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

TY - JOUR

T1 - D-serine deficiency attenuates the behavioral and cellular effects induced by the hallucinogenic 5-HT(2A) receptor agonist DOI

AU - Santini, Martin A

AU - Balu, Darrick T

AU - Puhl, Matthew D

AU - Hill-Smith, Tiffany E

AU - Berg, Alexandra R

AU - Lucki, Irwin

AU - Mikkelsen, Jens D

AU - Coyle, Joseph T

N1 - Copyright © 2013 Elsevier B.V. All rights reserved.

PY - 2014/2/1

Y1 - 2014/2/1

N2 - 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.

AB - 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.

KW - Amphetamines

KW - Animals

KW - Behavior, Animal

KW - Brain

KW - Dizocilpine Maleate

KW - Dose-Response Relationship, Drug

KW - Gene Expression Regulation

KW - Head Movements

KW - Hydroxyindoleacetic Acid

KW - Mice

KW - Mice, Knockout

KW - Proto-Oncogene Proteins c-fos

KW - RNA, Messenger

KW - Racemases and Epimerases

KW - Receptors, N-Methyl-D-Aspartate

KW - Serotonin

KW - Serotonin Receptor Agonists

U2 - 10.1016/j.bbr.2013.11.022

DO - 10.1016/j.bbr.2013.11.022

M3 - Comment/debate

C2 - 24269270

SN - 0166-4328

VL - 259

SP - 242

EP - 246

JO - Behavioural Brain Research

JF - Behavioural Brain Research

ER -