title: Inhibiting subthalamic D5 receptor constitutive activity alleviates abnormal electrical activity and reverses motor impairment in a rat model of Parkinson's disease.
abstract: Burst firing has been reported as a pathological activity of subthalamic nucleus (STN) neurons in Parkinson's disease. However, the origin of bursts and their causal link with motor deficits remain unknown. Here we tested the hypothesis that dopamine D5 receptors (D5Rs), characterized by a high constitutive activity, may contribute to the emergence of burst firing in STN. We tested whether inhibiting D5R constitutive activity depresses burst firing and alleviates motor impairments in the 6-OHDA rat model of Parkinson's disease. Intrasubthalamic microinjections of either an inverse agonist of D5Rs, flupenthixol, or a D2R antagonist, raclopride, were applied. Behavioral experiments, in vivo and in vitro electrophysiological recordings, and ex vivo functional neuroanatomy studies were performed. Using [(5)S]GTPγ binding autoradiography, we show that application of flupenthixol inhibits D5R constitutive activity within the STN. Furthermore, flupenthixol reduced evoked burst in brain slices and converted pathological burst firing into physiological tonic, single-spike firing in 6-OHDA rats in vivo. This later action was mimicked by calciseptine, a Cav1 channel blocker. Moreover, the same treatment dramatically attenuated motor impairment in this model and normalized metabolic hyperactivity in both STN and substantia nigra pars reticulata, the main output structure of basal ganglia in rats. In contrast, raclopride as well as saline did not reverse burst firing and motor deficits, confirming the selective action of flupenthixol on D5Rs. These results are the first to demonstrate that subthalamic D5Rs are involved in the pathophysiology of Parkinson's disease and that administering an inverse agonist of these receptors may lessen motor symptoms.
authors.affiliation: Université Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, CNRS, Institut des Maladies Neurodégénératives, UMR 5293, and CNRS, Institut Interdisciplinaire des Neurosciences, UMR 5297, F-33000 Bordeaux, France.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Chetrit
authors.forename: Anne
authors.initials: A
authors.lastname: Taupignon
authors.forename: Lionel
authors.initials: L
authors.lastname: Froux
authors.forename: Stephanie
authors.initials: S
authors.lastname: Morin
authors.forename: Rabia
authors.initials: R
authors.lastname: Bouali-Benazzouz
authors.forename: Frédéric
authors.initials: F
authors.lastname: Naudet
authors.forename: Nabila
authors.initials: N
authors.lastname: Kadiri
authors.forename: Christian E
authors.initials: CE
authors.lastname: Gross
authors.forename: Bernard
authors.initials: B
authors.lastname: Bioulac
authors.forename: Abdelhamid
authors.initials: A
authors.lastname: Benazzouz
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000831:Animals, Newborn; D004195:Disease Models, Animal; D018491:Dopamine Agonists / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005475:Flupenthixol / Q000494:pharmacology / Q000627:therapeutic use*; D066298:In Vitro Techniques; D008124:Locomotion / Q000187:drug effects / Q000502:physiology*; D008297:Male; D009474:Neurons / Q000187:drug effects; D016627:Oxidopamine / Q000633:toxicity; D010300:Parkinson Disease / Q000188:drug therapy* / Q000209:etiology; D020891:Raclopride / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D050641:Receptors, Dopamine D5 / Q000378:metabolism*; D018709:Statistics, Nonparametric; D020531:Subthalamic Nucleus / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology
chemical_list: D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D050641:Receptors, Dopamine D5; D020891:Raclopride; D016627:Oxidopamine; D005475:Flupenthixol
references.citation: J Physiol. 2012 Nov 15;590(22):5861-75
references.pmid: 22890706
references.citation: J Neurosci. 1986 Nov;6(11):3177-88
references.pmid: 3534157
references.citation: Eur J Neurosci. 2001 Jul;14(2):373-81
references.pmid: 11553287
references.citation: Front Neuroanat. 2010 Oct 27;4:139
references.pmid: 21103009
references.citation: Proc Natl Acad Sci U S A. 1991 May 1;88(9):3772-6
references.pmid: 2023928
references.citation: EMBO J. 2012 Aug 1;31(15):3239-51
references.pmid: 22692127
references.citation: Neuroscience. 2001;106(2):313-30
references.pmid: 11566503
references.citation: Trends Neurosci. 1989 Oct;12(10):366-75
references.pmid: 2479133
references.citation: FASEB J. 2003 Oct;17(13):1820-30
