|Jeremy Seamans (2007), Scholarpedia, 2(6):3737.||doi:10.4249/scholarpedia.3737||revision #73395 [link to/cite this article]|
Basic dopamine anatomy
The discovery of the biosynthetic pathways for catecholamines (including dopamine, noradrenaline, adrenaline) in adrenal medulla chromaffin cells (Blaschko, 1939; Blaschko and Welch, 1953; Blaschko et al, 1967) has paved the way for a later discovery of dopamine (DA) as a distinct bioactive substance in the brain and other peripheral tissues (Carlsson et al., 1958; see Carlsson, 2001; Benes, 2001 for a historical perspective). Since then, a great deal of information has accumulated on the anatomy, physiology, biochemistry, pharmacology, and potential computational functions of DA.
The dopaminergic innervation of the forebrain of mammals is constituted by a small number of highly collateralized neurons (~15,000 – 20,000 on each side of the rat brain) residing in the ventral mesencephalon (Fallon and Loughlin, 1995; Lindvall et al, 1984; Williams and Goldman-Rakic, 1998). Three major divisions of dopaminergic pathways innervate the forebrain and basal ganglia (Bjorklund and Lindval, 1984; Lewis et al., 1998; Goldman-Rakic,1998; Tzschentke, 2001 Thierry et al., 1973; Berger et al., 1974). These mesencephalic cell groups are designated as A8, A9, and A10, according to the nomenclature of Dahlström and Fuxe (1964), and generally correspond to the DA cells of the substantia nigra (SN, A9), ventral tegmental area (VTA, A10), and the retrorubral area (A8) (Berger et al, 1991; Porrino and Goldman-Rakic 1982; Williams and Goldman-Rakic, 1998). Broadly, these dopaminergic neurons are functionally involved in higher motor execution and goal-directed behavior, including motivation, reward learning and prediction, and working memory, and, when impaired, neurological and psychiatric disorders ensue (Egan & Weinberger 1997; Lewis et al., 1998; Schultz 1998; Goldman-Rakic,1998).
DA neurons are unique in that their axon can emanate from a primary dendrite (Fig 1) rather than directly from the soma as is usually the case in other neurons. In addition, the VTA contains a mixed population of DA, GABA and putative glutamatergic neurons (Yamaguchi et al. 2007; Hur & Zaborsky 2005) making it difficult to determine the exact cell type based on the waveform recorded with traditional extracellular electrodes (Margolis et al. 2006).
Ascending dopaminergic fibers innervate a large number of subcortical and cortical structures, including wide areas of neocortex (Fig 2). Structures of the basal ganglia, in particular the striatum, receive by far the densest dopaminergic input. Within the neocortex, an emerging pattern within both mammals and birds is a relative paucity of dopaminergic inputs to primary sensory areas (like primary visual cortex V1), while motor cortical, prefrontal (especially orbitofrontal) and anterior cingulate areas are among the most densely innervated (Swanson 1982; Björklund and Lindvall 1984; Berger and Gaspar, 1994; Durstewitz et al. 1999). This pattern of innervation agrees with DA’s primary role in motivational and reward-related, motor, and higher cognitive functions, rather than in basic sensory processes. In addition, there are layer-specific patterns of innervation: In the rat prefrontal cortex, the deep layers V-VI receive the strongest DA input while in primates superficial layers I-III are at least as densely innervated (Berger et al., 1988, 1991; Joyce et al., 1993; Berger and Gaspar, 1994; Goldman-Rakic et al., 1992; Lewis et al., 1992).
