.initials: DT
authors.lastname: Balu
authors.affiliation: Laboratory for Psychiatric and Molecular Neuroscience, McLean Hospital, Belmont, MA, USA; Department of Psychiatry, Harvard Medical School, Boston, MA, USA.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Puhl
authors.affiliation: Department of Pharmacology, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Tiffany E
authors.initials: TE
authors.lastname: Hill-Smith
authors.affiliation: Laboratory for Psychiatric and Molecular Neuroscience, McLean Hospital, Belmont, MA, USA.
authors.forename: Alexandra R
authors.initials: AR
authors.lastname: Berg
authors.affiliation: Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA; Department of Pharmacology, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Irwin
authors.initials: I
authors.lastname: Lucki
authors.affiliation: Neurobiology Research Unit, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark; Laboratory for Psychiatric and Molecular Neuroscience, McLean Hospital, Belmont, MA, USA.
authors.forename: Jens D
authors.initials: JD
authors.lastname: Mikkelsen
authors.affiliation: Laboratory for Psychiatric and Molecular Neuroscience, McLean Hospital, Belmont, MA, USA; Department of Psychiatry, Harvard Medical School, Boston, MA, USA. Electronic address: joseph_coyle@hms.harvard.edu.
authors.forename: Joseph T
authors.initials: JT
authors.lastname: Coyle
mesh_terms: D000662:Amphetamines / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects* / Q000502:physiology; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D019416:Head Movements / Q000187:drug effects / Q000502:physiology; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D019998:Racemases and Epimerases / Q000172:deficiency* / Q000235:genetics; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D000099300:Serine Racemase
chemical_list: D000662:Amphetamines; D016291:Dizocilpine Maleate; D006897:Hydroxyindoleacetic Acid; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D019998:Racemases and Epimerases; D016194:Receptors, N-Methyl-D-Aspartate; D012701:Serotonin; D017366:Serotonin Receptor Agonists; D000099300:Serine Racemase; C015952:4-iodo-2,5-dimethoxyphenylisopropylamine
keywords: 5-HT(2A) Receptor; D-Serine; Metabotropic glutamate 2 receptor; NMDA Receptor; Serotonin