title: Functional and morphological characterization of glutamate transporters in the rat locus coeruleus.
abstract: OBJECTIVE
  Excitatory amino acid transporters (EAATs) in the CNS contribute to the clearance of glutamate released during neurotransmission. The aim of this study was to explore the role of EAATs in the regulation of locus coeruleus (LC) neurons by glutamate.
  
  
  METHODS
  We measured the effect of different EAAT subtype inhibitors/enhancers on glutamate- and KCl-induced activation of LC neurons in rat slices. EAAT2-3 expression in the LC was also characterized by immunohistochemistry.
  
  
  RESULTS
  The EAAT2-5 inhibitor DL-threo-β-benzyloxaspartic acid (100 μM), but not the EAAT2, 4, 5 inhibitor L-trans-pyrrolidine-2,4-dicarboxylic acid (100 μM) or the EAAT2 inhibitor dihydrokainic acid (DHK; 100 μM), enhanced the glutamate- and KCl-induced activation of the firing rate of LC neurons. These effects were blocked by ionotropic, but not metabotrobic, glutamate receptor antagonists. DHK (100 μM) was the only EAAT inhibitor that increased the spontaneous firing rate of LC cells, an effect that was due to inhibition of EAAT2 and subsequent AMPA receptor activation. Chronic treatment with ceftriaxone (200 mg·kg(-1) i.p., once daily, 7 days), an EAAT2 expression enhancer, increased the actions of glutamate and DHK, suggesting a functional impact of EAAT2 up-regulation on the glutamatergic system. Immuhistochemical data revealed the presence of EAAT2 and EAAT3 surrounding noradrenergic neurons and EAAT2 on glial cells in the LC.
  
