Summary
Recent evidence of functional interactions between D1 and D2 dopamine receptor subtypes has led to the concept that many of the behavioural effects of dopamine agonists occur only with activation of both receptor subtypes. Thus, combined treatment with dopamine agonists selective for each of the D1 and D2 receptors may be an effective therapy for Parkinson's disease, chiefly characterized by loss of central dopamine-containing neurons. In addition, recent hypotheses of the possible pathogenesis of this disorder have suggested that metabolism of dopamine by monoamine oxidase in the presynaptic terminal may contribute to the loss of dopaminergic cells, through the production of reactive by-products. Therefore, the effects of chronic (15 day) treatment of rats with different doses of (+)-4-propyl-9-hydroxynaphthoxazine (PHNO, a D2 receptor agonist), SKF 38393 (a D1 receptor partial agonist) or combinations of both drugs on levels of brain monoamines and some of their acidic metabolites were investigated. Little or no effects of the drugs were observed on measures of dopamine or noradrenaline when given separately, while each selective agonist dose-dependently reduced serotonin levels. Combined treatment with the two agonists produced profound effects on the catecholamines, but with no effect on 3,4-dihydroxyphenylacetic acid, the metabolite of dopamine produced by monoamine oxidase. In addition, the effects of combined treatment on serotonin levels were opposite of those of the drugs given independently. Concomitant treatment of animals with both D1 and D2 receptor agonists can therefore increase tissue levels of dopamine without increasing the potentially harmful metabolism of dopamine by monoamine oxidase.
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References
Baker GB, Coutts RT, Rao TS (1987) Neuropharmacological and neurochemical properties of N-(2-cyanoethyl)-2-phenylethylamine, a prodrug of 2-phenylethylamine. Br J Pharmacol 92:243–255
Cedarbaum JM, Clark M, Toy LH and Green-Parsons A (1990) Sustained-release (+)-PHNO [MK-458 (HPMC)] in the treatment of Parkinson's disease: evidence for tolerance to a selective D2-receptor agonist administered as a long-acting formulation. Mov Disord 5:298–303
Clark D, White FJ (1987) Review: D1 dopamine receptor — the search for a function: a critical evaluation of the D1/D2 dopamine receptor classification and is functional implications. Synapse 1:347–388
Cohen G (1983) The pathobiology of Parkinson's disease: biochemical aspects of dopamine neuron senescence. J Neural Transm 19:89–103
Cohen G (1986) Monoamine oxidase, hydrogen peroxide, and Parkinson's disease. In: Yahr MD, Bergmann KJ (eds) Parkinson's disease. Raven Press, New York, pp 119–125
Fage D, Scatton B (1986) Opposing effects of D-1 and D-2 receptor antagonists on acetylcholine levels in the rat striatum. Eur J Pharmacol 129:359–362
Harnois C, Di Paolo T (1990) Decreased dopamine in the retinas of patients with Parkinson's disease. Invest Ophthalmol Vis Sci 31:2473–2475
Hornykiewicz O (1982) Brain neurotransmitter changes in Parkinson's disease. In: Marsden CD, Fahn S (eds) Movement Disorders. Butterworths, London, pp 41–58
Javoy-Agid F, Agid Y (1980) Is the mesocortical dopaminergic system involved in Parkinson's disease? Neurology 30:1326–1330
Kebabian JW, Calne DB (1979) Multiple receptors for dopamine. Nature 277:93–96
Martin-Iverson MT, Stahl SM, Iversen SD (1987) Factors determining the behavioral consequences of continuous treatment with 4-propyl-9-hydroxynaphthoxazine, a selective dopamine D2 agonist. In: Rose FC (ed) Parkinson's disease: Clinical and experimental advances. Libbey, London, pp 169–177
Martin-Iverson MT, Stahl SM, Iversen SD (1988a) Chronic administration of a selective dopamine D-2 agonist: factors determining behavioral tolerance and sensitization. Psychopharmacology 95:534–539
Martin-Iverson MT, Iversen SD, Stahl SM (1988b) Long-term motor stimulant effects of (+)-4-propyl-9-hydroxynaphthoxazine (PHNO), a dopamine D-2 receptor agonist: interactions with a dopamine D-1 receptor antagonist and agonist. Eur J Pharmacol 149:25–31
Nutt JG (1987) On-off phenomenon: relation to levodopa pharmacokinetics and pharmacodynamics. Ann Neurol 22:535–540
Robertson GS, Robertson HA (1986) Synergistic effects of D1 and D2 dopamine agonists on turning behaviour in rats. Brain Res 384:387–390
Ruggieri S, Stocchi F, Carta A, Bragoni M, Agostini C, Barbato L, Agnoli A (1989) One year treatment with lisuride delivery pump in Parkinson's disease. Prog Neuro-Psychopharmacol Biol Psychiat 13:173–183
Rupniak NMJ, Tye SJ, Jennings CA, Loper AE, Bondi JV, Hichens M, Hand E, Iversen SD, Stahl SM (1989) Antiparkinsonian efficacy of a novel transdermal delivery system for (+)-PHNO in MPTP-treated squirrel monkeys. Neurology 39:329–335
Stoessl AJ, Martin-Iverson MT, Barth TM, Dourish CT, Iversen SD (1989) Effects of aging on the behavioural responses to dopamine agonists: decreased yawning and locomotion, but increased stereotypy. Brain Res 495:20–30
Tetrud JW, Langston JW (1989) The effect of deprenyl (selegiline) on the natural history of Parkinson's disease. Science 245:519–522
Waddington JL, O'Boyle KM (1987) The D-1 dopamine receptor and the search for its functional role: from neurochemistry to behavior. Rev Neurosci 1:157–184
Weick BG, Walters JR (1987) Effects of D1 and D2 dopamine receptor stimulation on the activity of substantia nigra pars reticulata neurons in 6-hydroxydopamine lesioned rats: D1/D2 coactivation induces potentiated responses. Brain Res 405: 234–246
Wong JTF (1990) Analogues of β-phenylethylamine: effects on amino acids in the brain. PhD thesis 1990, University of Alberta, Edmonton
Zetterstrõm T, Sharp T, Collin AK, Ungerstedt U (1988) In vivo measurement of extracellular DA and DOPAC in rat striatum after various DA-releasing drugs: implications for the origin of extracellular DOPAC. Eur J Pharmacol 148:327–334
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Martin-Iverson, M.T. Chronic treatment with D1 and D2 dopamine receptor agonists: combined treatments interact to differentially affect brain levels of monoamines. Naunyn-Schmiedeberg's Arch Pharmacol 344, 281–285 (1991). https://doi.org/10.1007/BF00183001
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DOI: https://doi.org/10.1007/BF00183001