The effect of nicotine in combination with various dopaminergic drugs on nigrostriatal dopamine in rats

  • Sanna Janhunen
  • Paula Mielikäinen
  • Päivi Paldánius
  • Raimo K. Tuominen
  • Liisa AhteeEmail author
  • Seppo Kaakkola
Original Article


It is well established that nicotine activates brain dopaminergic systems and in addition has neuroprotective actions. Thus, nicotinic acetylcholine receptor (nAChR) agonists might be beneficial in the treatment of Parkinson’s disease, and it is important to study the interactions of nicotine with drugs affecting the nigrostriatal dopaminergic pathway. We used brain microdialysis to study the effects of nicotine on extracellular levels of dopamine (DA) and its metabolites in the rat dorsal striatum in combination with drugs inhibiting either DA uptake (nomifensine), catechol-O-methyltransferase (COMT; tolcapone), monoamine oxidase B (MAO-B; selegiline) or DA receptors (haloperidol). Nicotine (0.5 mg/kg, s.c.) modestly increased DA output, and this effect was antagonised by mecamylamine but not by hexamethonium. Nomifensine (3 mg/kg, i.p.) substantially further enhanced the nicotine-induced increase in DA output and nomifensine+nicotine also evoked a strong mecamylamine-sensitive ipsilateral rotational behaviour in 6-hydroxydopamine lesioned rats. Tolcapone (10 mg/kg, i.p.) did not alter DA output, but markedly decreased homovanillic acid (HVA) and increased 3,4-dihydroxyphenylacetic acid (DOPAC). Selegiline pretreatment (5×1 mg/kg, i.p.) significantly increased extracellular DA and decreased DOPAC and HVA. Haloperidol (0.1 mg/kg, s.c.) slightly increased DA output and more clearly DOPAC and HVA. Tolcapone, selegiline or haloperidol did not enhance the nicotine-induced DA output. These results indicate that the activation of nigrostriatal nAChRs induces a significant DA release in the striatum, which is potentiated by DA uptake inhibition but not by COMT, MAO-B or presynaptic DA receptor inhibition. Our findings therefore agree with the notion that the termination of the effect of DA in the synapse mainly occurs via neuronal reuptake. Thus, selective nAChR agonists, possibly in combination with a DA uptake inhibitor, might improve dopaminergic transmission in Parkinson’s disease.


Nicotine Nomifensine Tolcapone Selegiline Haloperidol Extracellular dopamine Rotational behaviour 



This study was supported by grants from the Helsinki University Central Hospital, the Sigrid Jusélius Foundation and the University of Helsinki’s Research Funds. The excellent technical assistance of Ms. Marjo Vaha is gratefully acknowledged.


  1. Allam MF, Campbell MJ, Hofman A, Del Castillo AS, Fernandez-Crehuet Navajas R (2004) Smoking and Parkinson’s disease: systematic review of prospective studies. Mov Disord 19:614–621PubMedGoogle Scholar
  2. Arqueros L, Naquira D, Zunino E (1978) Nicotine-induced release of catecholamines from rat hippocampus and striatum. Biochem Pharmacol 27:2667–2674PubMedGoogle Scholar
  3. Arroyo-Jimenez MM, Bourgeois JP, Marubio LM, Le Sourd AM, Ottersen OP, Rinvik E, Fairen A, Changeux JP (1999) Ultrastructural localization of the alpha4-subunit of the neuronal acetylcholine nicotinic receptor in the rat substantia nigra. J Neurosci 19:6475–6487PubMedGoogle Scholar
  4. Azam L, Winzer-Serhan UH, Chen Y, Leslie FM (2002) Expression of neuronal nicotinic acetylcholine receptor subunit mRNAs within midbrain dopamine neurons. J Comp Neurol 444:260–274PubMedGoogle Scholar
  5. Balfour DJ, Fagerström KO (1996) Pharmacology of nicotine and its therapeutic use in smoking cessation and neurodegenerative disorders. Pharmacol Ther 72:51–81PubMedGoogle Scholar