references.pmid: 14519661
references.citation: Nat Neurosci. 2011 Sep 25;14(11):1462-7
references.pmid: 21946325
references.citation: J Neurosci. 1995 May;15(5 Pt 2):3863-75
references.pmid: 7751951
references.citation: J Neurophysiol. 1994 Aug;72(2):507-20
references.pmid: 7983515
references.citation: Eur J Neurosci. 2002 Jan;15(1):133-42
references.pmid: 11860513
references.citation: Clin Neurophysiol. 2008 Jul;119(7):1459-74
references.pmid: 18467168
references.citation: Eur J Neurosci. 1993 Apr 1;5(4):382-9
references.pmid: 8261116
references.citation: Trends Neurosci. 2000 Oct;23(10 Suppl):S78-85
references.pmid: 11052224
references.citation: Eur J Neurosci. 2004 Oct;20(7):1788-802
references.pmid: 15380000
references.citation: J Pharmacol Exp Ther. 2005 May;313(2):510-7
references.pmid: 15644432
references.citation: J Neurosci Methods. 1996 Oct;68(2):211-23
references.pmid: 8912194
references.citation: Eur J Neurosci. 2000 Jan;12(1):337-44
references.pmid: 10651888
references.citation: J Neurosci. 2010 Nov 24;30(47):16025-40
references.pmid: 21106841
references.citation: Neuron. 2012 Feb 9;73(3):523-36
references.pmid: 22325204
references.citation: J Comp Neurol. 2000 May 29;421(2):247-55
references.pmid: 10813785
references.citation: Neuroscience. 2013 Apr 16;236:289-97
references.pmid: 23376117
references.citation: Science. 1990 Sep 21;249(4975):1436-8
references.pmid: 2402638
references.citation: J Biol Chem. 2003 Mar 7;278(10):8146-53
references.pmid: 12509438
references.citation: Cell Signal. 2010 Jan;22(1):106-16
references.pmid: 19786093
references.citation: FASEB J. 2005 Nov;19(13):1771-7
references.pmid: 16260646
references.citation: J Neurosci Methods. 1980 Dec;3(2):129-49
references.pmid: 6110810
references.citation: J Neurosci. 2003 Feb 1;23(3):816-25
references.pmid: 12574410
references.citation: J Neurosci. 2008 Apr 30;28(18):4795-806
references.pmid: 18448656
references.citation: J Neurophysiol. 2011 Oct;106(4):2012-23
references.pmid: 21813748
references.citation: J Biol Chem. 1994 Nov 11;269(45):27925-31
references.pmid: 7525564
references.citation: Neurosci Lett. 1986 Jan 2;63(1):96-100
references.pmid: 3005926
references.citation: Neuroscience. 2009 Dec 1;164(2):588-96
references.pmid: 19628021
references.citation: J Physiol. 1979 May;290(2):433-40
references.pmid: 469785
references.citation: Neuroscience. 1988 Jan;24(1):19-28
references.pmid: 3368048
references.citation: Exp Neurol. 2000 Mar;162(1):215-24
references.pmid: 10716902
references.citation: N Engl J Med. 1998 Oct 15;339(16):1105-11
references.pmid: 9770557
references.citation: J Neurosci. 1991 Dec;11(12):3830-9
references.pmid: 1683899
references.citation: Brain. 2001 Oct;124(Pt 10):2105-18
references.pmid: 11571226
references.citation: FASEB J. 2004 Mar;18(3):528-30
references.pmid: 14715698
references.citation: Mov Disord. 2008;23 Suppl 3:S534-47
references.pmid: 18781680
references.citation: Eur J Neurosci. 2005 Nov;22(10):2579-86
references.pmid: 16307600
references.citation: Proc Natl Acad Sci U S A. 1995 Aug 1;92(16):7242-6
references.pmid: 7638174
references.citation: Neuron. 2003 Jul 3;39(1):5-6
references.pmid: 12848926
references.citation: J Physiol. 2008 Apr 15;586(8):2121-42
references.pmid: 18292127
references.citation: Eur J Neurosci. 2007 Jan;25(2):397-405
references.pmid: 17284180
references.citation: Brain Res. 1987 Dec 22;437(1):35-44
references.pmid: 3427481
references.citation: Ann Neurol. 2012 Sep;72(3):464-76
references.pmid: 23034918
references.citation: Science. 2002 Oct 11;298(5592):425-9
references.pmid: 12376704
references.citation: PLoS One. 2009 Jul 09;4(7):e6208
references.pmid: 19587792
references.citation: Nat Neurosci. 2004 Jun;7(6):587-8
references.pmid: 15146189
references.citation: Neuroscience. 2011 Dec 15;198:54-68
references.pmid: 21723918
references.citation: J Biol Chem. 2000 Aug 4;275(31):23446-55
references.pmid: 10807903
references.citation: J Neurosci. 2002 Jun 15;22(12):5137-48
references.pmid: 12077209
references.citation: J Neurosci. 2013 Mar 13;33(11):4804-14
references.pmid: 23486951
references.citation: FEBS Lett. 2004 Oct 22;576(3):461-7
references.pmid: 15498581
references.citation: J Biol Chem. 1996 Nov 8;271(45):28071-6
references.pmid: 8910419
references.citation: Synapse. 2001 May;40(2):145-53
references.pmid: 11252026
references.citation: Eur J Pharmacol. 2001 May 25;420(2-3):73-82
references.pmid: 11408027
references.citation: J Neurosci. 2007 Sep 5;27(36):9595-606
references.pmid: 17804620