Chronic administration of the histamine H3 receptor agonist immepip decreases l-Dopa-induced dyskinesias in 6-hydroxydopamine-lesioned rats

Abstract

Rationale

Histamine H3 receptors (H3Rs) are co-expressed with dopamine D1 receptors (D1Rs) by striato-nigral medium spiny GABAergic neurons, where they functionally antagonize D1R-mediated responses.

Objectives and methods

We examined whether the chronic administration of the H3R agonist immepip modifies dyskinesias induced by l-3,4-dihydroxyphenylalanine, l-Dopa (LIDs), in rats lesioned with 6-hydroxydopamine in the substantia nigra pars compacta, and the effect of D1R and H3R co-activation on glutamate and GABA content in dialysates from the dorsal striatum of naïve rats.

Results

The systemic administration (i.p.) of l-Dopa for 14 days significantly increased axial, limb, and orolingual abnormal involuntary movements (AIMs) compared with the vehicle group. The chronic administration of the H3R agonist immepip alongside l-Dopa significantly decreased axial, limb, and orolingual AIMs compared with l-Dopa alone, but AIMs returned to previous values on immepip withdrawal. Chronic immepip was ineffective when administered prior to l-Dopa. The chronic administration of immepip significantly decreased GABA and glutamate content in striatal dialysates, whereas the administration of l-Dopa alone increased GABA and glutamate content.

Conclusions

These results indicate that chronic H3R activation reduces LIDs, and the effects on striatal GABA and glutamate release provide evidence for a functional interaction between D1Rs and H3Rs.

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References

  1. Ahlskog JE, Muenter MD (2001) Frequency of levodopa-related dyskinesias and motor fluctuations as estimated from the cumulative literature. Mov Disord 16:448–458

    Article  CAS  PubMed  Google Scholar 

  2. Albin RL, Young AB, Penney JB (1989) The functional-anatomy of basal ganglia disorders. Trends Neurosci 12:366–375

    Article  CAS  PubMed  Google Scholar 

  3. Alfaro-Rodriguez A, Alonso-Spilsbury M, Arch-Tirado E, Gonzalez-Pina R, Arias-Montano J-A, Bueno-Nava A (2013) Histamine H3 receptor activation prevents dopamine D1 receptor-mediated inhibition of dopamine release in the rat striatum: a microdialysis study. Neurosci Lett 552:5–9

    Article  CAS  PubMed  Google Scholar 

  4. Andersson M, Hilbertson A, Cenci MA (1999) Striatal fosB expression is causally linked with L-DOPA-induced abnormal involuntary movements and the associated upregulation of striatal prodynorphin mRNA in a rat model of Parkinson's disease. Neurobiol Dis 6:461–474

    Article  CAS  PubMed  Google Scholar 

  5. Arias-Montaño JA, Floran B, Garcia M, Aceves J, Young JM (2001) Histamine H3 receptor-mediated inhibition of depolarization-induced, dopamine D1 receptor-dependent release of [3H]-gamma-aminobutryic acid from rat striatal slices. Br J Pharmacol 133:165–171

    Article  PubMed  PubMed Central  Google Scholar 

  6. Bastide MF, Meissner WG, Picconi B, Fasano S, Fernagut PO, Feyder M, Francardo V, Alcacer C, Ding YM, Brambilla R, Fisone G, Stoessl AJ, Bourdenx M, Engeln M, Navailles S, De Deurwaerdere P, Ko WKD, Simola N, Morelli M, Groc L, Rodriguez MC, Gurevich EV, Quik M, Morari M, Mellone M, Gardoni F, Tronci E, Guehl D, Tison F, Crossman AR, Kang UJ, Steece-Collier K, Fox S, Carta M, Cenci MA, Bezard E (2015) Pathophysiology of L-dopa-induced motor and non-motor complications in Parkinson’s disease. Prog Neurobiol 132:96–168

    Article  CAS  PubMed  Google Scholar 

  7. Bolam JP, Hanley JJ, Booth PA, Bevan MD (2000) Synaptic organisation of the basal ganglia. J Anat 196(Pt 4):527–542

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Carta M, Bezard E (2011) Contribution of pre-synaptic mechanisms to L-DOPA-induced dyskinesia. Neuroscience 198:245–251

