Dear reader of, please excuse the disruption. needs about $63500 in 2024. In 2023 we received donations of about $ 32200. Unfortunately, 99.8% of our readers do not donate. If everyone who reads this request makes a small contribution, our fundraising campaign for 2024 would be over after a few days. This donation request is displayed 23,000 times a week, but only 75 people donate. If you find useful, please take a minute and support with your donation. Thank you!

Since 01.06.2021 is supported by the non-profit ADxS e.V..

$21963 of $63500 - as of 2024-05-31
Header Image
5. Release of dopamine


5. Release of dopamine

Dopamine is mainly released by dopaminergic neurons in the substantia nigra pars compacta and the ventral tegmentum. These nerve cells project via their axons to different regions of the brain, such as the striatum and the PFC, where they influence various functions such as movement, habit learning, reward and motivation. Noradrenergic neurons can also release dopamine, especially in the prefrontal cortex. There are different forms of neurotransmitter transmission, including endocrine transmission, volume transmission and synaptic transmission.
Dopamine is released from synaptic and non-synaptic varicosities. Dopamine release from synaptic varicosities occurs through the fusion of vesicles with the presynaptic plasma membrane. There are different types of vesicle fusion, including the simple event (complete vesicle fusion with the membrane) and the complex event (partial release from vesicles).
Dopamine can be released from the axon or the dendrites. Somatodendritic dopamine release plays a role in motor control, motivation and learning. Dopamine release from the dopamine transporter (DAT efflux) can be induced by changes in membrane potential and extracellular ion concentrations as well as by activation of intracellular signal transduction networks.
AMP and MPH (in addition to their primary function as dopamine reuptake inhibitors) cause increased dopamine release and thereby contribute to increased extracellular dopamine levels. AMP increases dopamine efflux by increasing the availability of inward DATs and inducing uncoupled currents. Methylphenidate facilitates the movement of dopamine vesicles from storage pools to functional pools.

5. Dopamine release

The illustrations in this article are based on the work of Liu and Kaeser 12
A very comprehensive description of dopaminergic neurons and their behavior can be found at Marinelli and McCutcheon.3

5.1. Nerve cells with dopamine release

5.1.1. Dopaminergic nerve cells

The tonic and phasic dopaminergic signals originate from dopamine neurons in the substantia nigra pars compacta and the VTA, both of which are located in the midbrain. These innervate the entire dorsal to ventral area of the striatum and the PFC, among others, via axons.4 The substantia nigra pars compacta contains more than 70 % of all dopaminergic neurons in humans (in young people a total of approx. 400,000).5
More on this in the previous article Dopamine formation and storage At Brain regions in which dopamine is produced

The dopaminergic projections of the substantia nigra into the dorsal striatum influence voluntary movements and habit learning, the VTA projections into the ventral striatum influence reward and motivation.6
More on this below.

5.1.2. Noradrenergic nerve cells

Since dopamine is also reabsorbed by NET in addition to DAT (see article Dopamine reuptake, dopamine degradation) and is stored by these in vesicles (especially in the PFC), the dopamine taken up in this way should also be released from noradrenergic cells. In the mPFC, dopamine appears to originate exclusively from noradrenergic neurons. If the noradrenergic cells of the locus coeruleus are inactivated, the extracellular dopamine and noradrenaline level in the mPFC decreases.7

5.2. Forms of neurotransmitter transmission

There are different forms of transmission of neurotransmitters. These differ in the precision of release and in the organization of the receptors.2

5.2.1. General forms of neurotransmitter transmission Endocrine transmission

Endocrine cells generally release hormones as transmitters. The release takes place on the cell surface. The transmitters travel distances of millimetres to meters through the extracellular space and the bloodstream to distant receptors. Endocrine cells often do not have specially designed release sites.2 Volume transfer

In volume transfer, transmitters diffuse over a wider area. The transmitters are usually released from specialized sites that are similar to the active zone. The distance to the receptors determines their activation and is therefore characterized by a steep transmitter concentration gradient.2 Volume transmission thus enables the neurotransmitter to spread over a greater distance (more than 10 μm, instead of only 30-40 nm in the classic synapse). As a result, volume transmission can address approximately 200 dopamine synapses instead of only one postsynaptic membrane in the classical synapse. This could be a factor in the cross-effect of dopamine.8
Volume transmission at dopaminergic synapses is sometimes doubted. The difference between volume transmission and synaptic transmission is universal and also affects the noradrenergic system, for example.9 Synaptic transmission

In synaptic transmission, there is a very close spatial coupling of a few tens of nanometers between the transmitter-releasing active zone and the receptor clusters. The active zone and receptor clusters are often aligned at the subsynaptic level. Signal transmission only takes place within the synaptic cleft, which results in precise and efficient receptor activation.2

5.2.2. Dopaminergic transmission

Dopamine is released from synaptic and non-synaptic varicosities.
Most dopamine varicosities are not bound to postsynaptic cells and densities. Various studies suggest a distributed localization.