  6. Baron JA (1986) Cigarette smoking and Parkinson’s disease. Neurology 36:1490–1496PubMedGoogle Scholar
  7. Benwell ME, Balfour DJ (1992) The effects of acute and repeated nicotine treatment on nucleus accumbens dopamine and locomotor activity. Br J Pharmacol 105:849–856PubMedGoogle Scholar
  8. Brazell MP, Mitchell SN, Joseph MH, Gray JA (1990) Acute administration of nicotine increases the in vivo extracellular levels of dopamine, 3,4-dihydroxyphenylacetic acid and ascorbic acid preferentially in the nucleus accumbens of the rat: comparison with caudate-putamen. Neuropharmacology 29:1177–1185PubMedGoogle Scholar
  9. Butcher SP, Fairbrother IS, Kelly JS, Arbuthnott GW (1990) Effects of selective monoamine oxidase inhibitors on the in vivo release and metabolism of dopamine in the rat striatum. J Neurochem 55:981–988PubMedGoogle Scholar
  10. Butcher SP, Liptrot J, Aburthnott GW (1991) Characterisation of methylphenidate and nomifensine induced dopamine release in rat striatum using in vivo brain microdialysis. Neurosci Lett 122:245–248PubMedGoogle Scholar
  11. Carboni E, Imperato A, Perezzani L, Di Chiara G (1989) Amphetamine, cocaine, phencyclidine and nomifensine increase extracellular dopamine concentrations preferentially in the nucleus accumbens of freely moving rats. Neuroscience 28:653–661PubMedGoogle Scholar
  12. Church WH, Justice JB Jr, Byrd LD (1987) Extracellular dopamine in rat striatum following uptake inhibition by cocaine, nomifensine and benztropine. Eur J Pharmacol 139:345–348PubMedGoogle Scholar
  13. Clarke PB, Pert A (1985) Autoradiographic evidence for nicotine receptors on nigrostriatal and mesolimbic dopaminergic neurons. Brain Res 348:355–358PubMedGoogle Scholar
  14. Clarke PB, Hommer DW, Pert A, Skirboll LR (1987) Innervation of substantia nigra neurons by cholinergic afferents from pedunculopontine nucleus in the rat: neuroanatomical and electrophysiological evidence. Neuroscience 23:1011–1019PubMedGoogle Scholar
  15. Clemens P, Baron JA, Coffey D, Reeves A (1995) The short-term effect of nicotine chewing gum in patients with Parkinson’s disease. Psychopharmacology 117:253–256PubMedGoogle Scholar
  16. Court J, Clementi F (1995) Distribution of nicotinic subtypes in human brain. Alzheimer Dis Assoc Disord 9 [Suppl 2]:6–14Google Scholar
  17. Damsma G, Westerink BH, de Vries JB, Horn AS (1988) The effect of systemically applied cholinergic drugs on the striatal release of dopamine and its metabolites, as determined by automated brain dialysis in conscious rats. Neurosci Lett 89:349–354PubMedGoogle Scholar
  18. Di Chiara G, Imperato A (1988) Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats. Proc Natl Acad Sci U S A 85:5274–5278PubMedGoogle Scholar
  19. Domino EF, Ni L, Zhang H (1999) Nicotine alone and in combination with L-DOPA methyl ester or the D(2) agonist N-0923 in MPTP-induced chronic hemiparkinsonian monkeys. Exp Neurol 158:414–421PubMedGoogle Scholar
  20. Drew KL, O’Connor WT, Kehr J, Ungerstedt U (1990) Regional specific effects of clozapine and haloperidol on GABA and dopamine release in rat basal ganglia. Eur J Pharmacol 187:385–397PubMedGoogle Scholar
  21. Ebersbach G, Stock M, Muller J, Wenning G, Wissel J, Poewe W (1999) Worsening of motor performance in patients with Parkinson’s disease following transdermal nicotine administration. Mov Disord 14:1011–1013PubMedGoogle Scholar
  22. Fagerström KO, Pomerleau O, Giordani B, Stelson F (1994) Nicotine may relieve symptoms of Parkinson’s disease. Psychopharmacology 116:117–119PubMedGoogle Scholar
