Elsevier

Neuroscience

Volume 198, 15 December 2011, Pages 112-137
Neuroscience

Cellular and Molecular
Review
Dopamine release in the basal ganglia

https://doi.org/10.1016/j.neuroscience.2011.08.066Get rights and content

Abstract

Dopamine (DA) is a key transmitter in the basal ganglia, yet DA transmission does not conform to several aspects of the classic synaptic doctrine. Axonal DA release occurs through vesicular exocytosis and is action potential- and Ca2+ -dependent. However, in addition to axonal release, DA neurons in midbrain exhibit somatodendritic release by an incompletely understood, but apparently exocytotic, mechanism. Even in striatum, axonal release sites are controversial, with evidence for DA varicosities that lack postsynaptic specialization, and largely extrasynaptic DA receptors and transporters. Moreover, DA release is often assumed to reflect a global response to a population of activities in midbrain DA neurons, whether tonic or phasic, with precise timing and specificity of action governed by other basal ganglia circuits. This view has been reinforced by anatomical evidence showing dense axonal DA arbors throughout striatum, and a lattice network formed by DA axons and glutamatergic input from cortex and thalamus. Nonetheless, localized DA transients are seen in vivo using voltammetric methods with high spatial and temporal resolution. Mechanistic studies using similar methods in vitro have revealed local regulation of DA release by other transmitters and modulators, as well as by proteins known to be disrupted in Parkinson's disease and other movement disorders. Notably, the actions of most other striatal transmitters on DA release also do not conform to the synaptic doctrine, with the absence of direct synaptic contacts for glutamate, GABA, and acetylcholine (ACh) on striatal DA axons. Overall, the findings reviewed here indicate that DA signaling in the basal ganglia is sculpted by cooperation between the timing and pattern of DA input and those of local regulatory factors.

This article is part of a Special Issue entitled: Function and Dysfunction of the Basal Ganglia.

Highlights

▶Dopamine is a key transmitter in the basal ganglia. ▶Dense axonal arbors and evidence for overlapping dopamine neuron activity argue against signaling specificity for dopamine. ▶However, discrete local regulation by transmitters and modulators alter release probability and phasic responsiveness to sculpt local signaling.

Section snippets

Overview

The transmitter dopamine (DA) is critical for movement, motivation, and cognition, as reviewed elsewhere in this issue (Carta and Bezard, 2011, Palmiter, 2011, Redgrave et al., 2011). Forebrain DA originates from midbrain DA neurons in the substantia nigra pars compacta (SNc) and the ventral tegmental area (VTA) (Dahlström and Fuxe, 1964). Axons from these neurons travel through the medial forebrain bundle (MFB) to provide rich DA innervation of the striatal complex, comprising the dorsal

DA release sites—designed for volume transmission

A continuing misconception about DA signaling is that it is analogous to the conventional view of glutamate synapse function, with synaptic release followed by activation of synaptic receptors and reuptake via intra- or perisynaptic transporters into pre- and perisynaptic cells. However, the similarity between DA and the classic picture of a glutamate synapse is limited. Although recycling of synaptic vesicles occurs after DA release, as seen at glutamatergic synapses (Mani and Ryan, 2009,

Sphere and pattern of DA influence and role of the DAT

As mentioned above, DA neurons form impressive axon arbors within the striatum, with total axonal lengths from individual rat nigrostriatal DA neurons extending up to 780,000 μm (78 cm) (Matsuda et al., 2009). The density of striatal DA varicosities is 1.0–1.7×108 per mm3 (Pickel et al., 1981, Doucet et al., 1986), giving a mean of 0.14 varicosity per μm3 (one varicosity per 7 μm3). Assuming each varicosity is a release site, the distance between release sites is at most 2.4 μm, using the

D2 autoreceptor regulation of DA release

The family of D2-like receptors includes DA autoreceptors that regulate axonal and somatodendritic DA release, DA neuron firing rate, and DA synthesis. In striatal slices, D2 agonists like quinpirole cause a concentration-dependent suppression of single-pulse-evoked [DA]o in rodent CPu and NAc (Palij et al., 1990, Bull and Sheehan, 1991, Stamford et al., 1991, Kennedy et al., 1992, Patel et al., 1995, Patel et al., 2003), and in the striatal analogue in avian brain, area X (Gale and Perkel, 2005

