D-serine deficiency attenuates the behavioral and cellular effects induced by the hallucinogenic 5-HT(2A) receptor agonist DOI

• Published in: Behavioural brain research 2014-02, Vol.259, p.242
• Main Authors: Santini, Martin A, Balu, Darrick T, Puhl, Matthew D, Hill-Smith, Tiffany E, Berg, Alexandra R, Lucki, Irwin, Mikkelsen, Jens D, Coyle, Joseph T
• Format: Article
• Language: English
• Subjects: Amphetamines - pharmacology; Animals; Behavior, Animal - drug effects; Behavior, Animal - physiology; Brain - drug effects; Brain - metabolism; Dizocilpine Maleate - pharmacology; Dose-Response Relationship, Drug; Gene Expression Regulation - drug effects; Gene Expression Regulation - genetics; Head Movements - drug effects; Head Movements - physiology; Hydroxyindoleacetic Acid - metabolism; Mice; Mice, Knockout; Proto-Oncogene Proteins c-fos - genetics; Proto-Oncogene Proteins c-fos - metabolism; Racemases and Epimerases - deficiency; Racemases and Epimerases - genetics; Receptors, N-Methyl-D-Aspartate - metabolism; RNA, Messenger - metabolism; Serotonin - metabolism; Serotonin Receptor Agonists - pharmacology
• ISSN: 1872-7549
• DOI: 10.1016/j.bbr.2013.11.022

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.