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Fischer KD, Houston ACW, Desai RI, et al. Behavioral phenotyping and dopamine dynamics in mice with conditional deletion of the glutamate transporter GLT-1 in neurons: resistance to the acute locomotor effects of amphetamine. Psychopharmacology (Berl). 2018;235(5):1371-1387doi: 10.1007/s00213-018-4848-1.
Fischer, K. D., Houston, A. C. W., Desai, R. I., Doyle, M. R., Bergman, J., Mian, M., Mannix, R., Sulzer, D. L., Choi, S. J., Mosharov, E. V., Hodgson, N. W., Bechtholt, A., Miczek, K. A., & Rosenberg, P. A. (2018). Behavioral phenotyping and dopamine dynamics in mice with conditional deletion of the glutamate transporter GLT-1 in neurons: resistance to the acute locomotor effects of amphetamine. Psychopharmacology, 235(5), 1371-1387. https://doi.org/10.1007/s00213-018-4848-1
Fischer, Kathryn D, et al. "Behavioral phenotyping and dopamine dynamics in mice with conditional deletion of the glutamate transporter GLT-1 in neurons: resistance to the acute locomotor effects of amphetamine." Psychopharmacology vol. 235,5 (2018): 1371-1387. doi: https://doi.org/10.1007/s00213-018-4848-1
Fischer KD, Houston ACW, Desai RI, Doyle MR, Bergman J, Mian M, Mannix R, Sulzer DL, Choi SJ, Mosharov EV, Hodgson NW, Bechtholt A, Miczek KA, Rosenberg PA. Behavioral phenotyping and dopamine dynamics in mice with conditional deletion of the glutamate transporter GLT-1 in neurons: resistance to the acute locomotor effects of amphetamine. Psychopharmacology (Berl). 2018 May;235(5):1371-1387. doi: 10.1007/s00213-018-4848-1. Epub 2018 Feb 22. PMID: 29468294; PMCID: PMC5999338.
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Psychopharmacology (Berl). 2018 May;235(5):1371-1387. doi: 10.1007/s00213-018-4848-1. Epub 2018 Feb 22.

Behavioral phenotyping and dopamine dynamics in mice with conditional deletion of the glutamate transporter GLT-1 in neurons: resistance to the acute locomotor effects of amphetamine.

Psychopharmacology

Kathryn D Fischer, Alex C W Houston, Rajeev I Desai, Michelle R Doyle, Jack Bergman, Maha Mian, Rebekah Mannix, David L Sulzer, Se Joon Choi, Eugene V Mosharov, Nathaniel W Hodgson, Anita Bechtholt, Klaus A Miczek, Paul A Rosenberg

Affiliations

  1. Department of Neurology and the F.M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA, 02115, USA.
  2. Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.
  3. Preclinical Pharmacology Program, McLean Hospital/Harvard Medical School, Belmont, MA, 02478, USA.
  4. Division of Emergency Medicine, Boston Children's Hospital, Boston, MA, 02115, USA.
  5. Department of Neurology, Columbia University, New York, NY, 10032, USA.
  6. National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, 20892, USA.
  7. Departments of Psychiatry, Pharmacology, and Neuroscience, Tufts University, Boston, MA, 02111, USA.
  8. Department of Neurology and the F.M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA, 02115, USA. [email protected].
  9. Program in Neuroscience, Harvard Medical School, Boston, MA, 02115, USA. [email protected].

PMID: 29468294 PMCID: PMC5999338 DOI: 10.1007/s00213-018-4848-1

Abstract

RATIONALE: GLT-1 is the major glutamate transporter in the brain and is expressed predominantly in astrocytes but is also present in excitatory axon terminals. To understand the functional significance of GLT-1 expressed in neurons, we generated a conditional GLT-1 knockout mouse and inactivated GLT-1 in neurons using Cre-recombinase expressed under the synapsin 1 promoter, (synGLT-1 KO).