In the prefrontal cortex (PFC) of rats and primates, dopaminergic fibers make between 40-90% specialized synaptic contacts (~39% in the sulcus principalis of primates, Smiley and Goldman-Rakic, 1993; ~56% in the suprarhinal, and ~93% in the anteromedial PFC of rats, Séguéla et al, 1988), while the remaining axonal varicosities constitute unspecialized release sites, and probably contribute to the actions of DA via volume transmission (Garris and Wightman, 1994; Smiley and Goldman-Rakic, 1993; Zoli et al 1998). DA axons can form both symmetric (type II) and asymmetric (type I) synaptic contacts, although the latter ones clearly represent a minority (3-22% of all DA synapses, where the variability may stem partly from differences in methodology (see Smiley and Goldman-Rakic, 1993 for a discussion of technical considerations) and partly from the area investigated, e.g. Descarries et al, 1987; Séguéla et al, 1988). Symmetric synapses are generally associated with inhibitory neurotransmission, while asymmetric synapses are characterized by an intense postsynaptic thickening, and are generally implicated in excitatory transmission (Colonnier, 1968; Gray, 1959). That DA axons in principle are associated with both types of synapses may reflect the fact that DA is neither an excitatory nor an inhibitory transmitter (see below). For rat medial PFC, where much of the electrophysiological data has been collected characterizing the PFC DA system, an estimate of 16% (Séguéla et al, 1988) would translate into ~150-200/mm3 of asymmetric DA synapses out of 1315x103 DA varicosities/mm3 reported for layer V (Descarries et al, 1987).
When DA is released from synaptic or non-synaptic varicosities the time course and local specificity of its action depend to a large extent on the regionally specific properties of uptake/breakdown of DA. In limbic and cortical regions such as the basolateral amygdala and PFC, DA clearance rates are slower than in the striatum (Cass and Gerhardt 1995; Garris et al, 1993, Garris and Wightman, 1994). Unlike in striatal regions, the PFC shows very low levels of DA transporter expression (Sesack et al, 1998), and the DA transporter accounts for only ~ 40% of DA uptake in the PFC, compared with ~ 95% in the striatum (Wayment et al, 2001). Rather, unlike in the striatum, a significant portion of DA uptake in the PFC is mediated by the norepinephrine transporter and catabolized enzymatically by catechol-O-methyltransferase and to a lesser degree monoamine oxidase (Cass and Gerhardt 1995; Moron et al, 2002; Wayment et al, 2001). This property can experimentally be exploited to manipulate or genetically target DA transmission relatively specifically in certain brain regions like the PFC and not the striatum (Meyer-Lindenberg & Weinberger 2007).
All the DA receptors cloned so far are G-protein-coupled receptors (GPCRs), with 7 trans-membrane regions. Unlike the fast ionotropic receptors (e.g. ionotropic glutamate receptors such as AMPA and NMDA receptors), all GPCRs are essentially slow, metabotropic receptors that functionally modulate other receptor systems and/or ion channels (Lachowicz and Sibley 1997; Missale et al., 1998). Hence, with a few exceptions, activation of dopamine receptors per se in the forebrain does not induce large postsynaptic currents that - at least in vitro - can be measured electrophysiologically (Yang and Seamans, 1996). Rather, activation of these receptors modulates, via intracellular cascades, a set of biophysical properties of the synapses and the postsynaptic neurons that changes their information processing properties.
There are at least five DA receptor subtypes in the CNS, which, based on G-protein coupling and the length of the 3rd cytoplasmic loop and the carboxyl tail, are grouped into two major classes: The Gs-, Gq or GOlf -coupled D1 family (D1, D5 receptors with longer 3rd cytoplasmic loop and carboxyl tail), and the Gi/o D2 family (D2, D3, D4 receptors with shorter 3rd cytoplasmic loop and carboxyl tail) (see Lachowicz and Sibley, 1997; Missale et al., 1998; Zhuang et al., 2000; Jin et al., 2001). Through their different G-protein coupling D1-class and D2-class receptors have opposing effects on adenylyl cyclase activity and cAMP concentration, as well as on phosphorylation of a DA- and cAMP-regulated phosphoprotein of molecular weight 32 kDa (DARPP-32) at the Thr34 residue (Hemmings & Greengard 1986; Nishi et al. 1997; Greengard et al. 1999). Through phosphorylation (induced by D1 and opposed by D2 activation) DARPP-32 is turned into a powerful inhibitor of the multi-functional protein phosphatase PP-1 with a series of effects on various voltage-gated and synaptic ion channels (see Dopamine Modulation section).
In the rodent and monkey PFC the distribution of both D1 receptor mRNA and D1 receptor binding sites are significantly (up to 10-fold) greater in amount when compared with the other DA receptor subtypes and may thus reflect its functional importance (Lidow et al., 1991; Goldman-Rakic et al., 1992; Joyce et al., 1993; Gasper et al., 1995). DA-immunoreactive terminals converge on both pyramidal neurons and parvalbumin-containing, DA-receptive fast-spiking interneurons in the primate PFC (Goldman-Rakic et al., 1989; Verney et al., 1990; Sesack et al. 1995; 1998; Gorelova et al., 2002). Likewise, in rodent PFC, both D1- and D2-like receptors are found on pyramidal and non-pyramidal neurons (Vincent et al. 1995; Benes and Berretta 2001).