    Article  CAS  PubMed  Google Scholar 

  9. Cenci MA, Lee CS, Bjorklund A (1998) L-DOPA-induced dyskinesia in the rat is associated with striatal overexpression of prodynorphin- and glutamic acid decarboxylase mRNA. Eur J Neurosci 10:2694–2706

    Article  CAS  PubMed  Google Scholar 

  10. Connolly BS, Lang AE (2014) Pharmacological treatment of Parkinson disease a review. Jama-J Am Med Assoc 311:1670–1683

    Article  CAS  Google Scholar 

  11. De la Fuente-Fernandez R, Sossi V, Huang ZG, Furtado S, Lu JQ, Calne DB, Ruth TJ, Stoessl AJ (2004) Levodopa-induced changes in synaptic dopamine levels increase with progression of Parkinson’s disease: implications for dyskinesias. Brain 127:2747–2754

    Article  PubMed  Google Scholar 

  12. Ding J, Peterson JD, Surmeier DJ (2008) Corticostriatal and thalamostriatal synapses have distinctive properties. J Neurosci 28:6483–6492

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Doreulee N, Yanovsky Y, Flagmeyer I, Stevens DR, Haas HL, Brown RE (2001) Histamine H3 receptors depress synaptic transmission in the corticostriatal pathway. Neuropharmacology 40:106–113

    Article  CAS  PubMed  Google Scholar 

  14. Ellender TJ, Huerta-Ocampo I, Deisseroth K, Capogna M, Bolam JP (2011) Differential modulation of excitatory and inhibitory striatal synaptic transmission by histamine. J Neurosci 31:15340–15351

    Article  CAS  PubMed  Google Scholar 

  15. Ferrada C, Moreno E, Casado V, Bongers G, Cortes A, Mallol J, Canela EI, Leurs R, Ferre S, Lluis C, Franco R (2009) Marked changes in signal transduction upon heteromerization of dopamine D1 and histamine H3 receptors. Br J Pharmacol 157:64–75

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Festing MF (1994) Reduction of animal use: experimental design and quality of experiments. Lab Anim 28:212–221

    Article  CAS  PubMed  Google Scholar 

  17. Garcia M, Floran B, Arias-Montaño JA, Young JM, Aceves J (1997) Histamine H3 receptor activation selectively inhibits dopamine D1 receptor-dependent [3H]GABA release from depolarization-stimulated slices of rat substantia nigra pars reticulata. Neuroscience 80:241–249

    Article  CAS  PubMed  Google Scholar 

  18. Garcia-Galvez AM, Escamilla-Sanchez J, Flores-Maldonado C, Contreras RG, Arias JM, Arias-Montano JA (2018) Differential homologous desensitization of the human histamine H-3 receptors of 445 and 365 amino acids expressed in CHO-K1 cells. Neurochem Int 112:114–123

    Article  CAS  PubMed  Google Scholar 

  19. Gomez-Ramirez J, Johnston TH, Visanji NP, Fox SH, Brotchie JM (2006) Histamine H3 receptor agonists reduce L-dopa-induced chorea, but not dystonia, in the MPTP-lesioned nonhuman primate model of Parkinson’s disease. Mov Disord 21:839–846

    Article  PubMed  Google Scholar 

  20. González-Sepúlveda M, Rosell S, Hoffmann HM, Castillo-Ruiz MM, Mignon V, Moreno-Delgado D, Michel V, Díaz J, Sabriá J, Ortiz J (2013) Cellular distribution of the histamine H3 receptor in the basal ganglia: functional modulation of dopamine and glutamate neurotransmission. Basal Ganglia 3:109–121

    Article  Google Scholar 

  21. Hely MA, Morris JGL, Reid WGJ, Trafficante R (2005) Sydney multicenter study of Parkinson’s disease: non-L-dopa-responsive problems dominate at 15 years. Mov Disord 20:190–199

    Article  PubMed  Google Scholar 

  22. Huot P, Johnston TH, Koprich JB, Fox SH, Brotchie JM (2013) The pharmacology of L-DOPA-induced dyskinesia in Parkinson’s disease. Pharmacol Rev 65:171–222