  • broadly localized to D1-MSN
  • with somatic, dendritic shaft and dendritic spine localizations
  • Sometimes they occur in groups.


  • widely distributed within D2-MSNs
  • possibly increased in distal dendrites

D1 and D2 are found in dopamine varicosities with synaptic-like contacts

  • rarely in the opposite postsynaptic membrane
  • often perisynaptic (within 100 nm of the edges of the synaptically similar apposition)
  • often extrasynaptic (beyond 100 nm of the synaptic-like contact)

Dopamine receptors therefore appear to be partially bundled on MSNs. The majority of dopamine receptors are (so far) not detectable in synaptic attachments.
Therefore, the term “dopamine synapse” should not be understood narrowly, in the sense of a postsynaptic structure containing dopamine receptors, but broadly, in the sense of a dopamine transmission system.2

Reserpine blocks VMAT and thus the storage of dopamine in the vesicles. Rabbits treated with reserpine are paralyzed. An administration of L-DOPA, a precursor of dopamine, restored the ability to move, despite persistent VMAT blockade. The brain can therefore metabolize L-DOPA and use it for locomotion without vesicle dopamine and without precise vesicular release in synapses.
Dopamine is thus able to transmit signals even without precise synaptic communication: so-called volume transmission.2

5.2. Dopamine release from vesicles

Vesicles are roundish to oval vesicles about one micrometer in size that are located in the cell and are surrounded by a double membrane or a net-like protein envelope. The vesicles form their own cell compartments in which various cellular processes take place. Vesicles are responsible for the storage of many different substances in the cell.

  • Exocytotic vesicles
    • store substances for release from the cell by fusion of the vesicles with the cell membrane:
      • Membrane proteins that are initially localized in the vesicle membrane and automatically belong to the cell membrane after fusion
      • synaptic vesicles for the release of neurotransmitters
  • endocytotic vesicles
    • serve to absorb substances into the cell and to recycle membrane proteins

Vesicles can be released from a cell between 170 and 4000 times per second.1011

5.2.1. Release through vesicle fusion with plasma membrane

The fusion of exocytic synaptic vesicles with the presynaptic plasma membrane is triggered by the formation of the SNARE complex. The SNARE complex consists of

  • the vesicular SNARE synaptobrevin-2/VAMP-2 and
  • the plasma membrane SNARE proteins Syntaxin-1 and SNAP-25.
    Dopamine release was also only found in dendrites where synaptobrevin-2/VAMP-2 was also detected.12
    A small proportion of the neurotransmitter-filled vesicles are bound by synapsin to the actin skeleton of the active zone near voltage-gated Ca2+ membrane channels, where they are activated. When an action potential depolarizes the presynaptic plasma membrane, Ca2+ enters through these channels and triggers the fusion of the vesicles with the membrane via synaptotagmin 1, 2 or 9, which act as Ca2+ sensors. The neurotransmitters then exit the vesicles into the synaptic cleft to activate postsynaptic receptors (or presynaptic autoreceptors, some of which are positioned very close to the presynaptic dopamine release)13.
    Botulinum toxin A and B cleave SNAP-25 and synaptobrevin-2 and thus inhibit the docking of the vesicles to the cell membrane. Tetanus toxin also cleaves synaptobrevin-2, but does not always inhibit the release of dopamine.1

5.2.2. Function of synapses

Fundamental to the function of synapses: German: Hinghofer-Szalkay.14 English: Synapseweb.15

Chemical synapses consist of

  • Presynaptic apparatus for transmitter release
  • Postsynaptic apparatus for receptor-mediated signal transduction

Gray type:

  • Gray type I
    • Asymmetrical synapse
  • Gray type II
    • Symmetrical synapse Dopaminergic synapses

Dopamine synapses are often found in dendritic shafts and spines of medium spiny projection neurons (MSN), the main neurons in the striatum.
Dopamine neurons of the midbrain project densely into the striatum and form so-called dopamine synapses at MSNs of other neurotransmitters. The postsynaptic dopamine receptors here are distant from dopamine synapses, so it is as yet unclear how dopamine synapses are involved in dopaminergic transmission. Single vesicular fusion events can activate D1 and D2, with nearby receptors more likely to be activated by dopamine than more distant ones. The exact organization of the dopamine receptors in relation to the release sites is not yet known.2

Dopaminergic dendritic synapses address GABA postsynaptically

One study found that dopamine synapses represent contacts between dopaminergic presynaptic and GABAergic postsynaptic structures:16
The presynaptic structure expressed:

  • Tyrosine hydroxylase (relevant for dopamine synthesis)
  • VMAT2 (Relevant for vesicle filling)
  • DAT (relevant for dopamine reuptake)

