Advertisement

Journal of Neural Transmission

, Volume 122, Issue 9, pp 1221–1238 | Cite as

Effects of sarizotan in animal models of ADHD: challenging pharmacokinetic–pharmacodynamic relationships

  • Wojciech Danysz
  • Gunnar Flik
  • Andrew McCreary
  • Carsten Tober
  • Wilfried Dimpfel
  • Jean C. Bizot
  • Richard Kostrzewa
  • Russell W. Brown
  • Claudia C. Jatzke
  • Sergio Greco
  • Ann-Kristin Jenssen
  • Christopher G. Parsons
Translational Neurosciences - Original Article

Abstract

Sarizotan 1-[(2R)-3,4-dihydro-2H-chromen-2-yl]-N-[[5-(4-fluorophenyl) pyridin-3-yl]methyl] methenamine, showed an in vivo pharmaco-EEG profile resembling that of methylphenidate which is used in attention deficit/hyperactivity disorder (ADHD). In turn, we tested sarizotan against impulsivity in juvenile rats measuring the choice for large delayed vs. a small immediate reward in a T-maze and obtained encouraging results starting at 0.03 mg/kg (plasma levels of ~11 nM). Results from rats treated neonatally with 6-hydroxydopamine (6-OHDA), also supported anti-ADHD activity although starting at 0.3 mg/kg. However, microdialysis studies revealed that free brain concentration of sarizotan at active doses were below its affinity for 5-HT1A receptors, the assumed primary target. In contrast, electrophysiological experiments in mid-brain Raphé serotonergic cells paralleled by plasma sampling showed that there was ~60 % inhibition of firing rate—indicating significant activation of 5-HT1A receptors—at a plasma concentration of 76 nM. In line with this, we observed that sarizotan concentrations in brain homogenates were similar to total blood levels but over 500 fold higher than free extracellular fluid (ECF) concentrations as measured using brain microdialysis. These data suggest that sarizotan may have potential anti-ADHD effects at low doses free of the previously reported side-effects. Moreover, in this case a classical pharmacokinetic–pharmacodynamic relationship based on free brain concentrations seems to be less appropriate than target engagement pharmacodynamic readouts.

Keywords

5-HT1A Microdialysis Receptor occupancy Impulsivity EEG In vivo electrophysiology 

Notes

Acknowledgments

We would like to thank Anita Vanaga, Christiane Güntner and Werner Feser-Zügner for their support in sarizotan analysis in biological samples and Sabrina David and Sabine Justal for their excellent technical work in the T-maze experiment. Lutz Franke and Barbara Valastro are kindly acknowledged for their contribution to the coordination of experimental activities and providing the idea of ADHD testing respectively.

