Advertisement

Reciprocal cross-sensitization of D1 and D3 receptors following pharmacological stimulation in the hemiparkinsonian rat

Abstract

In the majority of Parkinson’s disease (PD) patients, long-term dopamine (DA) replacement therapy leads to dyskinesia characterized by abnormal involuntary movements (AIMs). There are various mechanisms of dyskinesia, such as the sensitization of striatal DA D1 receptors (D1R) and upregulation of DA D3 receptors (D3R). These receptors interact physically and functionally in D1R-bearing medium spiny neurons to synergistically drive dyskinesia. However, the cross-receptor-mediated effects due to D1R-D3R cooperativity are still poorly understood. In pursuit of this, we examined whether or not pharmacological D1R or D3R stimulation sensitizes the dyskinetic response to the appositional agonist, a process known as cross-sensitization. First, we established D1R-D3R behavioral synergy in a cohort of 6-OHDA-lesioned female adult Sprague-Dawley rats. Then, in a new cohort, we tested for cross-sensitization in a between-subject design. Five groups received a sub-chronic regimen of either saline, the D1R agonist SKF38393 (1.0 mg/kg), or the D3R agonist PD128907 (0.3 mg/kg). For the final injection, each group received an acute injection of the other agonist. AIMs were monitored following each injection. Sub-chronic administration of both SKF38393 and PD128907 induced the development of dyskinesia. More importantly, cross-agonism tests revealed reciprocal cross-sensitization; chronic treatment with either SKF38393 or PD128907 induced sensitization to a single administration of the other agonist. This reciprocity was not marked by changes to either D1R or D3R striatal mRNA expression. The current study provides key behavioral data demonstrating the role of D3R in dyskinesia and provides behavioral evidence of D1R and D3R functional interactions.

This is a preview of subscription content, log in to check access.

Access options

Buy single article

Instant unlimited access to the full article PDF.

US$ 39.95

Price includes VAT for USA

Subscribe to journal

Immediate online access to all issues from 2019. Subscription will auto renew annually.

US$ 199

This is the net price. Taxes to be calculated in checkout.

Fig. 1
Fig. 2
Fig. 3

References

  1. Ahlskog JE, Muenter MD (2001) Frequency of levodopa-related dyskinesias and motor fluctuations as estimated from the cumulative literature. Mov Disord 16(3):448–458

  2. Alcacer C, Andreoli L, Sebastianutto I, Jakobsson J, Fieblinger T, Cenci MA (2017) Chemogenetic stimulation of striatal projection neurons modulates responses to Parkinson’s disease therapy. J Clin Invest 127(2):720–734. https://doi.org/10.1172/JCI90132

  3. Alcacer C, Santini E, Valjent E, Gaven F, Girault JA, Herve D (2012) Galpha(olf) mutation allows parsing the role of cAMP-dependent and extracellular signal-regulated kinase-dependent signaling in L-3,4-dihydroxyphenylalanine-induced dyskinesia. J Neurosci 32(17):5900–5910. https://doi.org/10.1523/JNEUROSCI.0837-12.2012

  4. Avalos-Fuentes A, Albarran-Bravo S, Loya-Lopez S, Cortes H, Recillas-Morales S, Magana JJ et al (2015) Dopaminergic denervation switches dopamine D3 receptor signaling and disrupts its Ca(2+) dependent modulation by CaMKII and calmodulin in striatonigral projections of the rat. Neurobiol Dis 74:336–346. https://doi.org/10.1016/j.nbd.2014.12.008

  5. Barnum CJ, Eskow KL, Dupre K, Blandino P Jr, Deak T, Bishop C (2008) Exogenous corticosterone reduces L-DOPA-induced dyskinesia in the hemi-parkinsonian rat: role for interleukin-1beta. Neuroscience 156(1):30–41. https://doi.org/10.1016/j.neuroscience.2008.07.016

  6. Berthet A, Porras G, Doudnikoff E, Stark H, Cador M, Bezard E, Bloch B (2009) Pharmacological analysis demonstrates dramatic alteration of D1 dopamine receptor neuronal distribution in the rat analog of L-DOPA-induced dyskinesia. J Neurosci 29(15):4829–4835. https://doi.org/10.1523/JNEUROSCI.5884-08.2009