  23. Ferger B, Kuschinsky K (1997) Biochemical studies support the assumption that dopamine plays a minor role in the EEG effects of nicotine. Psychopharmacology 129:192–196PubMedGoogle Scholar
  24. Futami T, Takakusaki K, Kitai ST (1995) Glutamatergic and cholinergic inputs from the pedunculopontine tegmental nucleus to dopamine neurons in the substantia nigra pars compacta. Neurosci Res 21:331–342PubMedGoogle Scholar
  25. Gerasimov MR, Franceschi M, Volkow ND, Rice O, Schiffer WK, Dewey SL (2000) Synergistic interactions between nicotine and cocaine or methylphenidate depend on the dose of dopamine transporter inhibitor. Synapse 38:432–437PubMedGoogle Scholar
  26. Giorguieff-Chesselet MF, Kemel ML, Wandscheer D, Glowinski J (1979) Regulation of dopamine release by presynaptic nicotinic receptors in rat striatal slices: effect of nicotine in a low concentration. Life Sci 25:1257–1262PubMedGoogle Scholar
  27. Gorell JM, Rybicki BA, Johnson CC, Peterson EL (1999) Smoking and Parkinson’s disease: a dose-response relationship. Neurology 52:115–119PubMedGoogle Scholar
  28. Grady SR, Marks MJ, Collins AC (1994) Desensitization of nicotine-stimulated [3H]dopamine release from mouse striatal synaptosomes. J Neurochem 62:1390–1398PubMedGoogle Scholar
  29. Haikala H (1987) Use of a novel type of rotating disc electrode and a flow cell with laminar flow pattern for the electrochemical detection of biogenic monoamines and their metabolites after Sephadex gel chromatographic purification and high-performance liquid chromatographic isolation from rat brain. J Neurochem 49:1033–1041PubMedGoogle Scholar
  30. Hoffmann I (1982) Pharmacology of nomifensine. Int Pharmacopsychiatry 17 [Suppl]:4–20PubMedGoogle Scholar
  31. Huotari M, Gainetdinov R, Mannisto PT (1999) Microdialysis studies on the action of tolcapone on pharmacologically-elevated extracellular dopamine levels in conscious rats. Pharmacol Toxicol 85:233–238PubMedGoogle Scholar
  32. Huotari M, Santha M, Lucas LR, Karayiorgou M, Gogos JA, Mannisto PT (2002) Effect of dopamine uptake inhibition on brain catecholamine levels and locomotion in catechol-O-methyltransferase-disrupted mice. J Pharmacol Exp Ther 303:1309–1316PubMedGoogle Scholar
  33. Imperato A, Mulas A, Di Chiara G (1986) Nicotine preferentially stimulates dopamine release in the limbic system of freely moving rats. Eur J Pharmacol 132:337–338PubMedGoogle Scholar
  34. Janhunen S, Kaakkola S, Tuominen RK, Ahtee L (2001) Nicotine induces rotation in combination with nomifensine in unilaterally 6-hydroxydopamine lesioned rats. Parkinsonism Relat Disord 7 [Suppl 1]:559Google Scholar
  35. Kaakkola S (1980) Contralateral circling behaviour induced by intranigral injection of morphine and enkephalin analogue FK 33-824 in rats. Acta Pharmacol Toxicol 47:385–393Google Scholar
  36. Kaakkola S (2000) Clinical pharmacology, therapeutic use and potential of COMT inhibitors in Parkinson’s disease. Drugs 59:1233–1250PubMedGoogle Scholar
  37. Kaakkola S, Wurtman RJ (1992) Effects of COMT inhibitors on striatal dopamine metabolism: a microdialysis study. Brain Res 587:241–249PubMedGoogle Scholar
  38. Kaakkola S, Wurtman RJ (1993) Effects of catechol-O-methyltransferase inhibitors and L-3,4-dihydroxyphenylalanine with or without carbidopa on extracellular dopamine in rat striatum. J Neurochem 60:137–144PubMedGoogle Scholar
  39. Kaakkola SK, Tuominen RK, Mielikäinen P, Paldanius P, Ahtee L (2000) Effects of nomifensine and tolcapone on nicotine-induced dopamine release in rat striatum. Soc Neurosci Abstr 26:900Google Scholar
  40. Kaiser S, Wonnacott S (2000) Alpha-bungarotoxin-sensitive nicotinic receptors indirectly modulate [3H]dopamine release in rat striatal slices via glutamate release. Mol Pharmacol 58:312–318PubMedGoogle Scholar
