title: Role of the NMDA-receptor in Prepulse Inhibition in the Rat.
abstract: Kynurenic acid (KYNA) is an endogenous metabolite of tryptophan. Studies have revealed increased brain KYNA levels in patients with schizophrenia. Prepulse inhibition (PPI) is a behavioral model for sensorimotor gating and found to be reduced in schizophrenia. Previous studies have shown that pharmacologically elevated brain KYNA levels disrupt PPI in the rat. The aim of the present study was to investigate the receptor(s) involved in this effect. Rats were treated with different drugs selectively blocking each of the sites that KYNA antagonizes, namely the glutamate recognition site of the N-methyl-D-aspartate receptor (NMDAR), the α7* nicotinic acetylcholine receptor (α7nAChR) and the glycine site of the NMDAR. Kynurenine (200 mg/kg) was given to replicate the effects of increased levels of KYNA on PPI. In order to block the glutamate recognition site of the NMDAR, CGS 19755 (10 mg/kg) or SDZ 220-581 (2.5 mg/kg) were administered and to antagonize the α7nAChR methyllycaconitine (MLA; 6 mg/kg) was given. L-701,324 (1 and 4 mg/kg) or 4-Chloro-kynurenine (4-Cl-KYN; 25, 50 and 100 mg/kg), a drug in situ converted to 7-Chloro-kynurenic acid, were used to block the glycine-site of the NMDAR. Administration of SDZ 220-581 or CGS 19755 was associated with a robust reduction in PPI, whereas L-701,324, 4-Cl-KYN or MLA failed to alter PPI. Kynurenine increased brain KYNA levels 5-fold and tended to decrease PPI. The present study suggests that neither antagonism of the glycine-site of the NMDA receptor nor antagonism of the α7nAChR disrupts PPI, rather with regard to the effects of KYNA, blockade of the glutamate recognition-site is necessary to reduce PPI.
authors.affiliation: Dept. of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Klas
authors.initials: K
authors.lastname: Linderholm
authors.forename: Susan
authors.initials: S
authors.lastname: Powell
authors.forename: Elin
authors.initials: E
authors.lastname: Olsson
authors.forename: Maria
authors.initials: M
authors.lastname: Holtze
authors.forename: Ralph
authors.initials: R
authors.lastname: Snodgrass
authors.forename: Sophie
authors.initials: S
authors.lastname: Erhardt
references.citation: J Neurochem. 2005 May;93(3):762-5
references.pmid: 15836634
references.citation: Can Psychiatr Assoc J. 1967 Apr;12(2):209-12
references.pmid: 6040448
references.citation: J Pharmacol Exp Ther. 1997 Dec;283(3):1264-75
references.pmid: 9400002
references.citation: Psychopharmacology (Berl). 2008 Aug;199(3):331-88
references.pmid: 18568339
references.citation: Amino Acids. 2001;20(4):353-62
references.pmid: 11452979
references.citation: Brain Res. 1992 Jul 31;587(1):130-6
references.pmid: 1525643
references.citation: Behav Brain Res. 2009 Aug 12;201(2):325-31
references.pmid: 19428652
references.citation: Psychophysiology. 1978 Jul;15(4):339-43
references.pmid: 693742
references.citation: Neuropsychopharmacology. 1999 Mar;20(3):201-25
references.pmid: 10063482
references.citation: Biol Psychiatry. 2004 Aug 15;56(4):255-60
references.pmid: 15312813
references.citation: Psychopharmacology (Berl). 1997 Mar;130(2):131-8
references.pmid: 9106910
references.citation: Schizophr Res. 2005 Dec 15;80(2-3):315-22
references.pmid: 16125901
references.citation: Psychopharmacology (Berl). 2001 Jul;156(2-3):234-58