  7. Bordet R, Ridray S, Carboni S, Diaz J, Sokoloff P, Schwartz JC (1997) Induction of dopamine D3 receptor expression as a mechanism of behavioral sensitization to levodopa. Proc Natl Acad Sci U S A 94(7):3363–3367

  8. Bordet R, Ridray S, Schwartz JC, Sokoloff P (2000) Involvement of the direct striatonigral pathway in levodopa-induced sensitization in 6-hydroxydopamine-lesioned rats. Eur J Neurosci 12(6):2117–2123

  9. Cenci MA (2014) Presynaptic mechanisms of l-DOPA-induced dyskinesia: the findings, the debate, and the therapeutic implications. Front Neurol 5:242. https://doi.org/10.3389/fneur.2014.00242

  10. Chang JW, Wachtel SR, Young D, Kang UJ (1999) Biochemical and anatomical characterization of forepaw adjusting steps in rat models of Parkinson’s disease: studies on medial forebrain bundle and striatal lesions. Neuroscience 88(2):617–628

  11. Chapuis S, Ouchchane L, Metz O, Gerbaud L, Durif F (2005) Impact of the motor complications of Parkinson’s disease on the quality of life. Mov Disord 20(2):224–230. https://doi.org/10.1002/mds.20279

  12. Chondrogiorgi M, Tatsioni A, Reichmann H, Konitsiotis S (2014) Dopamine agonist monotherapy in Parkinson’s disease and potential risk factors for dyskinesia: a meta-analysis of levodopa-controlled trials. Eur J Neurol 21(3):433–440. https://doi.org/10.1111/ene.12318

  13. Constantinescu R, Romer M, McDermott MP, Kamp C, Kieburtz K, CALM-PD Inverstigators of the Parkinson Stuedy Group (2007) Impact of pramipexole on the onset of levodopa-related dyskinesias. Mov Disord 22(9):1317–1319. https://doi.org/10.1002/mds.21292

  14. Conti MM, Goldenberg AA, Kuberka A, Mohamed M, Eissa S, Lindenbach D, Bishop C (2016) Effect of tricyclic antidepressants on L-DOPA-induced dyskinesia and motor improvement in hemi-parkinsonian rats. Pharmacol Biochem Behav 142:64–71. https://doi.org/10.1016/j.pbb.2016.01.004

  15. Conti MM, Ostock CY, Lindenbach D, Goldenberg AA, Kampton E, Dell'isola R et al (2014) Effects of prolonged selective serotonin reuptake inhibition on the development and expression of L-DOPA-induced dyskinesia in hemi-parkinsonian rats. Neuropharmacology 77:1–8. https://doi.org/10.1016/j.neuropharm.2013.09.017

  16. Cortes A, Moreno E, Rodriguez-Ruiz M, Canela EI, Casado V (2016) Targeting the dopamine D3 receptor: an overview of drug design strategies. Expert Opin Drug Discov 11(7):641–664. https://doi.org/10.1080/17460441.2016.1185413

  17. Cote SR, Kuzhikandathil EV (2015) Chronic levodopa treatment alters expression and function of dopamine D3 receptor in the MPTP/p mouse model of Parkinson’s disease. Neurosci Lett 585:33–37. https://doi.org/10.1016/j.neulet.2014.11.023

  18. Cruz-Trujillo R, Avalos-Fuentes A, Rangel-Barajas C, Paz-Bermudez F, Sierra A, Escartin-Perez E et al (2013) D3 dopamine receptors interact with dopamine D1 but not D4 receptors in the GABAergic terminals of the SNr of the rat. Neuropharmacology 67:370–378. https://doi.org/10.1016/j.neuropharm.2012.11.032

  19. Dekundy A, Lundblad M, Danysz W, Cenci MA (2007) Modulation of L-DOPA-induced abnormal involuntary movements by clinically tested compounds: further validation of the rat dyskinesia model. Behav Brain Res 179(1):76–89. https://doi.org/10.1016/j.bbr.2007.01.013

  20. Doremus-Fitzwater TL, Gano A, Paniccia JE, Deak T (2015) Male adolescent rats display blunted cytokine responses in the CNS after acute ethanol or lipopolysaccharide exposure. Physiol Behav 148:131–144. https://doi.org/10.1016/j.physbeh.2015.02.032

