Summary
The discovery of the nigrostriatal DA system in the rat was made possible by the highly specific and sensitive histochemical fluorescence method of Falck and Hillarp in combinations with electrolytic lesions in the substantia nigra and removal of major parts of the neostriatum. Recent work on DA neuron evolution shows that in the Bottlenose Dolphin the normal DA cell groups of the substantia nigra are very cell sparse, while there is a substantial expansion of the A9 medial and A10 lateral subdivisions forming an impressive “ventral wing” in the posterior substantia nigra. The nigrostriatal DA pathway mainly operates via Volume Transmission. Thus, DA diffuses along concentration gradients in the ECF to reach target cells with high affinity DA receptors. A novel feature of the DA receptor subtypes is their physical interaction in the plasma membrane of striatal neurons forming receptor mosaics (RM) with the existence of two types of RM. The “functional decoding unit” for DA is not the single receptor, but rather the RM that may affect not only the integration of signals in the DA neurons but also their trophic conditions. In 1991 A2A receptor antagonists were indicated to represent novel antiparkinsonian drugs based on the existence of A2A/D2 receptor-receptor interactions and here P2X receptor antagonists are postulated to be neuroprotective drugs in treatment of Parkinson’s Disease.
Access provided by Autonomous University of Puebla. Download to read the full chapter text
Chapter PDF
Similar content being viewed by others
Keywords
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.
References
Agnati LF, Cortelli P, Pettersson R, Fuxe K (1995) The concept of trophic units in the central nervous system. Prog Neurobiol 46: 561–574
Agnati LF, Ferre S, Lluis C, Franco R, Fuxe K (2003b) Molecular mechanisms and therapeutical implications of intramembrane receptor/receptor interactions among heptahelical receptors with examples from the striatopallidal GABA neurons. Pharmacol Rev 55: 509–550
Agnati LF, Fuxe K, Andersson K, Benfenati F, Cortelli P, D’Alessandro R (1980a) The mesolimbic dopamine system: evidence for a high amine turnover and for a heterogeneity of the dopamine neuron population. Neurosci Lett 18: 45–51
Agnati LF, Fuxe K, Zini I, Lenzi P, Hokfelt T (1980b) Aspects on receptor regulation and isoreceptor identification. Med Biol 58: 182–187
Agnati LF, Fuxe K, Ferre S (2005a) How receptor mosaics decode transmitter signals. Possible relevance of cooperativity. Trends Biochem Sci 30: 188–193
Agnati LF, Fuxe K, Zoli M, Rondanini C, Ogren SO (1982) New vistas on synaptic plasticity: the receptor mosaic hypothesis of the engram. Med Biol 60: 183–190
Agnati LF, Fuxe K, Zoli M, Ozini I, Toffano G, Ferraguti F (1986) A correlation analysis of the regional distribution of central enkephalin and beta-endorphin immunoreactive terminals and of opiate receptors in adult and old male rats. Evidence for the existence of two main types of communication in the central nervous system: the volume transmission and the wiring transmission. Acta Physiol Scand 128: 201–207
Agnati LF, Fuxe K, Zoli M, Ferraguti F, Benfenati F, Ouimet CC, Walaas SI, Hemmings HC Jr, Goldstein M, Greengard P (1988) Morphometrical evidence for a complex organization of tyrosine hydroxylase-, enkephalin-and DARPP-32-like immunoreactive patches and their codistribution at three rostrocaudal levels in the rat neostriatum. Neuroscience 27: 785–797
Agnati LF, Fuxe K, Benfenati F, Zini I, Zoli M, Fabbri L, Harfstrand A (1984) Computer-assisted morphometry and microdensitometry of transmitter-identified neurons with special reference to the mesostriatal dopamine pathway. Methodological aspects. Acta Physiol Scand [Suppl] 532: 5–36