Another important finding is that, in the striatum including the nucleus accumbens, most DA receptors can be found in the vicinity of glutamatergic asymmetric synapses, but are located at distant sites from a tyrosine-hydroxylase labeled DA synapse, further supporting the notion of volume transmission (Caille et al, 1996). A similar situation exists in PFC. Using mono and polyclonal antibodies directed at the C-terminal of the human D1 receptor, Smiley et al (1994) found that D1 immunoreactivity was usually displaced to the side of the postsynaptic density of large asymmetric synapses with ultrastructural features not indicative of DA synapses (see also Bergson et al. 1995). In fact, they report that none of the 21 synapses formed by tyrosine hydroxylase axons were labeled for D1 receptors. They conclude “that some or all cortical DA synapses do not utilize D1 receptors and that a substantial portion of D1 effects occur at sites other than synaptic specializations”. Likewise, Bergson et al (1991) reported a complementary expression pattern for non-synaptic D1 and D5 receptors in PFC, where D1 receptors appear in dendritic spines whereas D5 receptors predominate in shafts. Along these lines, Paspalas and Goldman-Rakic (2004) have discovered an exclusively extrasynaptic microdomain in the perisomatic plasma membrane of pyramidal neurons that facilitates selective coupling of the D5 receptor with calcium mobilization and the phosphoinositide system. D2 receptors, which are found in DA axons where they function as autoreceptors, may also be present in non-dopaminergic terminals in the striatum (Sesack et al, 1994), and in DA-like and non-DA-like PFC axons, as well as in dendrites extrasynaptically (Negyessy and Goldman-Rakic, 2005). Collectively, these data indicate that D1 and D5, and to a lesser extent D2 receptors are most often associated with non-DA terminals, and are typically displaced from the synapse in the peri- or extrasynaptic space of both pre- and postsynaptic membranes. In this way, DA is suited to modulate glutamate and GABA synaptic transmission, and cell excitability in a manner consistent with volume transmission.
- Benes, F.M. 2001 Carlsson and the discovery of dopamine. Trends Pharmacol. Sci. 22, 46-47.
- Benes, F.M., Berretta, S. 2001 GABAergic interneurons: implications for understanding schizophrenia and bipolar disorder. 25, 1-27.
- Berger, B. and Gaspar, P. 1994 Comparative anatomy of the catecholaminergic innervation of rat and primate cerebral cortex. In: Phylogeny and Development of Catecholamine Systems in the CNS of Vertebrates, pp. 293-324. Eds. W. J. A. J. Smeets and A. Reiner. Cambridge University Press, Cambridge, UK.
- Berger, B., Trottier, S., Verney, C., Gaspar, P. and Alvarez, C. 1988 Regional and laminar distribution of the dopamine and serotonin innervation in the macaque cerebral cortex: a radioautographic study. J. Comp. Neurol. 273, 99-119.
- Berger B., Gaspar P., Verney C. 1991 Dopaminergic innervation of the cerebral cortex: unexpected differences between rodents and primates. Trends Neurosci. 14, 21-7.
- Berger, B., Tassin, J.P., Blanc, G., Moyne, M.A., Thierry, A.M. 1974 Histochemical confirmation for dopaminergic innervation of the rat cerebral cortex after destruction of the noradrenergic ascending pathways. Brain Res. 81, 332-337.
- Bergson, C., Mrzljak, L., Smiley, J.F., Pappy, M., Levenson, R., Goldman-Rakic, P.S. 1995 Regional, cellular, and subcellular variations in the distribution of D1 and D5 dopamine receptors in primate brain. J. Neurosci. 15, 7821-7836.
- Björklund, A., Lindvall, O. 1984 Dopamine-containing systems in the CNS. In Björklund A, Hökfelt T eds, Handbook of Chemical Neuroanatomy: Classical Transmitter In The Rat. Amsterdam, Elsevier/North Holland, vol 2, pp 55-122.