  41. Kelton MC, Kahn HJ, Conrath CL, Newhouse PA (2000) The effects of nicotine on Parkinson’s disease. Brain Cogn 43:274–282PubMedGoogle Scholar
  42. Klink R, de Kerchove d’Exaerde A, Zoli M, Changeux JP (2001) Molecular and physiological diversity of nicotinic acetylcholine receptors in the midbrain dopaminergic nuclei. J Neurosci 21:1452–1463PubMedGoogle Scholar
  43. Kulak JM, Musachio JL, McIntosh JM, Quik M (2002) Declines in different β2* nicotinic receptor populations in monkey striatum after nigrostriatal damage. J Pharmacol Exp Ther 303:633–639PubMedGoogle Scholar
  44. Lamensdorf I, Youdim MB, Finberg JP (1996) Effect of long-term treatment with selective monoamine oxidase A and B inhibitors on dopamine release from rat striatum in vivo. J Neurochem 67:1532–1539PubMedGoogle Scholar
  45. Lamensdorf I, Porat S, Simantov R, Finberg JP (1999) Effect of low-dose treatment with selegiline on dopamine transporter (DAT) expression and amphetamine-induced dopamine release in vivo. Br J Pharmacol 126:997–1002PubMedGoogle Scholar
  46. Marks MJ, Grady SR, Collins AC (1993) Downregulation of nicotinic receptor function after chronic nicotine infusion. J Pharmacol Exp Ther 266:1268–1276PubMedGoogle Scholar
  47. Marshall DL, Redfern PH, Wonnacott S (1997) Presynaptic nicotinic modulation of dopamine release in the three ascending pathways studied by in vivo microdialysis: comparison of naive and chronic nicotine-treated rats. J Neurochem 68:1511–1519PubMedGoogle Scholar
  48. Marshall J, Schnieden H (1966) Effect of adrenaline, noradrenaline, atropine, and nicotine on some types of human tremor. J Neurol Neurosurg Psychiatry 29:214–218PubMedGoogle Scholar
  49. Menzaghi F, Whelan KT, Risbrough VB, Rao TS, Lloyd GK (1997) Interactions between a novel cholinergic ion channel agonist, SIB-1765F and L-DOPA in the reserpine model of Parkinson’s disease in rats. J Pharmacol Exp Ther 280:393–401PubMedGoogle Scholar
  50. Mihailescu S, Drucker-Colin R (2000) Nicotine, brain nicotinic receptors, and neuropsychiatric disorders. Arch Med Res 31:131–144PubMedGoogle Scholar
  51. Morens DM, Grandinetti A, Reed D, White LR, Ross GW (1995) Cigarette smoking and protection from Parkinson’s disease: false association or etiologic clue? Neurology 45:1041–1051PubMedGoogle Scholar
  52. Nakachi N, Kiuchi Y, Inagaki M, Inazu M, Yamazaki Y, Oguchi K (1995) Effects of various dopamine uptake inhibitors on striatal extracellular dopamine levels and behaviours in rats. Eur J Pharmacol 281:195–203PubMedGoogle Scholar
  53. O’Connor WT, Drew KL, Ungerstedt U (1995) Differential cholinergic regulation of dopamine release in the dorsal and ventral neostriatum of the rat: an in vivo microdialysis study. J Neurosci 15:8353–8361PubMedGoogle Scholar
  54. Paxinos G, Watson C (1986) The rat brain in stereotaxic coordinates, vol 2. Academic, New YorkGoogle Scholar
  55. Pietilä K, Laakso I, Ahtee L (1995) Chronic oral nicotine administration affects the circadian rhythm of dopamine and 5-hydroxytryptamine metabolism in the striata of mice. Naunyn-Schmiedebergs Arch Pharmacol 353:110–115PubMedGoogle Scholar
  56. Pietilä K, Salminen O, Leikola-Pelho T, Ahtee L (1996) Tolerance to nicotine’s effects on striatal dopamine metabolism in nicotine-withdrawn mice. Eur J Pharmacol 318:17–22PubMedGoogle Scholar
  57. Quik M (2004) Smoking, nicotine and Parkinson’s disease. Trends Neurosci 27:561–568PubMedGoogle Scholar
  58. Quik M, Kulak JA (2002) Nicotine and nicotinic receptors; relevance to Parkinson’s disease. Neurotoxicology 23:581–594PubMedGoogle Scholar