Agnati LF, Franzen O, Ferre S, Leo G, Franco R, Fuxe K (2003a) Possible role of intramembrane receptor-receptor interactions in memory and learning via formation of long-lived heteromeric complexes: focus on motor learning in the basal ganglia. J Neural Transm [Suppl]: 1–28
Agnati LF, Genedani S, Lenzi PL, Leo G, Mora F, Ferre S, Fuxe K (2005b) Energy gradients for the homeostatic control of brain ECF composition and for VT signal migration: introduction of the tide hypothesis. J Neural Transm 112: 45–63
Anden NE, Carlsson A, Dahlstroem A, Fuxe K, Hillarp NA, Larsson K (1964) Demonstration and mapping out of nigro-neostriatal dopamine neurons. Life Sci 15: 523–530
Anden NE, Dahlstroem A, Fuxe K, Larsson K (1965) Further evidence for the presence of nigro-neostriatal dopamine neurons in the rat. Am J Anat 116: 329–333
Antonelli T, Ferraro L, Agnati L, Tanganelli S, Fuxe K (2006) Experimental studies and theoretical aspects on A2A/D2 receptor interactions in a model of Parkinson’s disease. Relevance for l-dopa induced dyskinesias. J Neurol Sci (in press)
Avshalumov MV, Rice ME (2003) Activation of ATP-sensitive K+ (K(ATP)) channels by H2O2 underlies glutamate-dependent inhibition of striatal dopamine release. Proc Natl Acad Sci USA 100: 11729–11734
Baraldi PG, Di Virgilio F, Romagnoli R (2004) Agonists and antagonists acting at P2X7 receptor. Curr Top Med Chem 4: 1707–1717
Barja G (2004) Free radicals and aging. Trends Neurosci 27: 595–600
Battista A, Fuxe K, Goldstein M, Ogawa M (1972) Mapping of central monoamine neurons in the monkey. Experientia 28: 688–690
Beal MF (2000) Energetics in the pathogenesis of neurodegenerative diseases. Trends Neurosci 23: 298–304
Bjorklund A, Lindvall O (1975) Dopamine in dendrites of substantia nigra neurons: suggestions for a role in dendritic terminals. Brain Res 83: 531–537
Bordet R, Ridray S, Schwartz JC, Sokoloff P (2000) Involvement of the direct striatonigral pathway in levodopa-induced sensitization in 6-hydro-xydopamine-lesioned rats. Eur J Neurosci 12: 2117–2123
Braak H, Ghebremedhin E, Rub U, Bratzke H, Del Tredici K (2004) Stages in the development of Parkinson’s disease-related pathology. Cell Tissue Res 318: 121–134
Braak H, Rub U, Gai WP, Del Tredici K (2003) Idiopathic Parkinson’s disease: possible routes by which vulnerable neuronal types may be subject to neuroinvasion by an unknown pathogen. J Neural Transm 110: 517–536
Bryan J, Vila-Carriles WH, Zhao G, Babenko AP, Aguilar-Bryan L (2004) Toward linking structure with function in ATP-sensitive K+ channels. Diabetes 53[Suppl 3]: S104–S112
Burnstock G, Knight GE (2004) Cellular distribution and functions of P2 receptor subtypes in different systems. Int Rev Cytol 240: 31–304
Busija DW, Lacza Z, Rajapakse N, Shimizu K, Kis B, Bari F, Domoki F, Horiguchi T (2004) Targeting mitochondrial ATP-sensitive potassium channels — a novel approach to neuroprotection. Brain Res Brain Res Rev 46: 282–294
Canals M, Marcellino D, Fanelli F, Ciruela F, de Benedetti P, Goldberg SR, Neve K, Fuxe K, Agnati LF, Woods AS, Ferre S, Lluis C, Bouvier M, Franco R (2003) Adenosine A2A-dopamine D2 receptor-receptor heteromerization: qualitative and quantitative assessment by fluorescence and bioluminescence energy transfer. J Biol Chem 278: 46741–46749
Carlsson A, Falck B, Hillarp NA (1962) Cellular localization of brain monoamines. Acta Physiol Scand 56[Suppl 196]: 1–28
Chase TN (2004) Striatal plasticity and extrapyramidal motor dysfunction. Parkinsonism Relat Disord 10: 305–313
Ciruela F, Burgueno J, Casado V, Canals M, Marcellino D, Goldberg SR, Bader M, Fuxe K, Agnati LF, Lluis C, Franco R, Ferre S, Woods AS (2004) Combining mass spectrometry and pull-down techniques for the study of receptor heteromerization. Direct epitope-epitope electrostatic interactions between adenosine A2A and dopamine D2 receptors. Anal Chem 76: 5354–5363
