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, 6 (3), 123-148

Striatal Dopamine Neurotransmission: Regulation of Release and Uptake


Striatal Dopamine Neurotransmission: Regulation of Release and Uptake

David Sulzer et al. Basal Ganglia.


Dopamine (DA) transmission is governed by processes that regulate release from axonal boutons in the forebrain and the somatodendritic compartment in midbrain, and by clearance by the DA transporter, diffusion, and extracellular metabolism. We review how axonal DA release is regulated by neuronal activity and by autoreceptors and heteroreceptors, and address how quantal release events are regulated in size and frequency. In brain regions densely innervated by DA axons, DA clearance is due predominantly to uptake by the DA transporter, whereas in cortex, midbrain, and other regions with relatively sparse DA inputs, the norepinephrine transporter and diffusion are involved. We discuss the role of DA uptake in restricting the sphere of influence of DA and in temporal accumulation of extracellular DA levels upon successive action potentials. The tonic discharge activity of DA neurons may be translated into a tonic extracellular DA level, whereas their bursting activity can generate discrete extracellular DA transients.

Keywords: Parkinson’s disease; acetylcholine; addiction; amperometry; autoreceptor; carbon fiber; diffusion; dopamine transporter; drug dependence; electrochemistry; fast-scan cyclic voltammetry; heteroreceptor; microdialysis; nAChRs; quantal size; release; schizophrenia; uptake.


Figure 1
Figure 1. Features of synaptic vesicle activity in dopamine axons
(A) Fates of synaptic vesicle membrane. Striatal dopamine (DA) release sites are en passant structures on long axons, with many small synaptic vesicles in both axons and boutons and a smaller number of dense core vesicles (DCV) that are thought to both undergo exocytosis and deliver small synaptic vesicle membrane components following membrane recycling from endosomes. The source of vesicular DA can be from synthesis via tyrosine hydroxylase (TH) action on L-DOPA or from uptake of extracellular DA by the DA transporter (DAT), with subsequent accumulation in vesicle by the vesicular monoamine transporter, VMAT2. Synaptic DA vesicles can undergo fusion in a flickering mode (“complex event”) that involves transient and reversible exocytosis [17] or can undergo full fusion (“simple event”). After full fusion, vesicle membrane is recycled via an endosomal intermediate, via either “bulk endocytosis” or clathrin-coated intermediates. The endosomes may fuse with autophagosomes for retrograde transport and lysosomal degradation [68]. Recent evidence suggests that the majority of sites with many synaptic vesicles may not exhibit fusion (D. Pereiera et al, in submission). (B) A vastly simplified DA synaptic vesicles showing some components discussed in this article. These include the DA transporter VMAT2 which is thought to provide net antiport of two protons for each DA molecule, the vacuolar vesicular ATPase (vATPase) that pumps protons to the vesicle interior, an anion channel (the predominant chloride channel in vesicles is ClC-3) that provides net counterions (probably with proton efflux) to decreases the free energy required for the proton gradient DA uptake, and a v-SNARE protein, VAMP a.k.a. synaptobrevin, involved in synaptic vesicle fusion via formation of a SNARE complex with plasma membrane t-SNARES. Some DA synaptic vesicles might also possess the glutamate vesicular transporter, VGLUT2.
Figure 2
Figure 2. Striatal cholinergic innervation of dopamine axons and the cholinergic receptor subtypes involved
(A) The striatum receives dense innervation from intrinsic cholinergic interneurons (ChIs), shown by green fluorescence after injection of eYFP-containing constructs in ChAT-Cre mice (courtesy of KA Jennings and SJ Cragg). (B) Direct localization of β2-subunit-containing (β2*) nicotinic cholinergic receptors (nAChRs) (arrows) on dopamine (DA) axons, reproduced from [209] with permission. (C) Cartoon of the range of subtypes of striatal nAChRs and muscarinic cholinergic recepotors (mAChRs) and their locations on ChIs or DA axons that appear to govern the control of DA release by acetylcholine (Ach) in nucleus accumbens (NAc, left) and caudate-putamen (CPu, right). A broader range of nAChR and mAChR types (color-coded) appear to operate in CPu than in NAc. M2 and M4 mAChRs regulate dopamine by regulating ChIs, whereas M5 mAChRs regulate DA release directly.
Figure 3
Figure 3. Acetylcholine filters and drives dopamine transmission
(A) Cartoon of the effects of cholinergic interneuron (ChI) activity on dopamine (DA) release. Left of dashed line: When nicotinic cholinergic receptors (nAChRs) nAChRs on are “on” (activated), DA release level only weakly reflects frequency of activity in DA neurons or ChIs. Other inputs can regulate DA release by regulating ACh release. Right of dashed line: When nAChRs are “off”, e.g., during ChI pause or after desensitization by nicotine, DA release better reflects frequency of activity in DA neurons. Note that the effects of other inputs could be mediated via ChIs (e.g., left) or be direct on DA axons (e.g., right), but in either case could depend on activity in ChIs. (B) Light-activation of ChR2-expressing ChIs in striatum generates single action potentials in individual ChIs and directly drives large DA release events. Reproduced with permission from [289].
Figure 4
Figure 4. Neuropeptide regulation of DA release
(A) Upper left, Substance P enhances, diminishes, or has no effect on DA release depending on position within striosome-boundary-matrix compartments, identified by distance of recording site to nearest striosome edge (d1). Upper right, patchy striosomes are indicated by mu-opioid-receptor immunoreactivity (MOR-ir). Lower panels, show typical carbon-fibre microelectrode recordings sites (marked with yellow Fluosphere beads within green circles (25 µm radius) within striosomes (S), on the boundary with matrix (M), and within matrix. Scale bars 100, 200, 1000 µm as indicated. Adapted with permission, [248]. (B) Upper left, insulin (Ins) increases DA release in rat NAc shell, NAc core, and CPu; average single-pulse evoked [DA]o before and after Ins (30 nM); error bars omitted, ***p < 0.001. Upper right, representative recordings of peak evoked [DA]o vs. time at a single site in NAc core in the absence of drug application (Con), during application of insulin (30 nM), or when insulin was applied in the presence of an InsR inhibitor, HNMPA (5 µM). Middle, striatal ChI filled with biocytin, then immunolabeled for choline acetyltransferase (ChAT), and insulin receptor (InsR); merged shows InsR expression on ChIs; scale bar is 10 µm. Lower left, Single-pulse evoked [DA]o in rat NAc core before and after insulin (30 nM) in the presence of an nAChR antagonist, mecamylamine (Mec; 5 µM) or DHβE (1 µM), normalized to 100% peak control (p > 0.05 vs. control. Lower right, Single-pulse evoked [DA]o in ex vivo slices from heterozygous control (Het) and ChAT KO mice before and after insulin (30 nM). Insulin increases evoked [DA]o in Hets (**p < 0.01, ***p < 0.001 vs. control), but had no effect on evoked [DA]o in any striatal subregion of ChAT KO mice (P > 0.1). Adapted with permission, [318].

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