  59. Quik M, Polonskaya Y, Gillespie A, Lloyd GK, Langston JW (2000) Differential alterations in nicotinic receptor alpha6 and beta3 subunit messenger RNAs in monkey substantia nigra after nigrostriatal degeneration. Neuroscience 100:63–72PubMedGoogle Scholar
  60. Quik M, Polonskaya Y, McIntosh JM, Kulak JM (2002) Differential nicotinic receptor expression in monkey basal ganglia: effects of nigrostriatal damage. Neuroscience 112:619–630PubMedGoogle Scholar
  61. Quik M, Sum JD, Whiteaker P, McCallum SE, Marks MJ, Musachio J, McIntosh JM, Collins AC, Grady SR (2003) Differential declines in striatal nicotinic receptor subtype function after nigrostriatal damage in mice. Mol Pharmacol 63:1169–1179PubMedGoogle Scholar
  62. Raevskii KS, Gainetdinov RR, Budygin EA, Mannisto P, Wightman M (2002) Dopaminergic transmission in the rat striatum in vivo in conditions of pharmacological modulation. Neurosci Behav Physiol 32:183–188PubMedGoogle Scholar
  63. Rapier C, Lunt GG, Wonnacott S (1990) Nicotinic modulation of [3H]dopamine release from striatal synaptosomes: pharmacological characterisation. J Neurochem 54:937–945PubMedGoogle Scholar
  64. Rowell PP (1995) Nanomolar concentrations of nicotine increase the release of [3H]dopamine from rat striatal synaptosomes. Neurosci Lett 189:171–175PubMedGoogle Scholar
  65. Rusted JM, Newhouse PA, Levin ED (2000) Nicotinic treatment for degenerative neuropsychiatric disorders such as Alzheimer’s disease and Parkinson’s disease. Behav Brain Res 113:121–129PubMedGoogle Scholar
  66. Sacaan AI, Menzaghi F, Dunlop JL, Correa LD, Whelan KT, Lloyd GK (1996) Epibatidine: a nicotinic acetylcholine receptor agonist releases monoaminergic neurotransmitters: in vitro and in vivo evidence in rats. J Pharmacol Exp Ther 276:509–515PubMedGoogle Scholar
  67. Sakurai Y, Takano Y, Kohjimoto Y, Honda K, Kamiya HO (1982) Enhancement of [3H]dopamine release and its [3H]metabolites in rat striatum by nicotinic drugs. Brain Res 242:99–106PubMedGoogle Scholar
  68. Salminen O, Murphy KL, McIntosh JM, Drago J, Marks MJ, Collins AC, Grady SR (2004) Subunit composition and pharmacology of two classes of striatal presynaptic nicotinic acetylcholine receptors mediating dopamine release in mice. Mol Pharmacol 65:1526–1535PubMedGoogle Scholar
  69. Schiffer WK, Azmoodeh M, Gerasimov M, Volkow ND, Fowler JS, Dewey SL (2003) Selegiline potentiates cocaine-induced increases in rodent nucleus accumbens dopamine. Synapse 48:35–38PubMedGoogle Scholar
  70. Schneider JS, Pope-Coleman A, Van Velson M, Menzaghi F, Lloyd GK (1998) Effects of SIB-1508Y, a novel neuronal nicotinic acetylcholine receptor agonist, on motor behavior in parkinsonian monkeys. Mov Disord 13:637–642PubMedGoogle Scholar
  71. Seppä T, Ahtee L (2000) Comparison of the effects of epibatidine and nicotine on the output of dopamine in the dorsal and ventral striatum of freely-moving rats. Naunyn-Schmiedebergs Arch Pharmacol 362:444–447PubMedGoogle Scholar
  72. Seppä T, Ruotsalainen M, Laakso I, Tuominen R, Ahtee L (2000) Effect of acute nicotine administration on striatal dopamine output and metabolism in rats kept at different ambient temperatures. Br J Pharmacol 130:1147–1155PubMedGoogle Scholar
  73. Serova L, Sabban EL (2002) Involvement of alpha 7 nicotinic acetylcholine receptors in gene expression of dopamine biosynthetic enzymes in rat brain. J Pharmacol Exp Ther 303:896–903PubMedGoogle Scholar
  74. Sorenson EM, Shiroyama T, Kitai ST (1998) Postsynaptic nicotinic receptors on dopaminergic neurons in the substantia nigra pars compacta of the rat. Neuroscience 87:659–673PubMedGoogle Scholar