    Article  CAS  PubMed  Google Scholar 

  23. Johansson PA, Andersson M, Andersson KE, Cenci MA (2001) Alterations in cortical and basal ganglia levels of opioid receptor binding in a rat model of L-DOPA-induced dyskinesia. Neurobiol Dis 8:220–239

    Article  CAS  PubMed  Google Scholar 

  24. Lundblad M, Andersson M, Winkler C, Kirik D, Wierup N, Cenci MA (2002) Pharmacological validation of behavioural measures of akinesia and dyskinesia in a rat model of Parkinson’s disease. Eur J Neurosci 15:120–132

    Article  CAS  PubMed  Google Scholar 

  25. Molina-Hernandez A, Nunez A, Sierra JJ, Arias-Montano JA (2001) Histamine H3 receptor activation inhibits glutamate release from rat striatal synaptosomes. Neuropharmacology 41:928–934

    Article  CAS  PubMed  Google Scholar 

  26. Montes S, Alcaraz-Zubeldia M, Muriel P, Rios C (2003) Role of manganese accumulation in increased brain glutamine of the cirrhotic rat. Neurochem Res 28:911–917

    Article  CAS  PubMed  Google Scholar 

  27. Moreno E, Hoffmann H, Gonzalez-Sepulveda M, Navarro G, Casado V, Cortes A, Mallol J, Vignes M, McCormick PJ, Canela EI, Lluis C, Moratalla R, Ferre S, Ortiz J, Franco R (2011) Dopamine D-1-histamine H-3 receptor heteromers provide a selective link to MAPK signaling in GABAergic neurons of the direct striatal pathway. J Biol Chem 286:5846–5854

    Article  CAS  PubMed  Google Scholar 

  28. Nowak P, Bortel A, Dabrowska J, Biedka I, Slomian G, Roczniak W, Kostrzewa RM, Brus R (2008) Histamine H3 receptor ligands modulate L-dopa-evoked behavioral responses and L-dopa-derived extracellular dopamine in dopamine-denervated rat striatum. Neurotox Res 13:231–240

    Article  CAS  PubMed  Google Scholar 

  29. Olfert E, Cross B, Mc William A (1993) Guide for the care and use of experimental animals. Can Council Anim Care 1:211

    Google Scholar 

  30. Osorio-Espinoza A, Escamilla-Sanchez J, Aquino-Jarquin G, Arias-Montano JA (2014) Homologous desensitization of human histamine H3 receptors expressed in CHO-K1 cells. Neuropharmacology 77:387–397

    Article  CAS  PubMed  Google Scholar 

  31. Pagano G, Yousaf T, Politis M (2017) PET molecular imaging research of levodopa-induced dyskinesias in Parkinson’s disease. Curr Neurol Neurosci Reports 17:90

    Article  CAS  Google Scholar 

  32. Panula P, Pirvola U, Auvinen S, Airaksinen MS (1989) Histamine-immunoreactive nerve-fibers in the rat-brain. Neuroscience 28:585–610

    Article  CAS  PubMed  Google Scholar 

  33. Papathanou M, Jenner P, Iravani M, Jackson M, Stockwell K, Strang I, Zeng B-Y, McCreary AC, Rose S (2014) The H3 receptor agonist immepip does not affect L-dopa-induced abnormal involuntary movements in 6-OHDA-lesioned rats. Eur J Pharmacol 741:304–310

    Article  CAS  PubMed  Google Scholar 

  34. Paxinos G, Watson C (2007) The rat brain in stereotaxic coordinates, 6th edn. Academic Press, London

    Google Scholar 

  35. Pillot C, Heron A, Cochois V, Tardivel-Lacombe J, Ligneau X, Schwartz JC, Arrang JM (2002) A detailed mapping of the histamine H3 receptor and its gene transcripts in rat brain. Neuroscience 114:173–193

    Article  CAS  PubMed  Google Scholar 

  36. Porras G, De Deurwaerdere P, Li Q, Marti M, Morgenstern R, Sohr R, Bezard E, Morari M, Meissner WG (2014) L-dopa-induced dyskinesia: beyond an excessive dopamine tone in the striatum. Sci Rep 4:3730