  21. Dupre KB, Eskow KL, Negron G, Bishop C (2007) The differential effects of 5-HT(1A) receptor stimulation on dopamine receptor-mediated abnormal involuntary movements and rotations in the primed hemiparkinsonian rat. Brain Res 1158:135–143. https://doi.org/10.1016/j.brainres.2007.05.005

  22. Eskow KL, Dupre KB, Barnum CJ, Dickinson SO, Park JY, Bishop C (2009) The role of the dorsal raphe nucleus in the development, expression, and treatment of L-dopa-induced dyskinesia in hemiparkinsonian rats. Synapse 63(7):610–620. https://doi.org/10.1002/syn.20630

  23. Fanni S, Scheggi S, Rossi F, Tronci E, Traccis F, Stancampiano R, de Montis MG, Devoto P, Gambarana C, Bortolato M, Frau R, Carta M (2018) 5alpha-reductase inhibitors dampen L-DOPA-induced dyskinesia via normalization of dopamine D1-receptor signaling pathway and D1-D3 receptor interaction. Neurobiol Dis 121:120–130. https://doi.org/10.1016/j.nbd.2018.09.018

  24. Farre D, Munoz A, Moreno E, Reyes-Resina I, Canet-Pons J, Dopeso-Reyes IG et al (2015) Stronger dopamine D1 receptor-mediated neurotransmission in dyskinesia. Mol Neurobiol 52(3):1408–1420. https://doi.org/10.1007/s12035-014-8936-x

  25. Fiorentini C, Busi C, Gorruso E, Gotti C, Spano P, Missale C (2008) Reciprocal regulation of dopamine D1 and D3 receptor function and trafficking by heterodimerization. Mol Pharmacol 74(1):59–69. https://doi.org/10.1124/mol.107.043885

  26. Fiorentini C, Savoia P, Bono F, Tallarico P, Missale C (2015) The D3 dopamine receptor: from structural interactions to function. Eur Neuropsychopharmacol 25(9):1462–1469. https://doi.org/10.1016/j.euroneuro.2014.11.021

  27. Galaj E, Ewing S, Ranaldi R (2018) Dopamine D1 and D3 receptor polypharmacology as a potential treatment approach for substance use disorder. Neurosci Biobehav Rev 89:13–28. https://doi.org/10.1016/j.neubiorev.2018.03.020

  28. Gano A, Doremus-Fitzwater TL, Deak T (2016) Sustained alterations in neuroimmune gene expression after daily, but not intermittent, alcohol exposure. Brain Res 1646:62–72. https://doi.org/10.1016/j.brainres.2016.05.027

  29. Gershanik O, Jenner P (2012) Moving from continuous dopaminergic stimulation to continuous drug delivery in the treatment of Parkinson’s disease. Eur J Neurol 19(12):1502–1508. https://doi.org/10.1111/j.1468-1331.2011.03593.x

  30. Guitart, X., Moreno, E., Rea, W., Sanchez-Soto, M., Cai, N. S., Quiroz, C., . . . Ferre, S. (2019). Biased G protein-independent signaling of dopamine D1-D3 receptor heteromers in the nucleus accumbens. Mol Neurobiol doi:https://doi.org/10.1007/s12035-019-1564-8

  31. Guitart X, Navarro G, Moreno E, Yano H, Cai NS, Sanchez-Soto M et al (2014) Functional selectivity of allosteric interactions within G protein-coupled receptor oligomers: the dopamine D1-D3 receptor heterotetramer. Mol Pharmacol 86(4):417–429. https://doi.org/10.1124/mol.114.093096

  32. Heijtz RD, Beraki S, Scott L, Aperia A, Forssberg H (2002) Sex differences in the motor inhibitory and stimulatory role of dopamine D1 receptors in rats. Eur J Pharmacol 445(1–2):97–104

  33. Hely MA, Morris JG, Reid WG, Trafficante R (2005) Sydney Multicenter Study of Parkinson’s disease: non-L-dopa-responsive problems dominate at 15 years. Mov Disord 20(2):190–199. https://doi.org/10.1002/mds.20324

