Abstract
Rationale
Glutamate signalling through the N-methyl-d-aspartate (NMDA) receptor is of critical importance for normal central nervous system (CNS) function, as indicated by the marked behavioural disturbances produced by non-subtype selective NMDA antagonists such as dizocilpine (MK-801).
Objective
The present studies were designed to investigate the involvement of the two major NMDA receptor subunits in the central nervous system, i.e. NR2A and NR2B, on sensorimotor gating in mice.
Methods
These experiments utilised the non-subtype-selective NMDA antagonist dizocilpine, a line of NR2A-KO mice and the selective NR2B antagonist Ro 63–1908, in the study of pre-pulse inhibition of the startle response (PPI).
Results
The non-selective NMDA receptor antagonist dizocilpine (0.1–1 mg/kg, IP) robustly disrupted PPI in wild-type mice. Conversely, selective genetic or pharmacological inhibition of either the NMDA NR2A or NR2B receptor subunit containing receptors, respectively, had no effect on PPI. Thus, NR2A KO mice showed normal PPI compared with wild-type littermate controls, and administration of Ro 63-1908 (1–10 mg/kg IP) to wild-type mice did not affect PPI. However, selective inhibition of NR2A and NR2B by administration of Ro 63–1908 to NR2A KO mice significantly disrupted PPI.
Conclusions
These data imply that concomitant inhibition of both NR2A and NR2B subunit-containing NMDA receptors is necessary to disrupt PPI, suggesting that inhibition of NR2A and NR2B-containing NMDA receptors is required to elicit behaviours suggestive of psychomimetic effects in man.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Auberson YP, Allgeier H, Bischoff S, Lingenhoehl K, Moretti R, Schmutz M (2002) 5-Phosphonomethylquinoxalinediones as competitive NMDA receptor antagonists with a preference for the human 1A/2A, rather than 1A/2B receptor composition. Bioorg Med Chem Lett 12:1099–1102
Bakshi V, Geyer MA (1998) Multiple limbic regions mediate the disruption of prepulse inhibition produced in rats by the noncompetitive NMDA antagonist dizocilpine. J Neurosci 18:8394–8401
Bakshi V, Tricklebank M, Neijt HC, Lehmann-Masten V, Geyer MA (1999) Disruption of prepulse inhibition and increases in locomotor activity by competitive N-methyl-d-aspartate receptor antagonists in rats. J Pharmacol Exp Ther 288:643–652
Braff DL, Grillon C, Geyer MA (1992) Gating and habituation of the startle reflex in schizophrenic patients. Arch Gen Psychiatry 49:206–215
Branchi I, Ricceri L (2002) Transgenic and knock-out mouse pups: the growing need for behavioral analysis. Genes Brain Behav 1:135–141
Chaperon F, Muller W, Auberson YP, Tricklebank MD, Neijt HC (2003) Substitution for PCP, disruption of PPI induced by N-methyl-d-aspartate receptor antagonists: preferential involvement of the NR2B rather than NR2A subunit. Behav Pharmacol 14:477–487
Chenard BL, Menniti FS (1999) Antagonists selective for NMDA receptors containing the NR2B subunit. Curr Pharmaceut Design 5:381–404
Depoortere R, Perrault G, Sanger DJ (1999) Prepulse inhibition of the startle reflex in rats: effects of compounds acting at various sites on the NMDA receptor complex. Behav Pharmacol 10:51–62
Doyle KM, Feerick S, Kirkby DL, Eddleston A, Higgins GA (1998) Comparison of various N-methyl-d-aspartate receptor antagonists in a model of short-term memory and on overt behaviour. Behav Pharmacol 9:671–681
Fischer G, Mutel V, Trube G, Malherbe P, Kew JNC, Mohacsi E, Heitz M-P, Kemp JA (1997) Ro 25–6981, a highly potent and selective blocker of N-methyl-d-aspartate receptors containing the NR2B subunit. Characterization in vitro. J Pharmacol Exp Ther 283:1285–1292
Geyer M, Krebs-Thomson K, Braff D, Swerdlow NR (2001) Pharmacological studies of prepulse inhibition models of sensorimotor gating deficits in schizophrenia: a decade in review. Psychopharmacology 156:117–154
Gill R, Alanine A, Bourson A, Buttelman B, Fischer G, Heitz M-P, Kew JNC, Levet-Trafit B, Lorez H-P, Malherbe P, Miss M-T, Mutel V, Pinard E, Roever S, Schmitt M, Trube G, Wybrecht R, Wyler R, Kemp JA (2002) Pharmacological characterisation of Ro 63-1908, a novel sub-type selective NMDA antagonist. J Pharmacol Exp Ther 302:940–948
Higgins GA, Ballard TM, Huwyler J, Kemp JA, Gill R (2003) Evaluation of the NR2B-selective NMDA receptor antagonist Ro 63-1908 on rodent behaviour: evidence for an involvement of NR2B NMDA receptors in response inhibition. Neuropharmacology 44:324–341
Javitt DC, Zukin SR (1991) Recent advances in the phencyclidine model of schizophrenia. Am J Psychiatry 148:1301–1308
Kadotani H, Hirano T, Masugi M, Nakamura K, Nakao K, Katsuki M, Nakanishi S (1996) Motor discoordination results from combined gene disruption of the NMDA receptor NR2A and NR2C subunits, but not from single disruption of the NR2A or NR2C subunit. J Neurosci 16:7859–7867
Kemp JA, McKernan RM (2002) NMDA receptor pathways as drug targets. Nat Neurosci 5:1039–1042