References

  1. Assie MB, Dominguez H, Consul-Denjean N, Newman-Tancredi A (2006) In vivo occupancy of dopamine D2 receptors by antipsychotic drugs and novel compounds in the mouse striatum and olfactory tubercles. Naunyn-Schmiedebergs Archiv Pharmacol 373:441–450CrossRefGoogle Scholar
  2. Bartoszyk GD, Van Amsterdam C, Greiner HE, Rautenberg W, Russ H, Seyfried CA (2004) Sarizotan, a serotonin 5-HT1A receptor agonist and dopamine receptor ligand. 1. Neurochemical profile. J Neural Trans 111:113–126CrossRefGoogle Scholar
  3. Bizot JC, Chenault N, Houze B, Herpin A, David S, Pothion S, Trovero F (2007) Methylphenidate reduces impulsive behaviour in juvenile Wistar rats, but not in adult Wistar, SHR and WKY rats. Psychopharmacology 193:215–223CrossRefPubMedGoogle Scholar
  4. Bizot JC, David S, Trovero F (2011) Effects of atomoxetine, desipramine, d-amphetamine and methylphenidate on impulsivity in juvenile rats, measured in a T-maze procedure. Neurosci Lett 489:20–24CrossRefPubMedGoogle Scholar
  5. Brus R, Kostrzewa RM, Perry KW, Fuller RW (1994) Supersensitization of the oral response to SKF 38393 in neonatal 6-hydroxydopamine-lesioned rats is eliminated by neonatal 5,7-dihydroxytryptamine treatment. J Pharmacol Exp Therap 268:231–237Google Scholar
  6. Curatolo P, Paloscia C, D’Agati E, Moavero R, Pasini A (2010) The neurobiology of attention deficit/hyperactivity disorder. Eur J Paediatr Neurol 13:299–304CrossRefGoogle Scholar
  7. Davids E, Zhang K, Tarazi FI, Baldessarini RJ (2002) Stereoselective effects of methylphenidate on motor hyperactivity in juvenile rats induced by neonatal 6-hydroxydopamine lesioning. Psychopharmacology 160:92–98CrossRefPubMedGoogle Scholar
  8. Dimpfel W (2005) Pharmacological modulation of cholinergic brain activity and its reflection in special EEG frequency ranges from various brain areas in the freely moving rat (Tele-Stereo-EEG). Eur Neuropsychopharmacol 15:673–682CrossRefPubMedGoogle Scholar
  9. Dimpfel W (2007) Characterization of atypical antipsychotic drugs by a late decrease of striatal alpha1 spectral power in the electropharmacogram of freely moving rats. Br J Pharmacol 152:538–548PubMedCentralCrossRefPubMedGoogle Scholar
  10. Dimpfel W (2008) Pharmacological modulation of dopaminergic brain activity and its reflection in spectral frequencies of the rat electropharmacogram. Neuropsychobiology 58:178–186CrossRefPubMedGoogle Scholar
  11. Dimpfel W (2013) Pharmacological classification of herbal extracts by means of comparison to spectral EEG signatures induced by synthetic drugs in the freely moving rat. J Ethnopharmacol 149:583–589CrossRefPubMedGoogle Scholar
  12. Dimpfel W, Spuler M, Koch R, Schatton W (1987) Radioelectroencephalographic comparison of memantine with receptor-specific drugs acting on dopaminergic transmission in freely moving rats. Neuropsychobiology 18:212–218CrossRefPubMedGoogle Scholar
  13. Fan X, Hess EJ (2007) D2-like dopamine receptors mediate the response to amphetamine in a mouse model of ADHD. Neurobiol Dis 26:201–211PubMedCentralCrossRefPubMedGoogle Scholar
  14. Gallemann D, Wimmer E, Hofer CC, Freisleben A, Fluck M, Ladstetter B, Dolgos H (2010) In vitro characterization of sarizotan metabolism: hepatic clearance, identification and characterization of metabolites, drug-metabolizing enzyme identification, and evaluation of cytochrome p450 inhibition. Drug Metab Dispos 38:905–916CrossRefPubMedGoogle Scholar
  15. Goetz CG, Damier P, Hicking C, Laska E, Muller T, Olanow CW, Rascol O, Russ H (2007) Sarizotan as a treatment for dyskinesias in Parkinson’s disease: a double-blind placebo-controlled trial. Mov Disord 22:179–186CrossRefPubMedGoogle Scholar
  16. Goetz CG, Laska E, Hicking C, Damier P, Muller T, Nutt J, Warren Olanow C, Rascol O, Russ H (2008) Placebo influences on dyskinesia in Parkinson’s disease. Mov Disord 23:700–707PubMedCentralCrossRefPubMedGoogle Scholar
  17. Goldman D, Lappalainen J, Ozaki N (1996) Direct analysis of candidate genes in impulsive behaviours. Ciba Found Symp 194:139–152PubMedGoogle Scholar
  18. Kollins SH (2003) Comparing the abuse potential of methylphenidate versus other stimulants: a review of available evidence and relevance to the ADHD patient. J Clin Psychiatry 64(Suppl 11):14–18PubMedGoogle Scholar
  19. Kostrzewa RM, Gong L (1991) Supersensitized D1 receptors mediate enhanced oral activity after neonatal 6-OHDA. Pharmacol Biochem Behav 39:677–682CrossRefPubMedGoogle Scholar
  20. Kostrzewa RM, Brus R, Kalbfleisch JH, Perry KW, Fuller RW (1994) Proposed animal model of attention deficit hyperactivity disorder. Brain Res Bull 34:161–167CrossRefPubMedGoogle Scholar
  21. Kostrzewa RM, Kostrzewa JP, Kostrzewa RA, Nowak P, Brus R (2008) Pharmacological models of ADHD. J Neural Trans 115:287–298CrossRefGoogle Scholar
  22. Krosser S, Tillner J, Fluck M, Ungethum W, Wolna P, Kovar A (2007) Pharmacokinetics of sarizotan after oral administration of single and repeat doses in healthy subjects. Int J Clin Pharmacol Ther 45:271–280CrossRefPubMedGoogle Scholar
