Dopamine anatomy

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Jeremy Seamans (2007), Scholarpedia, 2(6):3737.

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Jeremy Seamans, Brain Research Centre, University of British Columbia, CANADA

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.

1 Basic dopamine anatomy
2 Dopamine synapses
3 Dopamine receptors
4 References
5 See also

Basic dopamine anatomy

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).

Figure 1: Anatomy of a dopaminergic VTA neuron, illustrating the distal dendritic location from which the axon can originate. Composite confocal images of a VTA neuron recorded in a coronal brain slice of a transgenic mouse expressing green fluorescent protein under the control of the TH gene promoter (TH-GFP+). The green cell was filled with a red dye (Alexa 594) during the recording, resulting in a yellow signal in the merged image. The insert represents a magnified view of the white square in the main picture. The arrow points where the axon (on the right) branches off the dendrite. Image courtesy of Sven Kroener as found in Lapish et al (2006).

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).

Dopamine synapses

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).

Figure 2: Main projections of the midbrain DA system. DA fibers leave the VTA and terminate with dense collateralization in forebrain regions such as the ventral striatum and frontal cortex. Taken from Schultz 1999.

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).

Dopamine receptors

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.

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