Axonal release

One similarity between axonal DA and glutamate release is that both are action-potential and Ca2+-dependent processes. Locally evoked DA release in CPu in vitro is prevented by tetrodotoxin (TTX), a blocker of voltage-gated Na+ channels, and by removal of extracellular Ca2+ (e.g. Chen and Rice, 2001). Determination of the Ca2+ dependence of striatal DA release evoked by single-pulse stimulation, which is unaffected by concurrently released glutamate and GABA (Chen et al., 2006), shows that in

Axonal DA release characteristics differ among basal ganglia regions

How DA neuron activation translates into axonal DA release can vary through a variety of subregion-dependent factors that regulate activity-dependent DA release probability. Regional differences are seen in patterns of evoked [DA]o during pulse-train stimulation (10 Hz): in CPu, evoked [DA]o is maximal <500 ms after stimulus initiation and then decays during continued stimulation, in part from D2 receptor activation (Trout and Kruk, 1992, Patel et al., 1992, Cragg and Greenfield, 1997), whereas

Glutamate and GABA

How glutamate and GABA regulate axonal DA release in striatum has been a long-standing conundrum. Much existing literature is based on in vivo microdialysis, which provides evaluation of net neurochemical changes over minutes. This is useful for revealing local, drug-induced neurochemical changes, but not necessarily for elucidating the origin or underlying mechanism of such changes, given the possibility of multiple sites of action in vivo. Even when a drug is applied locally through reverse

Glutamate and GABA

Glutamate and GABA provide the primary synaptic input to midbrain DA neurons (see Chen et al., 2002, Morikawa and Paladini, 2011, this issue) (Fig. 5A). However, the balance between excitatory and inhibitory input differs between SNc and VTA, with predominant GABA input to SNc (Bolam and Smith, 1990) and glutamate input to VTA (Smith et al., 1996, Sesack and Grace, 2010). In midbrain slices, single-pulse-evoked somatodendritic DA release in SNc is unaffected by a cocktail of ionotropic

ACh

ACh plays a major role in shaping DA release probability and dynamic short-term plasticity that underlies the frequency and activity dependence of axonal DA release. Large, aspiny striatal ChIs are only ∼2–5% of striatal neurons (Oorschot, 1996, Descarries and Mechawar, 2000), but produce an extensive axonal arbor within the striatal complex, analogous to that of DA axons (see Zhou et al., 2002, Exley and Cragg, 2008). Striatal ChIs show tonic activity in vivo and in vitro in slices, and also

Regulation of DA release by proteins associated with neurological disease: transgenic and knockout mouse models

Several studies have identified changes in DA release in striatum from mice that are mutant or knockout for PD-associated proteins, including those associated with autosomal-dominant PD, for example, α-synuclein (Abeliovich et al., 2000, Yavich et al., 2005, Senior et al., 2008, Anwar et al., 2011) and leucine-rich repeat kinase 2 (LRRK2) (Li et al., 2010), as well as those associated with early-onset recessive forms, for example, parkin (Goldberg et al., 2003, Kitada et al., 2009), DJ-1 (

Optogenetics and DA release

Most studies of DA release regulation have used electrical or chemical stimulation. However, advances in optogenetics permit optical stimulation (or suppression) of specific cell types (Deisseroth, 2010, Deisseroth, 2011, Zhang et al., 2010, Fenno et al., 2011, Kravitz and Kreitzer, 2011, Toettcher et al., 2011), allowing new questions about DA release to be addressed. For example, channelrhodopsin-2 (ChR2), which is permeable to Na+ and Ca2+, can be introduced into DA neurons e.g. through

Conclusions

Release of DA in the basal ganglia is best understood for striatum, which has the richest DA innervation in the CNS. The striatal DA-axon network contains overlapping projection fields from thousands of DA neurons that each contribute almost half a million synapses (plus other potential nonsynaptic release sites) from which released DA interacts by volume transmission with local neuronal elements. Nonetheless, locally discrete, subsecond [DA]o signals that vary within striatal subregions are

Acknowledgments

The authors gratefully acknowledge support from NIH/NINDS grant NS036362 (M.E.R.), the Attilio and Olympia Ricciardi Research Fund (M.E.R.), the Medical Research Council (S.J.C.) and Parkinson's UK (S.J.C.).

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