references.pmid: 11549226
references.citation: CNS Drugs. 2009;23(2):91-101
references.pmid: 19173370
references.citation: Life Sci. 2008 Aug 1;83(5-6):170-5
references.pmid: 18590745
references.citation: Synapse. 2006 Apr;59(5):290-8
references.pmid: 16416446
references.citation: Learn Mem. 1998 Sep-Oct;5(4-5):302-16
references.pmid: 10454356
references.citation: Neurosci Lett. 2001 Nov 2;313(1-2):96-8
references.pmid: 11684348
references.citation: J Pharmacol Exp Ther. 1999 Feb;288(2):643-52
references.pmid: 9918570
references.citation: J Neurochem. 2001 Aug;78(4):842-53
references.pmid: 11520905
references.citation: Neuropsychopharmacology. 1997 Sep;17(3):141-50
references.pmid: 9272481
references.citation: Glia. 2007 Jan 1;55(1):78-92
references.pmid: 17024659
references.citation: J Neurochem. 1995 Dec;65(6):2621-32
references.pmid: 7595559
references.citation: Psychopharmacology (Berl). 2001 Jul;156(2-3):117-54
references.pmid: 11549216
references.citation: J Neurochem. 1989 Apr;52(4):1319-28
references.pmid: 2538568
references.citation: J Neural Transm (Vienna). 2003 Jan;110(1):1-14
references.pmid: 12541009
references.citation: Psychopharmacology (Berl). 1995 Mar;118(2):230-2
references.pmid: 7617814
references.citation: Pharmacol Biochem Behav. 1997 Aug;57(4):909-13
references.pmid: 9259023
references.citation: J Neurosci. 2001 Oct 1;21(19):7463-73
references.pmid: 11567036
references.citation: Am J Psychiatry. 1991 Oct;148(10):1301-8
references.pmid: 1654746
references.citation: Brain Res. 1995 Dec 24;705(1-2):235-40
references.pmid: 8821754
references.citation: Pharmacol Biochem Behav. 2001 Jul-Aug;69(3-4):359-66
references.pmid: 11509192
references.citation: Neuropharmacology. 2007 Dec;53(8):918-24
references.pmid: 17959203
references.citation: Pharmacol Rev. 1993 Sep;45(3):309-79
references.pmid: 8248282
references.citation: Psychopharmacology (Berl). 1988;94(4):507-14
references.pmid: 3131796
references.citation: AMA Arch Neurol Psychiatry. 1959 Mar;81(3):363-9
references.pmid: 13626287
references.citation: Acta Physiol Scand. 2002 May;175(1):45-53
references.pmid: 11982504
references.citation: Schizophr Bull. 2007 May;33(3):797-804
references.pmid: 16920787
references.citation: Int J Tryptophan Res. 2009;2:1-19
references.pmid: 22084578
references.citation: Int J Neuropsychopharmacol. 2009 May;12(4):501-12
references.pmid: 18796185
references.citation: J Biol Chem. 2006 Aug 4;281(31):22021-22028
references.pmid: 16754668
references.citation: Br J Med Psychol. 1961;34:103-16
references.pmid: 13773940
references.citation: Neurotox Res. 2006 Dec;10(3-4):211-20
references.pmid: 17197371
references.citation: Brain Res. 1998 Jul 6;798(1-2):204-10
references.pmid: 9666129
references.citation: J Neural Transm (Vienna). 2006 May;113(5):557-71
references.pmid: 16082514
references.citation: Psychopharmacology (Berl). 2002 Jan;159(3):248-57
references.pmid: 11862357
references.citation: Behav Brain Res. 2006 Jun 30;170(2):326-32
references.pmid: 16621049
references.citation: Annu Rev Pharmacol Toxicol. 2001;41:237-60
references.pmid: 11264457
references.citation: Brain Res Bull. 1990 Sep;25(3):485-98
references.pmid: 2292046
references.citation: Neuropsychopharmacology. 1996 May;14(5):301-7
references.pmid: 8703299
references.citation: Behav Pharmacol. 1999 Feb;10(1):51-62
references.pmid: 10780302