  23. Kuenzel HE, Steiger A, Held K, Antonijevic IA, Frieboes RM, Murck H (2005) Changes in sleep electroencephalogram and nocturnal hormone secretion after administration of the antidyskinetic agent sarizotan in healthy young male volunteers. Psychopharmacology 180:327–332CrossRefPubMedGoogle Scholar
  24. Kuzhikandathil EV, Bartoszyk GD (2006) The novel antidyskinetic drug sarizotan elicits different functional responses at human D2-like dopamine receptors. Neuropharmacology 51:873–884CrossRefPubMedGoogle Scholar
  25. Kuzhikandathil EV, Oxford GS (2002) Classic D1 dopamine receptor antagonist R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-13H-benzaze pine hydrochloride (SCH23390) directly inhibits G protein-coupled inwardly rectifying potassium channels. Mol Pharmacol 62:119–126CrossRefPubMedGoogle Scholar
  26. Leo D, Adriani W, Cavaliere C, Cirillo G, Marco EM, Romano E, di Porzio U, Papa M, Perrone-Capano C, Laviola G (2009) Methylphenidate to adolescent rats drives enduring changes of accumbal Htr7 expression: implications for impulsive behavior and neuronal morphology. Genes Brain Behav 8:356–368CrossRefPubMedGoogle Scholar
  27. Markowitz JS, DeVane CL, Pestreich LK, Patrick KS, Muniz R (2006) A comprehensive in vitro screening of d-, l-, and dl-threo-methylphenidate: an exploratory study. J Child Adolesc Psychopharmacol 16:687–698CrossRefPubMedGoogle Scholar
  28. May DE, Kratochvil CJ (2010) Attention-deficit hyperactivity disorder: recent advances in paediatric pharmacotherapy. Drugs 70:15–40CrossRefPubMedGoogle Scholar
  29. Newman-Tancredi A, Assie MB, Leduc N, Ormiere AM, Danty N, Cosi C (2005) Novel antipsychotics activate recombinant human and native rat serotonin 5-HT1A receptors: affinity, efficacy and potential implications for treatment of schizophrenia. Int J Neuropsychopharmacol 8:341–356CrossRefPubMedGoogle Scholar
  30. Oades RD (2008) Dopamine-serotonin interactions in attention-deficit hyperactivity disorder (ADHD). Prog Brain Res 172:543–565CrossRefPubMedGoogle Scholar
  31. Olanow CW, Damier P, Goetz CG, Mueller T, Nutt J, Rascol O, Serbanescu A, Deckers F, Russ H (2004) Multicenter, open-label, trial of sarizotan in Parkinson disease patients with levodopa-induced dyskinesias (the SPLENDID Study). Clin Neuropharmacol 27:58–62CrossRefPubMedGoogle Scholar
  32. Park YH, Lee KK, Kwon HJ, Ha M, Kim EJ, Yoo SJ, Paik KC, Lim MH (2013) Association between HTR1A gene polymorphisms and attention deficit hyperactivity disorder in Korean children. Genet Test Mol Biomarkers 17:178–182CrossRefPubMedGoogle Scholar
  33. Pattij T, Vanderschuren LJ (2008) The neuropharmacology of impulsive behaviour. Trends Pharmacol Sci 29:192–199CrossRefPubMedGoogle Scholar
  34. Paxinos G, Watson C (1986) The rats brain in stereotaxic coordinates. Academic Press, Nww YorkGoogle Scholar
  35. Rabiner EA, Gunn RN, Wilkins MR, Sedman E, Grasby PM (2002) Evaluation of EMD 128 130 occupancy of the 5-HT1A and the D2 receptor: a human PET study with [11C]WAY-100635 and [11C]raclopride. J Psychopharmacol 16:195–199CrossRefPubMedGoogle Scholar
  36. Rascol O, Damier P, Goetz C, Hicking C, Hock K, Müller T, Olanow W, Russ H (2006) A large phase III study to evaluate the SAFETY and Efficacy of Sarizotan in the Treatment of Levodopa-induced Dyskinesia Associated with Parkinson´s Disease—the PADDY-1 Study. Movement Disorders. 10th International Congress of Parkinson’s Disease and Movement Disorders, Kyoto, JapanGoogle Scholar
  37. Russell VA (2007) Neurobiology of animal models of attention-deficit hyperactivity disorder. J Neurosci Methods 161:185–198CrossRefPubMedGoogle Scholar
  38. Tripp G, Wickens JR (2009) Neurobiology of ADHD. Neuropharmacology 57:579–589CrossRefPubMedGoogle Scholar
  39. Valastro B (2012) Sarizotan for use in the treatment of attention deficit hyperactivity disorder (adhd). Google PatentsGoogle Scholar
  40. Yates JR, Perry JL, Meyer AC, Gipson CD, Charnigo R, Bardo MT (2014) Role of medial prefrontal and orbitofrontal monoamine transporters and receptors in performance in an adjusting delay discounting procedure. Brain Res 1574:26–36PubMedCentralCrossRefPubMedGoogle Scholar
  41. Zhang K, Davids E, Tarazi FI, Baldessarini RJ (2002) Effects of dopamine D4 receptor-selective antagonists on motor hyperactivity in rats with neonatal 6-hydroxydopamine lesions. Psychopharmacology 161:100–106CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Wien 2015

Authors and Affiliations

  • Wojciech Danysz
    • 1
  • Gunnar Flik
    • 2
  • Andrew McCreary
    • 2
  • Carsten Tober
    • 3
  • Wilfried Dimpfel
    • 4
  • Jean C. Bizot
    • 5
  • Richard Kostrzewa
    • 6
  • Russell W. Brown
    • 6
  • Claudia C. Jatzke
    • 1
  • Sergio Greco
    • 1
  • Ann-Kristin Jenssen
    • 1
  • Christopher G. Parsons
    • 1
  1. 1.Merz Pharmaceuticals GmbHFrankfurt/MainGermany
  2. 2.Brains On-Line B.V.GroningenThe Netherlands
  3. 3.Rent-a-labReutlingenGermany
  4. 4.NeuroCode AGWetzlarGermany
  5. 5.Key-Obs SASOrléans Cedex 02France
  6. 6.Quillen College of MedicineEast Tennessee State UniversityJohnsonUSA

Personalised recommendations