Naunyn-Schmiedeberg's Archives of Pharmacology

, Volume 368, Issue 5, pp 342–351 | Cite as

The α2-adrenoceptor antagonist atipamezole potentiates anti-Parkinsonian effects and can reduce the adverse cardiovascular effects of dopaminergic drugs in rats

  • Antti Haapalinna
  • Tiina Leino
  • Esa Heinonen
Original Article


The present experiments investigated the effects of the specific α2-adrenoceptor antagonist atipamezole, alone and in combination with a dopamine agonist, on motor function in rats with a unilateral 6-hydroxydopamine lesion of the nigro-striatal pathway and on exploratory behaviour and cardiovascular function in rats equipped with telemetry transmitters. Dexmedetomidine, an α2-adrenoceptor agonist and the α2-adrenoceptor antagonists idazoxan and yohimbine were used as reference compounds. In the unilaterally lesioned animals, direct dopamine agonists, such as apomorphine, induce contralateral turning behaviour. Indirect agonists, such as amphetamine, induce ipsilateral circling in the animals. Atipamezole (0.3 mg/kg s.c) potentiated and dexmedetomidine (10 µg/kg s.c.) decreased contralateral circling evoked by apomorphine (50 µg/kg s.c.) and by l-3,4-dihydroxyphenylalanine (L-DOPA, 5 mg/kg i.p.). Atipamezole also prolonged the duration of action of L-DOPA. Atipamezole dose-dependently induced ipsilateral turning behaviour and potentiated turning induced by amphetamine (1 mg/kg i.p.). The α1-adrenoceptor antagonist prazosin (0.1 mg/kg i.p.) partially antagonised the effect of amphetamine and had a strong inhibitory effect on the atipamezole-induced potentiation of the amphetamine response. Prazosin did not have any major effect on either the apomorphine response itself or on the potentiation of the apomorphine response by atipamezole. This suggests that atipamezole can modulate motor function both indirectly, by stimulating the release of noradrenaline and directly, by blocking postsynaptic α2-adrenoceptors in neurones other than noradrenergic nerves. The α2-adrenoceptor antagonists, when tested at comparably effective central α2-adrenoceptor antagonising doses in a rat mydriasis model: atipamezole 0.3 mg/kg s.c., idazoxan 1 mg/kg s.c. and yohimbine 3 mg/kg s.c., all induced ipsilateral turning behaviour and potentiated apomorphine-induced contralateral circling. The effects of the α2-adrenoceptor antagonists were in general similar in these experiments. In habituated non-lesioned rats equipped with telemetry transmitters, apomorphine (50 µg/kg s.c.) decreased blood pressure in the home cage and in an open-field test. It also decreased spontaneous motor activity in the open field. Neither atipamezole (0.3 mg/kg s.c.) nor idazoxan (1 mg/kg s.c.) had any effect on blood pressure when given alone, but reversed the apomorphine-induced decrease in blood pressure. Atipamezole also diminished apomorphine-induced sedation in the open-field test. In conclusion, atipamezole improved the efficacy of L-DOPA and apomorphine in an animal model of Parkinson’s disease and also reduced adverse dopaminergic effects on vigilance and on cardiovascular function. These results suggest that an investigation of the effects of specific α2-adrenoceptor antagonists in Parkinson’s disease patients is warranted.


α2-Adrenoceptor antagonist Dopaminergic Substantia nigra Parkinson’s disease Telemetry Cardiovascular responses Motor activity 



We would like to thank Ms. A. Alatupa for her experienced technical assistance and Ms. K. Svärd and Mr. M. Makkonen for design and preparing the rotometer apparatuses used in the tests. Dr. J Sirviö and Dr. E. MacDonald are acknowledged for professional discussions and for revising the language of the manuscript.