OBJECTIVES: Abnormalities of glutamate homeostasis have been shown to affect hippocampal-related behaviors including learning and memory as well as responses to drugs of abuse. Here, we asked whether deletion of GLT-1 specifically from neurons would affect behaviors that assessed locomotor activity, cognitive function, sensorimotor gating, social interaction, as well as amphetamine-stimulated locomotor activity.

METHODS/RESULTS: We found that the neuronal GLT-1 KO mice performed similarly to littermate controls in the behavioral tests we studied. Although performance in open field testing was normal, the acute locomotor response to amphetamine was significantly blunted in the synGLT-1 KO (40% of control). We found no change in amphetamine-stimulated extracellular dopamine in the medial shell of the nucleus accumbens, no change in electrically stimulated or amphetamine-induced dopamine release, and no change in dopamine tissue content.

CONCLUSIONS: These results support the view that GLT-1 expression in neurons is required for amphetamine-induced behavioral activation, and suggest that this phenotype is not produced through a change in dopamine uptake or release. Although GLT-1 is highly expressed in neurons in the CA3 region of the hippocampus, the tests used in this study were not able to detect a behavioral phenotype referable to hippocampal dysfunction.

Keywords: Amphetamine; Behavior; Dopamine; Glutamate homeostasis; Glutamate transporter; Glutamate uptake; Locomotor response