- Blaschko, H. 1939 The specific action of 1-dopa decarboxylase. J. Physiol. (Lond) 96, 5OP-51P.
- Blaschko, H., Comline, R.S., Schneider, F.H., Silver, M., Smith, A.D. 1967 Secretion of a chromaffin granule protein, chromogranin, from the adrenal gland after splanchnic nerve stimulation. Nature, 215, 58-59.
- Blaschko, H., Welch, A.D. 1953 Localization of adrenaline in cytoplasmic particles of the bovine adrenal medulla. Naunyn-Schmiedebergs Arch. Exp. Pathol. Pharmacol 219, 17-22.
- Bymaster F.P., Katner J.S., Nelson D.L., Hemrick-Luecke S.K., Threlkeld P.G., Heiligenstein J.H., Morin S.M., Gehlert D.R., Perry K.W. 2002 Atomoxetine increases extracellular levels of norepinephrine and dopamine in prefrontal cortex of rat: a potential mechanism for efficacy in attention deficit/hyperactivity disorder. Neuropsychopharmacology 27, 699-711.
- Caille, I., Dumartin, B., Bloch, B. 1996 Ultrastructural localization of D1 dopamine receptor immunoreactivity in rat striatonigral neurons and its relation with dopaminergic innervation. Brain Res. 730, 17-31.
- Carlsson, A. 2001 A paradigm shift in brain research. Science 294, 1021-1024.
- Carlsson, A., Linqvist, M., Magnusson, T., Waldeck, B. 1958 On the presence of 3-hydroxytyramine in brain. Science 127, 471.
- Cass W.A., Gerhardt G.A. 1995 In vivo assessment of dopamine uptake in rat medial prefrontal cortex: comparison with dorsal striatum and nucleus accumbens. J. Neurochem. 65, 201-7.
- Colonnier M. 1968 Synaptic patterns on different cell types in the different laminae of the cat visual cortex. An electron microscope study. Brain Res. 9, 268-87.
- Dahlstrom A, Fuxe K. 1964 Localization of monoamines in the lower brain stem. Experientia 20, 398-9.
- Descarries L., Lemay B., Doucet G., Berger B. 1987 Regional and laminar density of the dopamine innervation in adult rat cerebral cortex. Neuroscience 21, 807-24.
- Durstewitz D., Kroner S., Gunturkun O. 1999 The dopaminergic innervation of the avian telencephalon. Prog. Neurobiol. 59,161-95.
- Egan, M.F., Weinberger, D.R. 1997 Neurobiology of schizophrenia. Curr. Opin. Neurobiol. 7,701-707.
- Fallon, J.H. and Loughlin, S.E. 1995 Substantia nigra. In: The Rat Nervous System, pp 215-237. Ed G. Paxinos. Academic Press: San Diego.
- Garris P.A., Collins L.B., Jones S.R., Wightman R.M. 1993 Evoked extracellular dopamine in vivo in the medial prefrontal cortex. J. Neurochem. 61, 637-47.
- Garris PA, Wightman RM. 1994 Different kinetics govern dopaminergic transmission in the amygdala, prefrontal cortex, and striatum: an in vivo voltammetric study. J. Neurosci. 14, 442-50.
- Gaspar, P., Bloch, B., Le Moine, C. 1995 D1 and D2 receptor gene expression in the rat frontal cortex: cellular localization in different classes of efferent neurons. Eur. J. Neurosci. 7, 1050-1063.
- Goldman-Rakic, P.S. 1998 The cortical dopamine system: role in memory and cognition. Adv. Pharmacol. 42, 707-711.
- Goldman-Rakic, P.S., Leranth, C., Williams, S.M., Mons, N., Geffardm, M. 1989 Dopamine synaptic complex with pyramidal neurons in primate cerebral cortex. Proc. Natl. Acad. Sci. (USA) 86, 9015-9019.
- Goldman-Rakic, P.S., Lidow, M.S., Smiley, J.F., Williams, M.S. 1992 The anatomy of dopamine in monkey and human prefrontal cortex. J. Neural Transm. (Suppl.) 36,163-177.
- Gorelova, N., Seamans, J.K., Yang, C.R. 2002 Mechanisms of dopamine activation of fast-spiking interneurons that exert inhibition in rat prefrontal cortex. J. Neurophysiol. 88, 3150-3166.
