Abstract
Rationale
Enhancement of N-methyl-d-aspartate receptor (NMDAR) activity through its glycine modulatory site (GMS) is a novel therapeutic approach in schizophrenia. Brain concentrations of endogenous GMS agonist d-serine and antagonist N-acetyl-aspartylglutamate are regulated by serine racemase (SR) and glutamic acid decarboxylase 2 (GCP2), respectively. Using mice genetically, under-expressing these enzymes may clarify the role of NMDAR-mediated neurotransmission in schizophrenia.
Objectives
We investigated the behavioral effects of two psychotomimetic drugs, the noncompetitive NMDAR antagonist, phencyclidine (PCP; 0, 1.0, 3.0, or 6.0 mg/kg), and the indirect dopamine receptor agonist, amphetamine (AMPH; 0, 1.0, 2.0, or 4.0 mg/kg), in SR −/− and GCP2 −/+ mice. Outcome measures were locomotor activity and prepulse inhibition (PPI) of the acoustic startle reflex. Acute effects of an exogenous GMS antagonist, gavestinel (0, 3.0, or 10.0 mg/kg), on PCP-induced behaviors were examined in wild-type mice for comparison to the mutants with reduced GMS activity.
Results
PCP-induced hyperactivity was increased in GCP2 −/+ mice, and PCP-enhanced startle reactivity was increased in SR −/− mice. PCP disruption of PPI was unaffected in either mutant. In contrast, gavestinel attenuated PCP-induced PPI disruption without effect on baseline PPI or locomotor activity. AMPH effects were similar to controls in both mutant strains.
Conclusions
The results of the PCP experiments demonstrate that convergence of pharmacological and genetic manipulations at NMDARs may confound the predictive validity of these preclinical assays for the effects of GMS activation in schizophrenia. The AMPH data provide additional evidence that hyperdopaminergia in schizophrenia may be distinct from NMDAR hypofunction.
Similar content being viewed by others
References
Abi-Dargham A, van de Giessen E, Slifstein M, Kegeles LS, Laruelle M (2009) Baseline and amphetamine-stimulated dopamine activity are related in drug-naïve schizophrenic subjects. Biol Psychiatry 65(12):1091–1093
Akbarian S, Sucher NJ, Bradley D, Tafazzoli A, Trinh D, Hetrick WP, Potkin SG, Sandman CA, Bunney WE Jr, Jones EG (1996) Selective alterations in gene expression for NMDA receptor subunits in prefrontal cortex of schizophrenics. J Neurosci 16(1):19–30
Allen NC, Bagade S, McQueen MB, Ioannidis JP, Kavvoura FK, Khoury MJ, Tanzi RE, Bertram L (2008) Systematic meta-analyses and field synopsis of genetic association studies in schizophrenia: the SzGene database. Nat Genet 40(7):827–834
Ballard TM, Pauly-Evers M, Higgins GA, Ouagazzal AM, Mutel V, Borroni E, Kemp JA, Bluethmann H, Kew JN (2002) Severe impairment of NMDA receptor function in mice carrying targeted point mutations in the glycine binding site results in drug-resistant nonhabituating hyperactivity. J Neurosci 22(15):6713–6723
Basu AC, Tsai GE, Ma CL, Ehmsen JT, Mustafa AK, Han L, Jiang ZI, Benneyworth MA, Froimowitz MP, Lange N, Snyder SH, Bergeron R, Coyle JT (2009) Targeted disruption of serine racemase affects glutamatergic neurotransmission and behavior. Mol Psychiatry 14(7):719–727
Belforte JE, Zsiros V, Sklar ER, Jiang Z, Yu G, Li Y, Quinlan EM, Nakazawa K (2010) Postnatal NMDA receptor ablation in corticolimbic interneurons confers schizophrenia-like phenotypes. Nat Neurosci 13(1):76–83
Beneyto M, Meador-Woodruff JH (2008) Lamina-specific abnormalities of NMDA receptor-associated postsynaptic protein transcripts in the prefrontal cortex in schizophrenia and bipolar disorder. Neuropsychopharmacology 33(9):2175–2186
Berger UV, Luthi-Carter R, Passani LA, Elkabes S, Black I, Konradi C, Coyle JT (1999) Glutamate carboxypeptidase II is expressed by astrocytes in the adult rat nervous system. J Comp Neurol 415(1):52–64
Bergeron R, Coyle JT, Tsai G, Greene RW (2005) NAAG reduces NMDA receptor current in CA1 hippocampal pyramidal neurons of acute slices and dissociated neurons. Neuropsychopharmacology 30(1):7–16
Bergeron R, Imamura Y, Frangioni JV, Greene RW, Coyle JT (2007) Endogenous N-acetylaspartylglutamate reduced NMDA receptor-dependent current neurotransmission in the CA1 area of the hippocampus. J Neurochem 100(2):346–357