  1. Brannan T, Martinez-Tica J, Yahr MD (1991) Effect of yohimbine on brain monoamines: an in vivo study. J Neural Transm 3:81–87Google Scholar
  2. Brefel-Courbon C, Thalamas C, Peyro Saint Paul H, Senard J-M, Montastruc J-L, Rascol O (1998) α2-Adrenoceptor antagonists. A new approach to Parkinson’s disease? CNS Drugs 10:189–207Google Scholar
  3. Brotchie JM (1998) Adjuncts to dopamine replacement: a pragmatic approach to reducing the problem of dyskinesia in the Parkinson’s disease. Mov Disord 13:871–876PubMedGoogle Scholar
  4. Brown WD, Taylor MD, Roberts AD, Oakes TR, Schueller MJ, Holden JE, Malischke BS, DeJesus OT, Nicles RJ (1999) FluoroDOPA PET shows the nondopamineergic as well as dopaminergic destinations of levodopa. Neurology 53:1212–1218PubMedGoogle Scholar
  5. Bucheler M, Hadamek K, Hein L (2002) Two α2-adrenergic receptors subtypes, α2A and α2C, inhibit transmitter release in the brain of gene targeted mice. Neuroscience 109:819–826CrossRefPubMedGoogle Scholar
  6. Calne DB, Brennan J, Spiers ASD, Stern GM (1970) Hypotension caused by L-DOPA. Br Med J:474–475Google Scholar
  7. Chamienia AL, Johns EJ (1996) The cardiovascular and renal functional responses to the 5-HT1A receptor agonist flesinoxan in two rat models of hypertension. Br J Pharmacol 118:1891–1898PubMedGoogle Scholar
  8. Chopin P, Colpaert FC, Marien M (1999) Effects of alpha-2 adrenoceptor agonists and antagonists on circling behavior in rats with unilateral 6-hydroxydopamine lesion of the nigrostriatal pathway. J Pharmacol Exp Ther 288:789–804Google Scholar
  9. Dickinson SL, Gadie B, Tulloch IF (1990) Specific α2-adrenoreceptor antagonists induce behavioural activation in the rat. J Psychopharmacol 4:90–99Google Scholar
  10. Dooley DJ, Bittiger H, Hauser KL, Bischoff SF, Waldmeier PC (1983) Alteration of central alpha2- and beta-adrenergic receptors in the rat after DSP-4, a selective noradrenergic neurotoxin. Neuroscience 9:889–898PubMedGoogle Scholar
  11. Eldrup E, Morgensen P, Jacobsen J, Pakkenberg H, Christensen NJ (1995) CSF and plasma concentrations of free norepinephrine, dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC), 3,4-dihydroxyphenylalanine (DOPA), and epinephrine in Parkinson’s disease. Acta Neurol Scand 92:116–121PubMedGoogle Scholar
  12. Engberg G, Eriksson E (1991) Effects of α2-adrenoceptor agonists on locus coeruleus firing rate and brain noradrenaline turnover in N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ)-treated rats. Naunyn-Schmiedeberg’s Arch Pharmacol 343:472–477Google Scholar
  13. Everett GM, Borcherding JW (1970) L-DOPA: effects on concentrations of dopamine, norepinephrine, and serotonin in brains of mice. Science 168:849–850Google Scholar
  14. Gaspar P, Berger B, Febvret A, Vigny A, Henry JP (1989) Catecholamine innervation of the human cerebral cortex as revealed by comparative immunohistochemistry of tyrosine hydroxylase and dopamine-beta-hydroxylase. J Comp Neurol 279:249–271PubMedGoogle Scholar
  15. Gaspar P, Duyckaerts C, Alvarez C, Javoy-Agid F, Berger B (1991) Alterations of dopaminergic and noradrenergic innervations in motor cortex in Parkinson’s disease. Ann Neurol 30:365–374PubMedGoogle Scholar
  16. German DC, Kebreten FM, White CL, Woodward DJ, McIntire, Smith WK, Kalaria RN, Mann MA (1992) Disease specific patterns of locus coeruleus cell loss. Ann Neurol 32:667–676PubMedGoogle Scholar
  17. Gomez-Mancilla B, Bedard PJ (1993) Effect of nondopaminergic drugs on L-DOPA-induced dyskinesias in MPTP-treated monkeys. Clin Neuropharmacol 16:418–427PubMedGoogle Scholar
  18. Grenhoff J, Svensson TH (1988) Clonidine regularizes substantia nigra dopamine cell firing. Life Sci 42:2003–2009CrossRefPubMedGoogle Scholar