Dahlstroem A, Fuxe K (1964a) Evidence for the existence of monoamine-containing neurons in the central nervous system. I. Demonstration of monoamines in the cell bodies of brain stem neurons. Acta Physiol Scand 62[Suppl 232]: 231–255
Dahlstroem A, Fuxe K (1964b) A method for the demonstration of monoamine-containing nerve fibres in the central nervous system. Acta Physiol Scand 60: 293–294
Da Silva J, Fuxe K, Manger P (2006) Nuclear parcellation of certain immunohistochemically identifiable neuronal systems in the midbrain and pons of the highveld molerat (Cryptomys hottentotus). J Chem Neuroanat 31: 37–50
Dauer W, Przedborski S (2003) Parkinson’s disease: mechanisms and models. Neuron 39: 889–909
de la Fuente-Fernandez R, Calne DB (2002) Evidence for environmental causation of Parkinson’s disease. Parkinsonism Relat Disord 8: 235–241
Descarries L, Beaudet A, Watkins KC (1975) Serotonin nerve terminals in adult rat neocortex. Brain Res 100: 563–588
Ferre S, von Euler G, Johansson B, Fredholm BB, Fuxe K (1991) Stimulation of high-affinity adenosine A2 receptors decreases the affinity of dopamine D2 receptors in rat striatal membranes. Proc Natl Acad Sci USA 88: 7238–7241
Fields RD, Stevens B (2000) ATP: an extracellular signaling molecule between neurons and glia. Trends Neurosci 23: 625–633
Fuxe K (1965a) Evidence for the existence of monoamine neurons in the central nervous system. 3. The monoamine nerve terminal. Z Zellforsch Mikrosk Anat 65: 573–596
Fuxe K (1965b) Evidence for the existence of monoamine neurons in the central nervous system. iv. Distribution of monoamine nerve terminals in the central nervous system. Acta Physiol Scand 64[Suppl 247]: 39–85
Fuxe K (1979) DA receptor agonists in brain research and as therpautic agents. TINS 2: 1–4
Fuxe K, Agnati LF, Benfenati F, Cimmino M, Algeri S, Hokfelt T, Mutt V (1981) Modulation by cholecystokinins of 3H-spiroperidol binding in rat striatum: evidence for increased affinity and reduction in the number of binding sites. Acta Physiol Scand 113: 567–556
Fuxe K, Agnati L, Bjelke B, Hedlund P, Ueki A, Tinner B, Bunneman, Steinbusch H, Ganten D, Cintra A (1993) Novel aspects on central 5-hydroxytryptamine transmission. Focus on the cerebellum. In: Trouillas P, Fuxe K (eds) Serotonin, the cerebellum and ataxia. Raven Press, New York, pp 1–37
Fuxe K, Agnati LF, Jacobsen K, Hillion J, Canals M, Torvinen M, Tinner-Staines B, Staines W, Rosin D, Terasmaa A, Popoli P, Leo G, Vergoni V, Lluis C, Ciruela F, Franco R, Ferre S (2003a) Receptor heteromerization in adenosine A2A receptor signaling: relevance for striatal function and Parkinson’s disease. Neurology 61: S19–S23
Fuxe K, Agnati L, Kalia M, Goldstein M, Andersson K, Härfstrand A (1985) Dopaminergic systems in the brain and pituitary. In: Fluckiger E, Muller EE, Thorner MO (eds) The dopaminergic system. Springer, Berlin Heidelberg, pp 11–25 (Basic and Clinical Aspects of Neuroscience)
Fuxe K, Ferre S, Franco R, Agnati L (2006) Adenosine receptor-dopamine receptor interactions in the basal ganglia and their relevance for brain function. Physiol Behav (in press)
Fuxe K, Ferre S, Zoli M, Agnati LF (1998) Integrated events in central dopamine transmission as analyzed at multiple levels. Evidence for intramembrane adenosine A2A/dopamine D2 and adenosine A1/dopamine D1 receptor interactions in the basal ganglia. Brain Res Brain Res Rev 26: 258–273
Fuxe K, Ferre S, Woods A, Rivera A, Höistad M, Franco R, Kehr J, Agnati L (2003b) Novel strategies for the treatment of Parkinson’s disease. Focus on receptor-receptor interactions in the basal ganglia. In: Kehr J, Fuxe K, Ungerstedt U, Svensson T (eds) Monitoring molecules in neuroscience. Karolinska Institutet, Stockholm, pp 199–202