Boulay D, Bergis O, Avenet P, Griebel G (2010) The glycine transporter-1 inhibitor SSR103800 displays a selective and specific antipsychotic-like profile in normal and transgenic mice. Neuropsychopharmacology 35(2):416–427
Bristow LJ, Hutson PH, Thorn L, Tricklebank MD (1993) The glycine/NMDA receptor antagonist, R-(+)-HA-966, blocks activation of the mesolimbic dopaminergic system induced by phencyclidine and dizocilpine (MK-801) in rodents. Br J Pharmacol 108(4):1156–1163
Coyle JT (1996) The glutamatergic dysfunction hypothesis for schizophrenia. Harv Rev Psychiatry 3(5):241–253
Crawley JN (2003) Behavioral phenotyping of rodents. Comp Med 53(2):140–146
Di Fabio R, Capelli AM, Conti N, Cugola A, Donati D, Feriani A, Gastaldi P, Gaviraghi G, Hewkin CT, Micheli F, Missio A, Mugnaini M, Pecunioso A, Quaglia AM, Ratti E, Rossi L, Tedesco G, Trist DG, Reggiani A (1997) Substituted indole-2-carboxylates as in vivo potent antagonists acting as the strychnine-insensitive glycine binding site. J Med Chem 40(6):841–850
Han L, Picker JD, Schaevitz LR, Tsai G, Feng J, Jiang Z, Chu HC, Basu AC, Berger-Sweeney J, Coyle JT (2009) Phenotypic characterization of mice heterozygous for a null mutation of glutamate carboxypeptidase II. Synapse 63(8):625–635
Hashimoto A, Nishikawa T, Oka T, Takahashi K (1993) Endogenous D-serine in rat brain: N-methyl-D-aspartate receptor-related distribution and aging. J Neurochem 60(2):783–786
Hashimoto K, Fujita Y, Horio M, Kunitachi S, Iyo M, Ferraris D, Tsukamoto T (2009) Co-administration of a D-amino acid oxidase inhibitor potentiates the efficacy of D-serine in attenuating prepulse inhibition deficits after administration of dizocilpine. Biol Psychiatry 65(12):1103–1106
Javitt DC, Sershen H, Hashim A, Lajtha A (1997) Reversal of phencyclidine-induced hyperactivity by glycine and the glycine uptake inhibitor glycyldodecylamide. Neuropsychopharmacology 17(3):202–204
Karcz-Kubicha M, Wedzony K, Zajaczkowski W, Danysz W (1999) NMDA receptor antagonists acting at the glycineB site in rat models for antipsychotic-like activity. J Neural Transm 106(11–12):1189–1204
Kew JN, Koester A, Moreau JL, Jenck F, Ouagazzal AM, Mutel V, Richards JG, Trube G, Fischer G, Montkowski A, Hundt W, Reinscheid RK, Pauly-Evers M, Kemp JA, Bluethmann H (2000) Functional consequences of reduction in NMDA receptor glycine affinity in mice carrying targeted point mutations in the glycine binding site. J Neurosci 20(11):403
Kristiansen LV, Beneyto M, Haroutunian V, Meador-Woodruff JH (2006) Changes in NMDA receptor subunits and interacting PSD proteins in dorsolateral prefrontal and anterior cingulate cortex indicate abnormal regional expression in schizophrenia. Mol Psychiatry 11(8):737–747, 705
Krystal JH, Karper LP, Seibyl JP, Freeman GK, Delaney R, Bremner JD, Heninger GR, Bowers MB Jr, Charney DS (1994) Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Arch Gen Psychiatry 51(3):199–214
Krystal JH, D'Souza DC, Mathalon D, Perry E, Belger A, Hoffman R (2003) NMDA receptor antagonist effects, cortical glutamatergic function, and schizophrenia: toward a paradigm shift in medication development. Psychopharmacology (Berl) 169(3–4):215–233
Lahti AC, Weiler MA, Tamara Michaelidis BA, Parwani A, Tamminga CA (2001) Effects of ketamine in normal and schizophrenic volunteers. Neuropsychopharmacology 25(4):455–467
Laruelle M, Abi-Dargham A, van Dyck CH, Gil R, D'Souza CD, Erdos J, McCance E, Rosenblatt W, Fingado C, Zoghbi SS, Baldwin RM, Seibyl JP, Krystal JH, Charney DS, Innis RB (1996) Single photon emission computerized tomography imaging of amphetamine-induced dopamine release in drug-free schizophrenic subjects. Proc Natl Acad Sci USA 93(17):9235–9240
Laube B, Kuhse J, Betz H (1998) Evidence for a tetrameric structure of recombinant NMDA receptors. J Neurosci 18(8):2954–2961
Li D, He L (2007a) Association study between the NMDA receptor 2B subunit gene (GRIN2B) and schizophrenia: a HuGE review and meta-analysis. Genet Med 9(1):4–8
Li D, He L (2007b) G72/G30 genes and schizophrenia: a systematic meta-analysis of association studies. Genetics 175(2):917–922
Lisman JE, Coyle JT, Green RW, Javitt DC, Benes FM, Heckers S, Grace AA (2008) Circuit-based framework for understanding neurotransmitter and risk gene interactions in schizophrenia. Trends Neurosci 31(5):234–242