  19. Haapalinna A, Viitamaa T, MacDonald E, Savola J-M, Tuomisto L, Virtanen R, Heinonen E (1997) Evaluation of the effects of a specific α2-adrenoceptor antagonist, atipamezole, on α1- and α2-adrenoceptor subtype binding, brain neurochemistry and behaviour in comparison with yohimbine. Naunyn-Schmiedeberg’s Arch Pharmacol 356:570–582Google Scholar
  20. Jellinger KA (1999) Post mortem studies in Parkinson’s disease—is it possible to detect brain areas for specific symptoms? J Neural Transm 56:1–29PubMedGoogle Scholar
  21. Juhila J, Haapalinna A, Sirviö J, Sallinen J, Honkanen A, Korpi ER, Scheinin M (2003) The α2-adrenoceptor antagonist atipamezole reduces the development and expression of d-amphetamine-induced behavioural sensitization. Naunyn-Schmiedeberg’s Arch Pharmacol 367:274–280Google Scholar
  22. Lategan AJ, Marien MR, Colpaert FC (1992) Suppression of nigro striatal and mesolimbic dopamine release in vivo following noradrenaline depletion by DSP-4: a microdialysis study. Life Sci 50:995–999CrossRefPubMedGoogle Scholar
  23. Llado J, Esteban S, Garcia-Sevilla JA (1996) The α2-adrenoceptor antagonist idazoxan is an agonist at 5-HT1A autoreceptors modulating serotonin synthesis in the rat brain in vivo. Neurosci Lett 218:111–114PubMedGoogle Scholar
  24. Mavridis M, Colpaert FC, Millan MJ (1991) Differential modulation of (+)-amphetamine-induced rotation in unilateral substantia nigra-lesioned rats by α1 as compared to α2 agonists and antagonists. Brain Res 562:216–224PubMedGoogle Scholar
  25. McCall RB, Patel BN, Harris LT (1987) Effects of serotonin1 and serotonin2 receptor agonists and antagonists on blood pressure, heart rate and sympathetic nerve activity. J Pharmacol Exp Ther 242:1152–1159PubMedGoogle Scholar
  26. McCall RB, Harris LT, King KA (1991) Sympatholytic action of yohimbine mediated by 5-HT1A receptors. Eur J Pharmacol 199:263–265CrossRefPubMedGoogle Scholar
  27. Millan MJ, Newman-Tancredi A, Audinot V, Cussac D, Lejeune F, Nicolas J-P, Cogé F, Galizzi J-P, Boutin JA, Rivet J-M, Dekeyne A, Gobert A (2000) Agonist and antagonist actions of yohimbine as compared to fluparoxan at α2-adrenergic receptors (AR)s, serotonin (5-HT)1A, 5-HT1B, 5-HT1D and dopamine D2 and D3 receptors. Significance for the modulation of frontocortical monoaminergic transmission and depressive states. Synapse 35:79–95CrossRefPubMedGoogle Scholar
  28. Newman-Tancredi A, Tancredi J-P, Audinot V, Gavaudan S, Verrièle L, Touzard M, Chaput C, Richard N, Millan M (1998) Actions of alpha-2 adrenoceptor ligands at alpha-2A and 5-HT-1A receptors: the antagonist, atipamezole, and the agonist, dexmedetomidine, are highly selective for alpha-2A adrenoceptors. Naunyn-Schmiedeberg’s Arch Pharmacol 358:197–206Google Scholar
  29. Olanow WC, Watts RL, Koller WC (2001) An algorithm (decision tree) for the management of Parkinson’s disease (2001): treatment guidelines. Neurology 56:S1–S88Google Scholar
  30. Ordway GA (1995) Effect of noradrenergic lesions on subtypes of α2-adrenoceptors in rat brain. J Neurochem 64:1118–1126PubMedGoogle Scholar
  31. Papeschi R (1974) An investigation on the behavioral and hypothermic effects of yohimbine: interaction with drugs affecting central and peripheral monoamines. Arch Int Pharmacodyn 208:61–80PubMedGoogle Scholar
  32. Parkes JD, Tarsy D, Marsden CD, Bovill KT, Phipps JA, Rose P, Asselman P (1975) Amphetamines in the treatment of Parkinson’s disease. J Neurol Neurosurg Psychiatr 38:232–237PubMedGoogle Scholar
  33. Parkinson Study Group (2000) Pramipexole vs levodopa as initial treatment for Parkinson’s disease—a randomised controlled trial. JAMA 284:1931–1938PubMedGoogle Scholar
  34. Paxinos G, Watson C (1986) The rat brain in stereotaxic coordinates, 2nd Edn. Academic Press, New YorkGoogle Scholar
  35. Pettibone DJ, Pfleuger AB, Totaro JA (1985) Comparison of the effects of recently developed α2-adrenergic antagonists with yohimbine and rauwolscine on monoamine synthesis in rat brain. Biochem Pharmacol 34:1093–1097CrossRefPubMedGoogle Scholar