Fuxe K, Hökfelt T, Ungerstedt U (1971) Localization of monoamines in the central nervous system. In: Ajuriaguerra J, Gauthier G (eds) Monoamines noyeaux gris centraux et syndrome de Parkinson. Georg & Cie S. A., Geneve, pp 23–60
Fuxe K, Stromberg I, Popoli P, Rimondini-Giorgini R, Torvinen M, Ogren SO, Franco R, Agnati LF, Ferre S (2001) Adenosine receptors and Parkinson’s disease. Relevance of antagonistic adenosine and dopamine receptor interactions in the striatum. Adv Neurol 86: 345–353
Fuxe K, Tinner B, Zoli M, Pettersson RF, Baird A, Biagini G, Chadi G, Agnati LF (1996) Computerassisted mapping of basic fibroblast growth factor immunoreactive nerve cell populations in the rat brain. J Chem Neuroanat 11: 13–35
Fuxe K, Ungerstedt U (1970) Histochemical, biochemical and functional studies on central monoamine neurons after acute and chronic amphetamine administration. In: Costa E, Garattini S (eds) Amphetamines and related compounds. Raven Press, New York, pp 257–288
Fuxe K, Ungerstedt U (1974) Action of caffeine and theophyllamine on supersensitive dopamine receptors: considerable enhancement of receptor response to treatment with DOPA and dopamine receptor agonists. Med Biol 52: 48–54
Gerfen CR (2004) Basal ganglia. In: Paxinos G (ed) The rat nervous system, 3rd edn. Elsevier, Amsterdam, pp 455–508
Gines S, Hillion J, Torvinen M, Le Crom S, Casado V, Canela EI, Rondin S, Lew JY, Watson S, Zoli M, Agnati LF, Verniera P, Lluis C, Ferre S, Fuxe K, Franco R (2000) Dopamine D1 and adenosine A1 receptors form functionally interacting heteromeric complexes. Proc Natl Acad Sci USA 97: 8606–8611
Grondin R, Zhang Z, Yi A, Cass WA, Maswood N, Andersen AH, Elsberry DD, Klein MC, Gerhardt GA, Gash DM (2002) Chronic, controlled GDNF infusion promotes structural and functional recovery in advanced parkinsonian monkeys. Brain 125: 2191–2201
Hillion J, Canals M, Torvinen M, Casado V, Scott R, Terasmaa A, Hansson A, Watson S, Olah ME, Mallol J, Canela EI, Zoli M, Agnati LF, Ibanez CF, Lluis C, Franco R, Ferre S, Fuxe K (2002) Coaggregation, cointernalization, and codesensitization of adenosine A2A receptors and dopamine D2 receptors. J Biol Chem 277: 18091–18097
Hoistad M, Kehr J, Andbjer B, Jansson A, Fuxe K (2000) Intracerebral infusion of H-dopamine and H-mannitol in the striatum of halothane-anaesthetized male rats. A dual-probe microdialysis study of long-distance diffusion. Eur J Neurosci 12: 2505–2514
Horvath TL, Warden CH, Hajos M, Lombardi A, Goglia F, Diano S (1999) Brain uncoupling protein 2: uncoupled neuronal mitochondria predict thermal synapses in homeostatic centers. J Neurosci 19: 10417–10427
Iadecola C (1998) Neurogenic control of the cerebral microcirculation: is dopamine minding the store? Nat Neurosci 1: 263–265
Jacobowitz DM, Kallarakal AT (2004) Flotillin-1 in the substantia nigra of the Parkinson brain and a predominant localization in catecholaminergic nerves in the rat brain. Neurotox Res 6: 245–257
Janson AM, Fuxe K, Goldstein M, Deutch AY (1991) Hypertrophy of dopamine neurons in the primate following ventromedial mesencephalic tegmentum lesion. Exp Brain Res 87: 232–238
Jansson A, Descarries L, Cornea-Hebert V, Riad M, Verge D, Bancila, M, Agnati L, Fuxe K (2002) Transmitter-receptor mismatches in central dopamine, serotonin, and neuropeptide systems. Further evidence for volume transmission. In: Walz W (ed) The neuronal environment: brain homeostasis in health and disease. Humana Press Inc, Totowa, NJ
Jansson A, Goldstein M, Tinner B, Zoli M, Meador-Woodruff JH, Lew JY, Levey AI, Watson S, Agnati LF, Fuxe K (1999) On the distribution patterns of D1, D2, tyrosine hydroxylase and dopamine transporter immunoreactivities in the ventral striatum of the rat. Neuroscience 89: 473–489
Kamiya T, Saitoh O, Yoshioka K, Nakata H (2003) Oligomerization of adenosine A2A and dopamine D2 receptors in living cells. Biochem Biophys Res Commun 306: 544–549