Matsui T, Sekiguchi M, Hashimoto A, Tomita U, Nishikawa T, Wada K (1995) Functional comparison of D-serine and glycine in rodents: the effect on cloned NMDA receptors and the extracellular concentration. J Neurochem 65(1):454–458
Mohn AR, Gainetdinov RR, Caron MG, Koller BH (1999) Mice with reduced NMDA receptor expression display behaviors related to schizophrenia. Cell 98(4):427–436
Mothet JP, Parent AT, Wolosker H, Brady RO Jr, Linden DJ, Ferris CD, Rogawski MA, Snyder SH (2000) D-Serine is an endogenous ligand for the glycine site of the N-methyl-D-aspartate receptor. Proc Natl Acad Sci USA 97(9):4926–4931
Moy SS, Perez A, Koller BH, Duncan GE (2006) Amphetamine-induced disruption of prepulse inhibition in mice with reduced NMDA receptor function. Brain Res 1089(1):186–194
National Research Council (2003) Guidelines for the care and use of mammals in neuroscience and behavioral research. National Academy Press
Nilsson M, Carlsson A, Carlsson ML (1997) Glycine and D-serine decrease MK-801-induced hyperactivity in mice. J Neural Transm 104(11–12):1195–1205
Robinson MB, Blakely RD, Couto R, Coyle JT (1987) Hydrolysis of the brain dipeptide N-acetyl-L-aspartyl-L-glutamate. Identification and characterization of a novel N-acetylated alpha-linked acidic dipeptidase activity from rat brain. J Biol Chem 262(30):14498–14506
Schell MJ, Molliver ME, Snyder SH (1995) D-Serine, an endogenous synaptic modulator: localization to astrocytes and glutamate-stimulated release. Proc Natl Acad Sci USA 92(9):3948–3952
Shimizu E, Tang YP, Rampon C, Tsien JZ (2000) NMDA receptor-dependent synaptic reinforcement as a crucial process for memory consolidation. Science 290(5494):1170–1174
Snyder SH (1976) The dopamine hypothesis of schizophrenia: focus on the dopamine receptor. Am J Psychiatry 133(2):197–202
Swerdlow NR, Shoemaker JM, Crain S, Goins J, Onozuka K, Auerbach PP (2004) Sensitivity to drug effects on prepulse inhibition in inbred and outbred rat strains. Pharmacol Biochem Behav 77(2):291–302
Swerdlow NR, Weber M, Qu Y, Light GA, Braff DL (2008) Realistic expectations of prepulse inhibition in translational models for schizophrenia research. Psychopharmacology (Berl) 199(3):331–388
Tsai GE, Lin PY (2010) Strategies to enhance N-methyl-D-aspartate receptor-mediated neurotransmission in schizophrenia, a critical review and meta-analysis. Curr Pharm Des 16(5):522–537
van den Buuse M (2010) Modeling the positive symptoms of schizophrenia in genetically modified mice: pharmacology and methodology aspects. Schizophr Bull 36(2):246–270
Vollenweider FX, Geyer MA (2001) A systems model of altered consciousness: integrating natural and drug-induced psychoses. Brain Res Bull 56(5):495–507
Wolosker H, Blackshaw S, Snyder SH (1999) Serine racemase: a glial enzyme synthesizing D-serine to regulate glutamate-N-methyl-D-aspartate neurotransmission. Proc Natl Acad Sci USA 96(23):13409–13414
Wroblewska B, Wroblewski JT, Pshenichkin S, Surin A, Sullivan SE, Neale JH (1997) N-Acetylaspartylglutamate selectively activates mGluR3 receptors in transfected cells. J Neurochem 69(1):174–181
Yee BK, Chang DL, Feldon J (2004) The effects of dizocilpine and phencyclidine on prepulse inhibition of the acoustic startle reflex and on prepulse-elicited reactivity in C57BL6 mice. Neuropsychopharmacology 29(10):1865–1877
Acknowledgments
This research was supported by NIH Grants MH05129 (JTC) and P50 MH060450 (JTC) and the Andrew P. Merrill Memorial Research Fellowship (MAB). JTC holds a patent on the use of d-serine to treat serious mental illness that is owned by the Massachusetts General Hospital but could yield royalties. We thank Jonathan Picker and William Carlezon for the use of behavioral testing equipment. We thank Jiamin Feng for genotyping and maintaining our animal colony.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Benneyworth, M.A., Basu, A.C. & Coyle, J.T. Discordant behavioral effects of psychotomimetic drugs in mice with altered NMDA receptor function. Psychopharmacology 213, 143–153 (2011). https://doi.org/10.1007/s00213-010-2023-4
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00213-010-2023-4