References

  1. CNS Neurol Disord Drug Targets. 2015;14(6):745-56 - PubMed
  2. Behav Brain Res. 1988 Nov 1;31(1):47-59 - PubMed
  3. J Neurochem. 1996 Jul;67(1):352-63 - PubMed
  4. Neuron. 2010 Mar 11;65(5):643-56 - PubMed
  5. Synapse. 2006 Oct;60(5):399-405 - PubMed
  6. Exp Neurobiol. 2013 Sep;22(3):224-31 - PubMed
  7. Neuroscience. 2008 Nov 11;157(1):80-94 - PubMed
  8. Proc Natl Acad Sci U S A. 2006 Nov 14;103(46):17501-6 - PubMed
  9. Neurochem Int. 2016 Sep;98 :19-28 - PubMed
  10. Addict Biol. 2015 Jan;20(1):91-103 - PubMed
  11. J Neurosci. 2012 Nov 28;32(48):17477-91 - PubMed
  12. Prog Neurobiol. 2001 Sep;65(1):1-105 - PubMed
  13. J Neurosci. 1998 Oct 1 ;18(19):7709-16 - PubMed
  14. Neurosci Lett. 2006 Jan 30;393(2-3):127-30 - PubMed
  15. J Pharmacol Exp Ther. 2003 Jul;306(1):116-23 - PubMed
  16. Psychopharmacology (Berl). 2012 May;221(2):227-37 - PubMed
  17. Psychopharmacology (Berl). 1997 Jul;132(2):169-80 - PubMed
  18. Elife. 2017 Jul 13;6:null - PubMed
  19. J Neurosci. 2002 Oct 15;22(20):9134-41 - PubMed
  20. Neuropsychopharmacology. 2015 Jun;40(7):1700-8 - PubMed
  21. J Neurosci Methods. 1984 May;11(1):47-60 - PubMed
  22. Psychopharmacology (Berl). 2014 Apr;231(8):1797-807 - PubMed
  23. Genesis. 2006 Jan;44(1):44-9 - PubMed
  24. Ment Retard Dev Disabil Res Rev. 2004;10(4):248-58 - PubMed
  25. Neuropharmacology. 2003 May;44(6):717-27 - PubMed
  26. Neuroscience. 1992 Oct;50(4):751-67 - PubMed
  27. Prog Neurobiol. 1998 Apr;54(6):679-720 - PubMed
  28. Anat Embryol (Berl). 1998 Jul;198(1):13-30 - PubMed
  29. Brain Res. 1989 Jun 26;490(2):255-67 - PubMed
  30. Behav Brain Res. 1996 Nov;81(1-2):123-33 - PubMed
  31. J Neurosci. 2015 Apr 1;35(13):5187-201 - PubMed
  32. Annu Rev Physiol. 2012;74:225-43 - PubMed
  33. Nat Rev Neurosci. 2009 Aug;10(8):561-72 - PubMed
  34. Front Mol Neurosci. 2012 Jun 27;5:72 - PubMed
  35. Neuropharmacology. 2014 Jan;76 Pt B:329-41 - PubMed
  36. Psychopharmacology (Berl). 2004 Jul;174(2):266-73 - PubMed
  37. Science. 1997 Jun 13;276(5319):1699-702 - PubMed
  38. Neurochem Int. 2016 Sep;98 :29-45 - PubMed
  39. Nature. 2001 May 31;411(6837):583-7 - PubMed
  40. Neuropsychopharmacology. 2010 Sep;35(10):2049-59 - PubMed
  41. Neurosci Lett. 2006 Aug 14;404(1-2):182-6 - PubMed
  42. Neuron. 2011 Feb 24;69(4):650-63 - PubMed
  43. J Neurosci. 2003 Jul 16;23 (15):6295-303 - PubMed
  44. J Comp Neurol. 2005 Nov 7;492(1):78-89 - PubMed
  45. Behav Brain Res. 1994 Mar 31;61(1):59-64 - PubMed
  46. Proc Natl Acad Sci U S A. 1996 May 14;93(10):4765-9 - PubMed
  47. J Neurosci. 2004 Feb 4;24(5):1136-48 - PubMed
  48. Cell Metab. 2013 Jul 2;18(1):21-8 - PubMed
  49. J Cereb Blood Flow Metab. 2011 Jan;31(1):351-61 - PubMed
  50. BMC Neurosci. 2013 Sep 22;14:102 - PubMed
  51. Neuropsychopharmacology. 2016 Jan;41(2):464-76 - PubMed
  52. J Neurosci. 1998 Mar 15;18(6):1979-86 - PubMed
  53. Neuron. 1994 Sep;13(3):713-25 - PubMed
  54. J Neurochem. 2000 Oct;75(4):1634-44 - PubMed
  55. Psychopharmacology (Berl). 2007 Jun;192(2):261-73 - PubMed
  56. Neuron. 2014 Jul 16;83(2):404-416 - PubMed
  57. Neurosci Biobehav Rev. 1979 Winter;3(4):247-63 - PubMed
  58. J Pharmacol Exp Ther. 2009 Sep;330(3):802-9 - PubMed
  59. J Neurosci. 1995 Feb;15(2):1308-17 - PubMed
  60. J Neurosci. 2001 Aug 15;21(16):5916-24 - PubMed
  61. Mol Brain. 2014 Apr 23;7:31 - PubMed
  62. Pharmacol Rev. 2016 Jul;68(3):816-71 - PubMed
  63. Psychopharmacology (Berl). 1994 Aug;115(4):516-28 - PubMed
  64. J Alzheimers Dis. 2011;26(3):447-55 - PubMed
  65. Nat Rev Neurosci. 2009 Jul;10(7):519-29 - PubMed
  66. J Pharmacol Exp Ther. 2005 May;313(2):613-20 - PubMed
  67. Neuropharmacology. 2014 Dec;87:180-7 - PubMed
  68. Neuron. 2011 Feb 24;69(4):628-49 - PubMed
  69. J Exp Med. 2015 Mar 9;212(3):319-32 - PubMed
  70. J Pharmacol Exp Ther. 2010 Jun;333(3):834-43 - PubMed
  71. Synapse. 1998 Aug;29(4):310-22 - PubMed
  72. Neuropsychopharmacology. 2010 May;35(6):1253-60 - PubMed
  73. Prog Brain Res. 2014;211:141-64 - PubMed

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