  75. Teng L, Crooks PA, Buxton ST, Dwoskin LP (1997) Nicotinic-receptor mediation of S(-)nornicotine-evoked -3H-overflow from rat striatal slices preloaded with -3H-dopamine. J Pharmacol Exp Ther 283:778–787PubMedGoogle Scholar
  76. Toth E, Sershen H, Hashim A, Vizi ES, Lajtha A (1992) Effect of nicotine on extracellular levels of neurotransmitters assessed by microdialysis in various brain regions: role of glutamic acid. Neurochem Res 17:265–271PubMedGoogle Scholar
  77. Vernier JM, Holsenback H, Cosford ND, Whitten JP, Menzaghi F, Reid R, Rao TS, Sacaan AI, Lloyd GK, Suto CM, Chavez-Noriega LE, Washburn MS, Urrutia A, McDonald IA (1998) Conformationally restricted analogues of nicotine and anabasine. Bioorg Med Chem Lett 8:2173–2178PubMedGoogle Scholar
  78. Vieregge A, Sieberer M, Jacobs H, Hagenah JM, Vieregge P (2001) Transdermal nicotine in PD: a randomized, double-blind, placebo-controlled study. Neurology 57:1032–1035PubMedGoogle Scholar
  79. Villafane G, Degos J-D, Lagrue G, Cesaro P (2001) Long-term nicotine treatment in Parkinson’s disease: report of a case. Parkinsonism Relat Disord 7 [Suppl 1]:S73Google Scholar
  80. Westerink BH, de Vries JB (1989) On the mechanism of neuroleptic induced increase in striatal dopamine release: brain dialysis provides direct evidence for mediation by autoreceptors localized on nerve terminals. Neurosci Lett 99:197–202PubMedGoogle Scholar
  81. Westfall TC (1974) Effect of nicotine and other drugs on the release of 3H-norepinephrine and 3H-dopamine from rat brain slices. Neuropharmacology 13:693–700PubMedGoogle Scholar
  82. Whiteaker P, Garcha HS, Wonnacott S, Stolerman IP (1995) Locomotor activation and dopamine release produced by nicotine and isoarecolone in rats. Br J Pharmacol 116:2097–2105PubMedGoogle Scholar
  83. Wonnacott S (1997) Presynaptic nicotinic ACh receptors. Trends Neurosci 20:92–98PubMedGoogle Scholar
  84. Wonnacott S, Kaiser S, Mogg A, Soliakov L, Jones IW (2000) Presynaptic nicotinic receptors modulating dopamine release in the rat striatum. Eur J Pharmacol 393:51–58PubMedGoogle Scholar
  85. Wu WR, Zhu ZT, Zhu XZ (2000) Differential effects of L-deprenyl on MPP+- and MPTP-induced dopamine overflow in microdialysates of striatum and nucleus accumbens. Life Sci 67:241–250PubMedGoogle Scholar
  86. Yahr MD, Mendoza MR, Moros D, Bergmann KJ (1983) Treatment of Parkinson’s disease in early and late phases. Use of pharmacological agents with special reference to deprenyl (selegiline). Acta Neurol Scand Suppl 95:95–102PubMedGoogle Scholar
  87. Zdonczyk D, Royse V, Koller WC (1988) Nicotine and tremor. Clin Neuropharmacol 11:282–286PubMedGoogle Scholar
  88. Zhou FM, Liang Y, Dani JA (2001) Endogenous nicotinic cholinergic activity regulates dopamine release in the striatum. Nat Neurosci 4:1224–1229PubMedGoogle Scholar
  89. Zoli M, Moretti M, Zanardi A, McIntosh JM, Clementi F, Gotti C (2002) Identification of the nicotinic receptor subtypes expressed on dopaminergic terminals in the rat striatum. J Neurosci 22:8785–8789PubMedGoogle Scholar
  90. Zürcher G, Dingemanse J, Da Prada M (1993) Potent COMT inhibition by Ro 40-7592 in the periphery and in the brain. Preclinical and clinical findings. Adv Neurol 60:641–647PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  • Sanna Janhunen
    • 1
  • Paula Mielikäinen
    • 1
  • Päivi Paldánius
    • 1
  • Raimo K. Tuominen
    • 1
  • Liisa Ahtee
    • 1
    Email author
  • Seppo Kaakkola
    • 2
  1. 1.Division of Pharmacology and Toxicology, Faculty of PharmacyUniversity of HelsinkiHelsinkiFinland
  2. 2.Department of NeurologyUniversity of HelsinkiHelsinkiFinland

Personalised recommendations