- Gray EG. 1959 Electron microscopy of synaptic contacts on dendrite spines of the cerebral cortex. Nature 183: 1592-3
- Greengard, P. 2001. The neurobiology of slow synaptic transmission. Science 294, 1024-1030.
- Hemmings H.C., Greengard P. 1986 DARPP-32, a dopamine- and adenosine 3':5'-monophosphate-regulated phosphoprotein: regional, tissue, and phylogenetic distribution. J. Neurosci. 1986, 1469-81.
- Jin, L.Q., Wang, H.Y., Friedman, E. 2001 Stimulated D1 dopamine receptors couple to multiple Galpha proteins in different brain regions. J. Neurochem. 78, 981-990.
- Joyce, J.N., Goldsmith, S. and Murray, A. 1993 Neuroanatomical localization of D1 versus D2 receptors: similar organization in the basal ganglia of the rat, cat and human and disparate organization in the cortex and limbic system. In: D1:D2 Dopamine Receptor Interactions, pp. 23±49. Ed. J. L. Waddington. Academic Press, London.
- Lachowicz, J.E., Sibley, D.R. 1997 Molecular characteristics of mammalian dopamine receptors. Pharmacol. Toxicol. 81,105-113.
- Lewis, D.A., Hayes, T.L., Lund, J.S. and Oeth, K.M. 1992 Dopamine and the neural circuitry of primate prefrontal cortex: implications for schizophrenia research. Neuropsychopharmacology 6, 127-134.
- Lewis, D.A., Sesack, S.R., Levey, A.I., Rosenberg, D.R. 1998 Dopamine axons in primate prefrontal cortex: specificity of distribution, synaptic targets, and development. Adv. Pharmacol. 42, 703-6.
- Lidow, M.S., Goldman-Rakic, P.S., Gallager, D.W., Rakic, P. 1991 Distribution of dopaminergic receptors in the primate cerebral cortex, quantitative autoradiographic analysis using [3H]raclopride, [3H]spiperone and [3H]SCH23390. Neuroscience 40, 657-671.
- Lindvall O., Bjorklund A., Skagerberg G. 1984 Selective histochemical demonstration of dopamine terminal systems in rat di- and telencephalon: new evidence for dopaminergic innervation of hypothalamic neurosecretory nuclei. Brain Res. 306, 19-30.
- Meyer-Lindenberg A., Weinberger D.R. 2006 Intermediate phenotypes and genetic mechanisms of psychiatric disorders. Nat. Rev. Neurosci. 7, 818-27.
- Missale, C., Nash, S.R., Robinson, S.W., Jaber, M., Caron, M.G. 1998 Dopamine receptors: from structure to function. Physiol. Rev. 78,189-225.
- Moron J.A., Brockington A., Wise R.A., Rocha B.A., Hope B.T. 2002 Dopamine uptake through the norepinephrine transporter in brain regions with low levels of the dopamine transporter: evidence from knock-out mouse lines. J. Neurosci. 22, 389-95.
- Negyessy L., Goldman-Rakic P.S. 2005 Subcellular localization of the dopamine D2 receptor and coexistence with the calcium-binding protein neuronal calcium sensor-1 in the primate prefrontal cortex. J. Comp. Neurol. 488, 464-75.
- Nishi, A., Snyder, G.L., Greengard, P. 1997 Bidirectional regulation of DARPP-32 phosphorylation by dopamine. J. Neurosci. 17, 8147-8155.
- Paspalas C.D., Goldman-Rakic P.S. 2004 Microdomains for dopamine volume neurotransmission in primate prefrontal cortex. J. Neurosci. 24, 5292-5300.
- Porrino L.J., Goldman-Rakic P.S. 1982 Brainstem innervation of prefrontal and anterior cingulate cortex in the rhesus monkey revealed by retrograde transport of HRP. J. Comp. Neurol. 205, 63-76.
- Schultz, W. 1998 Predictive reward signal of dopamine neurons. J. Neurophysiol. 80, 1-27.
- Schultz W. 1999 The Reward Signal of Midbrain Dopamine Neurons. News Physiol. Sci. 14, 249-255.
- Seguela P., Watkins K.C., Descarries L. 1988 Ultrastructural features of dopamine axon terminals in the anteromedial and the suprarhinal cortex of adult rat. Brain Res. 442, 11-22.