Kew JNC, Richards JG, Mutel V, Kemp JA (1998) Developmental changes in NMDA receptor glycine affinity and ifenprodil sensitivity reveal three distinct populations of NMDA receptors in individual rat cortical neurons. J Neurosci 18:1935–1943
Koek W, Colpaert FC (1990) Selective blockade of N-methyl-d-aspartate (NMDA)-induced convulsions by NMDA antagonists and putative glycine antagonists: relationship with phencyclidine-like behavioural effects. J Pharmacol Exp Ther 252:349–357
Kutsuwada T, Sakimura K, Manabe T, Takayama C, Katakura N, Kushiya E, Natsume R, Watanabe M, Inoue Y, Yagi T, Aizawa S, Arakawa M, Takahashi T, Nakamura Y, Mori H, Mishina M (1996) Impairment of suckling response, trigeminal neuronal pattern formation, and hippocampal LTD in NMDA receptor ε2 subunit mutant mice. Neuron 16:333–344
Logue SF, Owen EH, Rasmussen DL, Wehner JM (1997) Assessment of locomotor activity, acoustic and tactile startle, and prepulse inhibition of startle in inbred mouse strains and F1 hybrids: implications of genetic background for single gene and quantitative trait loci analysis. Neuroscience 80:1075–1086
McBain CJ, Mayer ML (1994) N-methy-d-aspartic acid receptor structure and function. Physiol Rev 74:723–760
Mansbach RS, Geyer MA (1991) Effects of phencyclidine and phencyclidine biologs on sensorimotor gating in the rat. Neuropsychopharmacology 2:299–308
Miyamoto Y, Yamada K, Noda Y, Mori H, Mishina M, Nabeshima T (2001) Hyperfunction of dopaminergic and serotonergic neuronal systems in mice lacking the NMDA receptor ε1 subunit. J Neurosci 21:750–757
Monyer H, Burnashev N, Laurie DJ, Sakmann B, Seeburg PH (1994) Developmental and regional expression in the rat brain and functional properties of four NMDA receptors. Neuron 12:529–540
Muir KW, Lees KR (1995) Clinical experience with excitatory amino acid antagonist drugs. Stroke 26:503–513
Mutel V, Buchy D, Klingelschmidt A, Messer J, Bluel Z, Kemp JA, Richards JG (1998) In vitro binding properties in rat brain of [3H] Ro 25-6981, a potent and selective antagonist of NMDA receptors containing NR2B subunits. J Neurochem 70:2147–2155
Narayan S, Willins D, Dalia A, Wallace L, Uretsky N (1996) Role of dopaminergic mechanisms in the stimulatory effects of MK-801 injected into the ventral tegmental area and the nucleus accumbens. Pharmacol Biochem Behav 54:565–573
Ouagazzal A-M, Almaric M (1995) Competitive NMDA receptor antagonists do not produce locomotor hyperactivity by a dopamine-dependant mechanism. Eur J Pharmacol 294:137–146
Paylor R, Crawley JN (1997) Inbred strain differences in prepulse inhibition of the mouse startle response. Psychopharmacology 132:169-180
Rigby M, Le Bourdelles B, Heavens RP, Kelly S, Smith D, Butler A, Hammans R, Hills R, Xuereb JH, Hill RG, Whiting PJ, Sirinathsinghji DJ (1996) The messenger RNAs for the N-methyl-d-aspartate receptor subunits show region-specific expression of different subunit composition in the human brain. Neuroscience 73:429–447
Rudolf GD, Cronin CA, Landwehrmeyer GB, Standaert DG, Penney JB, Young AB (1996) Expression of N-methyl-d-aspartate glutamate receptor subunits in the prefrontal cortex of the rat. Neuroscience 73:417–427
Sakimura K, Kutsuwada T, Ito I, Manabe T, Takayama C, Kushiya E, Yagi T, Aizawa S, Inoue Y, Sugiyama H, Mishina M (1995) Reduced hippocampal LTP and spatial learning in mice lacking NMDA receptor ε1 subunit. Nature 373:151–155
Sanger DJ, Perrault G, Audi E (1995) The anti-ischaemic drug, eliprodil, blocks hyperactivity induced by intra-accumbens injection of spermine. Behav Pharmacol 6:520–526
Tricklebank MD, Singh L, Oles RJ, Preston C, Iversen SD (1989) The behavioural effects of MK801: a comparison with antagonists acting non-competitively and competitively at the NMDA receptor. Eur J Pharmacol 167:127–135
Varty GB, Higgins GA (1994) Differences between three rat strains in sensitivity to prepulse inhibition of an acoustic startle response: influence of apomorphine and phencyclidine pretreatment. J Psychopharmacol 8:148–156
Wenzel A, Fritschy JM, Mohler H, Benke D (1997) NMDA receptor heterogeneity during postnatal development of the rat brain: differential expression of the NR2A, NR2B, and NR2C subunit proteins. J Neurochem 68:469–478
Wiley J (1998) Nitric oxide synthase inhibitors attenuate phencyclidine-induced disruption of prepulse inhibition. Neuropsychopharmacology 19:86–94
Winer BJ (1971) Statistical principles in experimental design, 2nd edn. McGraw Hill, New York
Willetts J, Balster RL, Leander JD (1990) The behavioural pharmacology of NMDA receptor antagonists Trends Pharmacol Sci 11:423–428
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Spooren, W., Mombereau, C., Maco, M. et al. Pharmacological and genetic evidence indicates that combined inhibition of NR2A and NR2B subunit containing NMDA receptors is required to disrupt prepulse inhibition. Psychopharmacology 175, 99–105 (2004). https://doi.org/10.1007/s00213-004-1785-y
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00213-004-1785-y