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Rangel-Barajas C, Silva I, Lopez-Santiago LM, Aceves J, Erlij D, Floran B (2011) L-dopa-induced dyskinesia in hemiparkinsonian rats is associated with up-regulation of adenylyl cyclase type V/VI and increased GABA release in the substantia nigra reticulata. Neurobiol Dis 41:51–61

    Article  CAS  PubMed  Google Scholar 

  38. Rapanelli M (2017) The magnificent two: histamine and the H3 receptor as key modulators of striatal circuitry. Prog Neuro-Psychopharmacol Biol Psychiatry 73:36–40

    Article  CAS  Google Scholar 

  39. Rodriguez-Ruiz M, Moreno E, Moreno-Delgado D, Navarro G, Mallol J, Cortes A, Lluis C, Canela EI, Casado V, McCormick PJ, Franco R (2017) Heteroreceptor complexes formed by dopamine D1, histamine H3, and N-methyl-D-aspartate glutamate receptors as targets to prevent neuronal death in Alzheimer’s disease. Mol Neurobiol 54:4537–4550

    Article  CAS  PubMed  Google Scholar 

  40. Ryu JH, Yanai K, Iwata R, Ido T, Watanabe T (1994) Heterogeneous distributions of histamine H3, dopamine D1 and D2 receptors in rat-brain. Neuroreport 5:621–624

    Article  CAS  PubMed  Google Scholar 

  41. Sanchez-Lemus E, Arias-Montano JA (2004) Histamine H3 receptor activation inhibits dopamine D1 receptor-induced cAMP accumulation in rat striatal slices. Neurosci Lett 364:179–184

    Article  CAS  PubMed  Google Scholar 

  42. Schlicker E, Fink K, Detzner M, Gothert M (1993) Histamine inhibits dopamine release in the mouse striatum via presynaptic-H3 receptors. J Neural Transm-Gen Sect 93:1–10

    Article  CAS  PubMed  Google Scholar 

  43. Silberberg G, Bolam JP (2015) Local and afferent synaptic pathways in the striatal microcircuitry. Curr Opin Neurobiol 33:182–187

    Article  CAS  PubMed  Google Scholar 

  44. Smith Y, Raju DV, Pare JF, Sidibe M (2004) The thalamostriatal system: a highly specific network of the basal ganglia circuitry. Trends Neurosci 27:520–527

    Article  CAS  PubMed  Google Scholar 

  45. Spigolon G, Fisone G (2018) Signal transduction in l-dopa-induced dyskinesia: from receptor sensitization to abnormal gene expression. J Neural Transm 125:1171–1186

    Article  CAS  PubMed  Google Scholar 

  46. Surmeier DJ, Obeso JA, Halliday GM (2017) Selective neuronal vulnerability in Parkinson disease. Nat Rev Neurosci 18:101–113

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

We thank MVZ Hugo Lecona Butrón for the support with housing, care, maintenance, and monitoring of the health of the experimental animals at the Instituto Nacional de Rehabilitación Luis Guillermo Ibarra Ibarra. We thank MVZ Javier Pérez Gallaga for the technical support. The authors wish to thank Dr. Ivonne M. Heuze de Icaza for her support with the experimental animals.

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Correspondence to Antonio Bueno-Nava.

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Electronic supplementary material

Effect of the administration of L-Dopa (6.25 mg/kg) and the co-administration of L-Dopa and the H3R agonist immepip (1 mg/kg) in 6-OHDA-lesioned rats. Note that the administration of immepip reduces LIDs in 6-OHDA-lesioned rats (MP4 38915 kb)

Effects of the chronic administration of immepip+L-Dopa for 14 days, and immepip withdrawal on day 15. Drugs administration was as described for Video 1 (MP4 31326 kb)

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Avila-Luna, A., Ríos, C., Gálvez-Rosas, A. et al. Chronic administration of the histamine H3 receptor agonist immepip decreases l-Dopa-induced dyskinesias in 6-hydroxydopamine-lesioned rats. Psychopharmacology 236, 1937–1948 (2019). https://doi.org/10.1007/s00213-019-5182-y

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Keywords

  • Dopamine
  • Histamine
  • D1 receptor
  • H3 receptor
  • Dyskinesia
  • Striatum
  • Parkinson’s disease
  • l-Dopa
  • Immepip