D-serine deficiency attenuates the behavioral and cellular effects induced by the hallucinogenic 5-HT(2A) receptor agonist DOI
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D-serine deficiency attenuates the behavioral and cellular effects induced by the hallucinogenic 5-HT(2A) receptor agonist DOI. / Santini, Martin A; Balu, Darrick T; Puhl, Matthew D; Hill-Smith, Tiffany E; Berg, Alexandra R; Lucki, Irwin; Mikkelsen, Jens D; Coyle, Joseph T.
In: Behavioural Brain Research, Vol. 259, 01.02.2014, p. 242-246.Research output: Contribution to journal › Comment/debate › Research › peer-review
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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
VL - 259
SP - 242
EP - 246
JO - Behavioural Brain Research
JF - Behavioural Brain Research
SN - 0166-4328
ER -
ID: 138777725