  34. Hernandez FL, Castela I, Ruiz-DeDiego I, Obeso JA, Moratalla R (2017) Striatal activation by optogenetics induces dyskinesias in the 6-hydroxydopamine rat model of Parkinson disease. Mov Disord 32(4):530–537. https://doi.org/10.1002/mds.26947

  35. Hueston CM, Deak T (2014) The inflamed axis: the interaction between stress, hormones, and the expression of inflammatory-related genes within key structures comprising the hypothalamic-pituitary-adrenal axis. Physiol Behav 124:77–91. https://doi.org/10.1016/j.physbeh.2013.10.035

  36. Lanza K, Meadows SM, Chambers NE, Nuss E, Deak MM, Ferre S, Bishop C (2018) Behavioral and cellular dopamine D1 and D3 receptor-mediated synergy: implications for L-DOPA-induced dyskinesia. Neuropharmacology 138:304–314. https://doi.org/10.1016/j.neuropharm.2018.06.024

  37. Lindenbach D, Conti MM, Ostock CY, Dupre KB, Bishop C (2015) Alterations in primary motor cortex neurotransmission and gene expression in hemi-parkinsonian rats with drug-induced dyskinesia. Neuroscience 310:12–26. https://doi.org/10.1016/j.neuroscience.2015.09.018

  38. Lindenbach D, Das B, Conti MM, Meadows SM, Dutta AK, Bishop C (2017) D-512, a novel dopamine D2/3 receptor agonist, demonstrates greater anti-parkinsonian efficacy than ropinirole in parkinsonian rats. Br J Pharmacol 174(18):3058–3071. https://doi.org/10.1111/bph.13937

  39. Lindgren HS, Rylander D, Ohlin KE, Lundblad M, Cenci MA (2007) The “motor complication syndrome” in rats with 6-OHDA lesions treated chronically with L-DOPA: relation to dose and route of administration. Behav Brain Res 177(1):150–159. https://doi.org/10.1016/j.bbr.2006.09.019

  40. 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(1):120–132

  41. Manson A, Stirpe P, Schrag A (2012) Levodopa-induced-dyskinesias clinical features, incidence, risk factors, management and impact on quality of life. J Park Dis 2(3):189–198. https://doi.org/10.3233/JPD-2012-120103

  42. Marcellino D, Ferre S, Casado V, Cortes A, Le Foll B, Mazzola C et al (2008) Identification of dopamine D1-D3 receptor heteromers. Indications for a role of synergistic D1-D3 receptor interactions in the striatum. J Biol Chem 283(38):26016–26025. https://doi.org/10.1074/jbc.M710349200

  43. Martelle SE, Nader SH, Czoty PW, John WS, Duke AN, Garg PK, Garg S, Newman AH, Nader MA (2014) Further characterization of quinpirole-elicited yawning as a model of dopamine D3 receptor activation in male and female monkeys. J Pharmacol Exp Ther 350(2):205–211. https://doi.org/10.1124/jpet.114.214833

  44. Mulas G, Espa E, Fenu S, Spiga S, Cossu G, Pillai E, Carboni E, Simbula G, Jadžić D, Angius F, Spolitu S, Batetta B, Lecca D, Giuffrida A, Carta AR (2016) Differential induction of dyskinesia and neuroinflammation by pulsatile versus continuous l-DOPA delivery in the 6-OHDA model of Parkinson’s disease. Exp Neurol 286:83–92. https://doi.org/10.1016/j.expneurol.2016.09.013

  45. Prieto GA (2017) Abnormalities of dopamine D3 receptor signaling in the diseased brain. J Cent Nerv Syst Dis 9:1179573517726335. https://doi.org/10.1177/1179573517726335

  46. Prieto GA, Perez-Burgos A, Fiordelisio T, Salgado H, Galarraga E, Drucker-Colin R, Bargas J (2009) Dopamine D(2)-class receptor supersensitivity as reflected in Ca2+ current modulation in neostriatal neurons. Neuroscience 164(2):345–350. https://doi.org/10.1016/j.neuroscience.2009.08.030