Kanda T, Jackson MJ, Smith LA, Pearce RK, Nakamura J, Kase H, Kuwana Y, Jenner P (1998) Adenosine A2A antagonist: a novel antiparkinsonian agent that does not provoke dyskinesia in parkinsonian monkeys. Ann Neurol 43: 507–513
Lee FJ, Xue S, Pei L, Vukusic B, Chery N, Wang Y, Wang YT, Niznik HB, Yu XM, Liu F (2002) Dual regulation of NMDA receptor functions by direct protein-protein interactions with the dopamine D1 receptor. Cell 111: 219–230
Liss B, Roeper J (2001) ATP-sensitive potassium channels in dopaminergic neurons: transducers of mitochondrial dysfunction. News Physiol Sci 16: 214–217
Manger P (2005) Establishing order at the systems level in mammalian brain evolution. Brain Res Bull 66: 282–289
Manger PR, Fuxe K, Ridgway SH, Siegel JM (2004) The distribution and morphological characteristics of catecholaminergic cells in the diencephalon and midbrain of the bottlenose dolphin (Tursiops truncatus). Brain Behav Evol 64: 42–60
Malmfors T (1965) Studies on adrenergic nerves. The use of rat and mouse iris for direct observations on their physiology and pharmacology at cellular and subcellular levels. Acta Physiol Scand 64[Suppl 248]: 241–293
Marshall FH (2001) Heterodimerization of G-proteincoupled receptors in the CNS. Curr Opin Pharmacol 1: 40–44
North RA (2002) Molecular physiology of P2X receptors. Physiol Rev 82: 1013–1067
Olson L, Seiger A, Fuxe K (1972) Heterogeneity of striatal and limbic dopamine innervation: highly fluorescent islands in developing and adult rats. Brain Res 44: 283–288
Rivera A, Agnati L, Horvath TL, de la Calle A, Fuxe K (2006) Uncoupling 2/3 immunoreactivity and the ascending dopaminergic and noradrenergic neuron systems. Relevance for volume transmission. Neuroscience 137: 1447–1461
Rivera A, Cuellar B, Giron FJ, Grandy DK, de la Calle A, Moratalla R (2002) Dopamine D4 receptors are heterogeneously distributed in the striosomes/matrix compartments of the striatum. J Neurochem 80: 219–229
Ruan T, Lin YS, Lin KS, Kou YR (2005) Sensory transduction of pulmonary reactive oxygen species by capsaicin-sensitive vagal lung afferent fibres in rats. J Physiol 565: 563–578
Tennyson VM, Barrett RE, Cohen G, Cote L, Heikkila R, Mytilineou C (1972) The developing neostriatum of the rabbit: correlation of fluorescence histochemistry, electron microscopy, endogenous dopamine levels, and (3H) dopamine uptake. Brain Res 46: 251–285
Torvinen M, Marcellino D, Canals M, Agnati LF, Lluis C, Franco R, Fuxe K (2005) Adenosine A2A receptor and dopamine D3 receptor interactions: evidence of functional A2A/D3 heteromeric complexes. Mol Pharmacol 67: 400–407
Tsukimoto M, Harada H, Ikari A, Takagi K (2005) Involvement of chloride in apoptotic cell death induced by activation of ATP-sensitive P2X7 purinoceptor. J Biol Chem 280: 2653–2658
Woods A, Ciruela F, Fuxe K, Agnati LF, Lluis C, Franco R, Ferre S (2005) The role of electrostatic interactions in receptor-receptor heteromerization. J Mol Neurosci 26: 125–132
Zoli M, Agnati LF, Hedlund PB, Li XM, Ferre S, Fuxe K (1993) Receptor-receptor interactions as an integrative mechanism in nerve cells. Mol Neurobiol 7: 293–334
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2006 Springer-Verlag
About this paper
Cite this paper
Fuxe, K., Manger, P., Genedani, S., Agnati, L. (2006). The nigrostriatal DA pathway and Parkinson’s disease. In: Riederer, P., Reichmann, H., Youdim, M.B.H., Gerlach, M. (eds) Parkinson’s Disease and Related Disorders. Journal of Neural Transmission. Supplementa, vol 70. Springer, Vienna . https://doi.org/10.1007/978-3-211-45295-0_13
Download citation
DOI: https://doi.org/10.1007/978-3-211-45295-0_13
Publisher Name: Springer, Vienna
Print ISBN: 978-3-211-28927-3
Online ISBN: 978-3-211-45295-0
eBook Packages: MedicineMedicine (R0)