- Sesack S.R., Aoki C., Pickel V.M. 1994 Ultrastructural localization of D2 receptor-like immunoreactivity in midbrain dopamine neurons and their striatal targets. J. Neurosci. 14, 88-106.
- Sesack S.R., Hawrylak V.A., Guido M.A., Levey A.I. 1998 Cellular and subcellular localization of the dopamine transporter in rat cortex. Adv. Pharmacol. 42, 171-4.
- Sesack, S.R., Hawrylak, V.A., Melchitzky, D.S., Lewis, D.A. 1998 Dopamine innervation of a subclass of local circuit neurons in monkey prefrontal cortex: ultrastructural analysis of tyrosine hydroxylase and parvalbumin immunoreactive structures. Cereb. Cortex 8, 614-622.
- Sesack, S.R., Snyder, C.L., Lewis, D.A. 1995 Axon terminals immunolabeled for dopamine or tyrosine hydroxylase synapse on GABA-immunoreactive dendrites in rat and monkey cortex. J. Comp. Neurol. 363,264-280.
- Smiley J.F., Goldman-Rakic P.S. 1993 Heterogeneous targets of dopamine synapses in monkey prefrontal cortex demonstrated by serial section electron microscopy: a laminar analysis using the silver-enhanced diaminobenzidine sulfide (SEDS) immunolabeling technique. Cereb. Cortex 3, 223-38.
- Smiley, J.F., Levey, A.I., Ciliax, B.J., Goldman-Rakic, P.S. 1994 D1 dopamine receptor immunoreactivity in human and monkey cerebral cortex: predominant and extrasynaptic localization in dendritic spines. Proc. Natl. Acad. Sci. (U.S.A.) 91, 5720-5724.
- Swanson L.W. 1982 The projections of the ventral tegmental area and adjacent regions: a combined fluorescent retrograde tracer and immunofluorescence study in the rat. Brain Res. Bull. 9, 321-53.
- Thierry, A.-M., Blanc, G., Sobel, A., Stinus, L., Golwinski, J. 1973 Dopaminergic terminals in the rat cortex. Science. 182, 499-501.
- Tzschentke, T.M. 2001 Pharmacology and behavioral pharmacology of the mesocortical dapamine system. Prog. Neurobiol. 63, 241-320.
- Vérney, C., Alvarez, C., Geffard, M., Berger, B. 1990 Ultrastructural double-labelling study of dopamine terminals and GABA-containing neurons in rat anteromedial cerebral cortex. Eur. J. Neurosci. 2, 960-972.
- Vincent, S.L., Khan, Y., Benes, F.M. 1995 Cellular colocalization of dopamine D1 and D2 receptors in rat medial prefrontal cortex. Synapse 19, 112-120.
- Wayment H.K., Schenk J.O., Sorg B.A. 2001 Characterization of extracellular dopamine clearance in the medial prefrontal cortex: role of monoamine uptake and monoamine oxidase inhibition. J Neurosci. 21, 35-44.
- Williams S.M., Goldman-Rakic P.S. 1998 Widespread origin of the primate mesofrontal dopamine system. Cereb. Cortex 8, 321-45.
- Yang, C.R., Seamans, J.S. 1996 Dopamine D1 receptor actions in layer V-VI rat prefrontal cortex neurons in vitro: modulation of dendritic-somatic signal integration. J. Neurosci. 16,1922-1935.
- Zhuang, X., Belluscio, L., Hen, R. 2000 GOLF mediates dopamine D1 receptor signaling. J. Neurosci. 20, RC91.
- Zoli M., Torri C., Ferrari R., Jansson A., Zini I., Fuxe K., Agnati L.F. 1998 The emergence of the volume transmission concept. Brain Res. Brain Res. Rev. 26, 136-47.
- Peter Redgrave (2007) Basal ganglia. Scholarpedia, 2(6):1825.
- Valentino Braitenberg (2007) Brain. Scholarpedia, 2(11):2918.
- Eugene Roberts (2007) Gamma-aminobutyric acid. Scholarpedia, 2(10):3356.
- Wolfram Schultz (2007) Reward. Scholarpedia, 2(3):1652.
- Wolfram Schultz (2007) Reward signals. Scholarpedia, 2(6):2184.