  47. Prieto GA, Perez-Burgos A, Palomero-Rivero M, Galarraga E, Drucker-Colin R, Bargas J (2011) Upregulation of D2-class signaling in dopamine-denervated striatum is in part mediated by D3 receptors acting on Ca V 2.1 channels via PIP2 depletion. J Neurophysiol 105(5):2260–2274. https://doi.org/10.1152/jn.00516.2010

  48. 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(1):51–61. https://doi.org/10.1016/j.nbd.2010.08.018

  49. Rascol O, Nutt JG, Blin O, Goetz CG, Trugman JM, Soubrouillard C, Carter JH, Currie LJ, Fabre N, Thalamas C, Giardina WJ, Wright S (2001) Induction by dopamine D1 receptor agonist ABT-431 of dyskinesia similar to levodopa in patients with Parkinson disease. Arch Neurol 58(2):249–254

  50. Solis O, Garcia-Montes JR, Gonzalez-Granillo A, Xu M, Moratalla R (2015) Dopamine D3 receptor modulates l-DOPA-induced dyskinesia by targeting D1 receptor-mediated striatal signaling. Cereb Cortex 27(1):435–446. https://doi.org/10.1093/cercor/bhv231

  51. Solis O, Moratalla R (2018) Dopamine receptors: homomeric and heteromeric complexes in L-DOPA-induced dyskinesia. J Neural Transm (Vienna) 125(8):1187–1194. https://doi.org/10.1007/s00702-018-1852-x

  52. Stathis P, Konitsiotis S, Antonini A (2015) Dopamine agonists early monotherapy for the delay of development of levodopa-induced dyskinesias. Expert Rev Neurother 15(2):207–213. https://doi.org/10.1586/14737175.2015.1001747

  53. Stocchi F, Rascol O, Kieburtz K, Poewe W, Jankovic J, Tolosa E, Barone P, Lang AE, Olanow CW (2010) Initiating levodopa/carbidopa therapy with and without entacapone in early Parkinson disease: the STRIDE-PD study. Ann Neurol 68(1):18–27. https://doi.org/10.1002/ana.22060

  54. Suh DC, Pahwa R, Mallya U (2012) Treatment patterns and associated costs with Parkinson’s disease levodopa induced dyskinesia. J Neurol Sci 319(1–2):24–31. https://doi.org/10.1016/j.jns.2012.05.029

  55. Taylor JL, Bishop C, Walker PD (2005) Dopamine D1 and D2 receptor contributions to L-DOPA-induced dyskinesia in the dopamine-depleted rat. Pharmacol Biochem Behav 81(4):887–893. https://doi.org/10.1016/j.pbb.2005.06.013

  56. Titova N, Levin O, Katunina E, Ray Chaudhuri K (2018) ‘Levodopa Phobia’: a review of a not uncommon and consequential phenomenon. NPJ Parkinsons Dis 4:31. https://doi.org/10.1038/s41531-018-0067-z

  57. Umeh CC, Perez A, Augustine EF, Dhall R, Dewey RB Jr, Mari Z et al (2014) No sex differences in use of dopaminergic medication in early Parkinson disease in the US and Canada—baseline findings of a multicenter trial. PLoS One 9(12):e112287. https://doi.org/10.1371/journal.pone.0112287

  58. Westin JE, Vercammen L, Strome EM, Konradi C, Cenci MA (2007) Spatiotemporal pattern of striatal ERK1/2 phosphorylation in a rat model of L-DOPA-induced dyskinesia and the role of dopamine D1 receptors. Biol Psychiatry 62(7):800–810. https://doi.org/10.1016/j.biopsych.2006.11.032

Download references

Author information

Correspondence to Christopher Bishop.

Ethics declarations

Conflict of interest

On behalf of all authors, the corresponding author states that there is no conflict of interest.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Lanza, K., Chemakin, K., Lefkowitz, S. et al. Reciprocal cross-sensitization of D1 and D3 receptors following pharmacological stimulation in the hemiparkinsonian rat. Psychopharmacology 237, 155–165 (2020). https://doi.org/10.1007/s00213-019-05353-6

Download citation

Keywords

  • Parkinson’s disease
  • L-DOPA-induced dyskinesia
  • Dopamine 1 receptor
  • Dopamine 3 receptor
  • D1R-D3R