  36. Raiteri M, Maura G, Folghera S, Cavazzani P, Andrioli GC, Schlicker E, Schalnus R, Göthert M (1990) Modulation of 5-hydroxytryptamine release by presynaptic inhibitory α2-adrenoceptors in the human cerebral cortex. Naunyn-Schmiedeberg’s Arch Pharmacol 342:508–512Google Scholar
  37. Rascol O, Arnulf I, Brefel C (1997) L-DOPA-induced dyskinesias, improvement by an α2 antagonists, idaxozan, in patients with Parkinson’s disease. Mov Disord 12:111PubMedGoogle Scholar
  38. Rascol O, Brooks DJ, Kroczyn AD, DeDeyn PP, Clarke CE, Lang AE (2000) A five-year study of the incidence of dyskinesia in patients with early Parkinson’s disease who were treated with ropinorole and levodopa. 056 Study Group. N Engl J Med 342:1484–1491CrossRefPubMedGoogle Scholar
  39. Riblet LA, Taylor DP, Eison MS, Stanton HC (1982) Pharmacology and neurochemistry of buspirone. J Clin Psychiatry 34:11–16Google Scholar
  40. Romero JA, Chalmers JP, Cottman K, Lytle LD, Wurtman RJ (1972) Regional effects of l-dihydroxyphenylalanine (L-DOPA) on norepinephrine metabolism in rat brain. J Pharmacol Exp Ther 180:277–285PubMedGoogle Scholar
  41. Sallinen J, Haapalinna A, Viitamaa T, Kobilka B, Scheinin M (1998) d-Amphetamine and l-5-hydroxytryptophan-induced behaviours in mice with genetically-altered expression of the alpha2C-adrenergic receptor subtype. Neuroscience 86:959–965PubMedGoogle Scholar
  42. Savola J-M, Virtanen R (1991) Central α2-adrenoceptors highly stereoselective for dexmedetomidine, the dextro enantiomer of medetomidine. Eur J Pharmacol 195:193–199CrossRefPubMedGoogle Scholar
  43. Scatton B, Zivkovic B, Dedek J (1980) Antidopaminergic properties of yohimbine. J Pharmacol Exp Ther 215:494–499PubMedGoogle Scholar
  44. Scatton B, Javoy-Agid F, Rouquier L, Dubois B, Agid Y (1983) Reduction of cortical dopamine, noradrenaline, serotonin and their metabolites in Parkinson’s disease. Brain Res 275:321–328PubMedGoogle Scholar
  45. Schechter LE, Bolanos FJ, Gozlan H, Lanfumey L, Haj-Dahmane S, Laporte A-M, Fattccini C-M, Hamon M (1990) Alterations of central serotonergic and dopaminergic neurotransmission in rats chronically treated with ipsapirone: biochemical and electrophysiological studies. J Pharmacol Exp Ther 255:1335–1347PubMedGoogle Scholar
  46. Singewald N, Philippu A (1996) Involvement of biogenic amines and amino acids in the central regulation of cardiovascular homeostasis. Trends Pharmacol Sci 17:356–363PubMedGoogle Scholar
  47. Trendelenburg A-U, Starke K, Limberger N (1994) Presynaptic alpha-2A-adrenoceptors inhibit the release of endogenous dopamine in rabbit caudate nucleus slices. Naunyn-Schmiedeberg’s Arch Pharmacol 350:473–481Google Scholar
  48. Turkka JT, Juujärvi KK, Myllylä VV (1987) Correlation of autonomic dysfunction to CSF concentrations of noradrenaline and 3-methoxy-4-hydroxyphenylglycol in Parkinson’s disease. Eur Neurol 26:29–34PubMedGoogle Scholar
  49. Ungerstedt U, Arbuthnott GW (1970) Quantitative recording of rotational behavior in rats after 6-hydroxy-dopamine lesions of the nigrostriatal dopamine system. Brain Res 24:485–493Google Scholar
  50. Van Oene JC, de Vries JB, Horn AS (1984) The effectiveness of yohimbine in blocking central dopamine autoreceptors in vivo. Naunyn-Schmiedeberg’s Arch Pharmacol 327:301–304Google Scholar
  51. Virtanen R, Savola J-M, Saano V, Nyman L (1988) Characterization of the selectivity, specificity and potency of medetomidine as an α2-adrenoceptor agonist. Eur J Pharmacol 150:9–14CrossRefPubMedGoogle Scholar
  52. Yavich L, Lappalainen R, Sirviö J, Haapalinna A, MacDonald E (1997) α2-adrenergic control of dopamine overflow and metabolism in mouse striatum. Eur J Pharmacol 339:113–119CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2003

Authors and Affiliations

  1. 1.Orion CorporationOrion PharmaTurkuFinland

Personalised recommendations