  
  CONCLUSIONS
  These results remark the importance of EAAT2 and EAAT3 in the regulation of rat LC by glutamate. Neuronal EAAT3 would be responsible for terminating the action of synaptically released glutamate, whereas glial EAAT2 would regulate tonic glutamate concentrations in this nucleus.
authors: Department of Pharmacology, Faculty of Medicine and Odontology, University of the Basque Country (UPV/ EHU), Bizkaia, Spain.
authors: M C
authors: MC
authors: Medrano
authors: I
authors: I
authors: Gerrikagoitia
authors: L
authors: L
authors: Martínez-Millán
authors: A
authors: A
authors: Mendiguren
authors: J
authors: J
authors: Pineda
mesh_terms: D059331:Adrenergic Neurons / Q000378:metabolism*; D000818:Animals; D002443:Ceftriaxone / Q000494:pharmacology; D027342:Excitatory Amino Acid Transporter 2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D050580:Excitatory Amino Acid Transporter 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005973:Glutamine / Q000378:metabolism; D066298:In Vitro Techniques; D007608:Kainic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D008125:Locus Coeruleus / Q000166:cytology* / Q000378:metabolism*; D008297:Male; D009457:Neuroglia / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D027342:Excitatory Amino Acid Transporter 2; D050580:Excitatory Amino Acid Transporter 3; C493398:Slc1a1 protein, rat; D005973:Glutamine; C020889:dihydrokainic acid; D002443:Ceftriaxone; D007608:Kainic Acid
keywords: EAAT2; EAAT3; KCl; firing; glutamate; locus coeruleus
references: Naunyn Schmiedebergs Arch Pharmacol. 1989 Mar;339(3):312-4
references: 2566932
references: Neuropharmacology. 2007 Feb;52(2):617-25
references: 17070872
references: Brain Res Brain Res Rev. 2003 Apr;42(1):33-84
references: 12668290
references: Brain Res. 1992 Dec 11;598(1-2):185-95
references: 1336704
references: Anat Embryol (Berl). 1998 Jul;198(1):13-30
references: 9683064
references: Expert Opin Ther Targets. 2009 Jun;13(6):719-31
references: 19456273
references: Biochem Pharmacol. 2004 Jun 1;67(11):2115-27
references: 15135308
references: Epilepsia. 2008 Feb;49(2):226-36
references: 17868051
references: Pharmacol Ther. 2005 Sep;107(3):271-85
references: 16112332
references: Sleep Med. 2005 Jun;6 Suppl 1:S3-7
references: 16140243
references: Epilepsy Res. 2005 Aug-Sep;66(1-3):145-53
references: 16150575
references: J Neurosci Res. 2004 Oct 15;78(2):200-7
references: 15378511
references: Neuroscience. 1997 Dec;81(4):1031-42
references: 9330365
references: J Neurosci. 1994 Nov;14(11 Pt 1):6754-62
references: 7965076
references: J Neurosci. 1984 Jan;4(1):161-70
references: 6319626
references: Med Res Rev. 2009 Jan;29(1):3-28
references: 18623169
references: J Neurosci. 1993 Aug;13(8):3582-98
references: 8393486
references: Br J Pharmacol. 2011 Nov;164 Suppl 1:S1-324
references: 22040146
references: J Biol Chem. 2008 May 9;283(19):13116-23
references: 18326497
references: Neuroscience. 1993 Feb;52(3):515-39
references: 8450957
references: J Neurochem. 2001 Oct;79(2):297-302
references: 11677257
references: Amino Acids. 2011 Feb;40(2):761-4
references: 20383795
references: Neurosci Lett. 2006 Oct 16;407(1):64-9
references: 16949209
references: Eur J Neurosci. 2004 Jan;19(1):221-6
references: 14750980
references: Br J Pharmacol. 2009 Feb;156(4):649-61
references: 19226256
references: Neurochem Int. 2002 Nov;41(5):313-8
references: 12176072
references: J Neurosci. 1994 Feb;14(2):667-96
references: 8301357
references: Neurosci Lett. 2004 Jun 3;363(1):1-5
references: 15157983
references: J Physiol. 2006 Apr 15;572(Pt 2):407-23
references: 16455692
references: Neuron. 1994 Sep;13(3):713-25
references: 7917301
references: Mol Neurobiol. 2001 Apr-Jun;23(2-3):155-71
references: 11817217
references: Science. 1986 Nov 7;234(4777):734-7
references: 3775363
references: Br J Pharmacol. 2010 Aug;160(7):1577-9
references: 20649561
references: J Neurochem. 2006 Aug;98(4):1007-18
references: 16800850
references: Psychopharmacology (Berl). 1991;105(4):508-12
references: 1771218
references: Eur J Pharmacol. 2004 Feb 6;485(1-3):201-10
references: 14757142
references: Nature. 2005 Jan 6;433(7021):73-7
references: 15635412
references: J Physiol. 1988 Dec;406:431-42
references: 2908183
references: Eur J Pharmacol. 1993 Aug 3;239(1-3):149-57
references: 7901027
references: Nature. 1995 Jun 15;375(6532):599-603
references: 7791878
references: Bioorg Med Chem Lett. 2000 Nov 6;10(21):2407-10
references: 11078189
references: Brain Res. 1994 Feb 4;636(1):126-30
references: 7908850
references: J Comp Neurol. 2005 Dec 5;493(1):99-110
references: 16254995
references: Neuroscience. 1997 Sep;80(2):511-21
references: 9284353
references: Behav Pharmacol. 2010 Mar;21(2):161-4
references: 20215965
references: Eur J Pharmacol. 2001 May 4;419(1):39-45
references: 11348628
references: Br J Pharmacol. 2010 Aug;160(7):1573-6
references: 20649560
references: Eur J Neurosci. 2005 Dec;22(11):2744-54
references: 16324108
references: Prog Neurobiol. 1998 Oct;56(2):237-67
references: 9760703
references: Trends Neurosci. 1992 May;15(5):186-91
references: 1377426
references: Eur J Pharmacol. 2010 Jul 25;638(1-3):65-71
references: 20423712
references: J Comp Neurol. 2000 Mar 13;418(3):255-69
references: 10701825
references: Mol Pharmacol. 1998 Feb;53(2):195-201
references: 9463476
references: Eur J Pharmacol. 2009 Jan 5;602(1):23-7
references: 19041863
references: Naunyn Schmiedebergs Arch Pharmacol. 2007 Jul;375(5):337-47
references: 17473915
references: Prog Neurobiol. 2001 Sep;65(1):1-105
references: 11369436