The postsynaptic structure of the dopamine synapses expressed GABAergic molecules:

  • Neuroligin-2 (postsynaptic adhesion molecule)
    • promotes presynaptic differentiation in axons of midbrain dopamine neurons and striatal GABAergic neurons
  • Gephyrin (postsynaptic scaffold molecule)
  • GABA-A-α1 receptors
  • without specific clustering of dopamine receptors

Elimination of neuroligin-2 in the striatum resulted in

  • significant decrease in dopamine synapses
  • reciprocal increase in GABAergic synapses at MSN dendrites

Neuroligin-2 appears to control the formation of synapses in the striatum by giving heterologous dopamine synapses a competitive advantage over conventional GABAergic synapses. Since MSN dendrites are preferred targets of dopamine synapses and express high levels of dopamine receptors, the formation of dopamine synapses may serve to increase the specificity and efficacy of dopaminergic modulation of striatal output by anchoring dopamine release sites to dopamine sensor targets.

Dopamine receptors cannot be detected in postsynaptic structures with the instruments currently available (2021), so it remains to be seen whether and to what extent dopamine receptors are found in dopamine synapses.2 Domain overlap model

Increasing evidence suggests that dopamine signaling is not only temporally dynamic but also spatially organized.
In addition to synaptic point-to-point transmission and broad (extracellular?) neurotransmitter transmission, a domain overlap model could be relevant, in which release and receptors are arranged in micrometer-sized structures relative to each other. This is based on rapid release followed by diffusion with a micrometer-sized release-receptor organization.
This model should allow for activation of receptor subsets located in micrometer-sized domains of release sites during baseline activity on the one hand, and broader receptor activation with domain overlap when firing is synchronized across dopamine neuron populations on the other. This signaling structure, together with the properties of dopamine release, may explain how the switching of firing modes supports a broad and dynamic role of dopamine and may lead to distinct pathway modulation.2

5.2.3. Types of vesicle fusion: simple event / complex event

The fusion pore of large dense-core vesicles can exist in at least two states:17

  • “simple event”
    • single traditional spike (80 to 85 % of vesicle fusions)
    • complete merger
    • releases as much vesicular DA as the first flicker of a complex event
    • Vesicle membrane is then recycled, either via “bulk endocytosis” or via clathrin-coated intermediates.18
  • “complex event”, “kiss and run”, a rapid sequence of spikes whose amplitude gradually decreases from the first to the last spike (15 to 20 % of vesicle fusions)1011
    • transient fusion via a fusion pore without fusing completely (“kiss-and-run” fusion = transient and reversible exocytosis)
    • corresponding to a flickering of the vesicle fusion pore, a “foot” with a small (~3 nm diameter) reversible fusion pore
    • each “flicker” released 25 to 30 % of the vesicular DA (vs. < 1 %)
    • enables rapid reuse of vesicles without going through slow recycling
    • occurs in adrenal chromaffin and other large dense-core vesicles
    • is significantly shorter than a complete vesicle fusion (100-150 µs vs. 10,000-500,000 µs)
    • occurs in adrenal chromaffin vesicles at a much higher frequency than in dense-core vesicles (4000 Hz vs. 170 Hz)

The modulation of the fusion pore can thus influence the amount and kinetics of transmitter release and possibly occurs via protein kinase C.19
Medication can influence PKC.1720

  • Increased protein kinase C activity:
    • increases the number of events per stimulus
    • reduces the proportion of complex events
    • enlarges the fusion pore, increases simple events / complete fusion
  • Reduced protein kinase C activity (e.g. due to the non-selective kinase inhibitor staurosporine):
    • reduces the number of events per stimulus with increased stimulus frequency
    • increases the proportion of complex events
    • Knockout or inhibition of atypical protein kinase C theta (but not the related atypical protein kinase C delta) reduces catecholamine quanta21

5.2.4. Slow replenishment of dopaminergic vesicles

The pool of easily releasable dopamine vesicles only replenishes slowly. The depletion of dopamine release after a single stimulus lasts for several dozen seconds. It therefore takes one to two orders of magnitude longer to restore the readiness for release than with fast synapses. Since the replenishment speed is crucial for the frequency range in which a transmission system can operate, and since dopamine receptors are “slow” GPCRs, the dopamine system is not well suited for high-frequency information transmission.2

The amount and frequency of neurotransmitter release from vesicles is variable.22 The idea that each release releases an equally high, fixed amount of the neurotransmitter (the “quantum”) is outdated.

Vertebrate dopamine receptors are also slow. These are exclusively G-protein-coupled receptors (D1-like receptors: Gs/olf; D2-like receptors: Gi/o), which are orders of magnitude slower than ionotropic receptors.2

5.3. Axonal and somatodendritic release

In principle, neurotransmitters can be transmitted in several ways:23

  • From the axon (axoaxonal)
    • Axon trunk to synapse
    • Axon terminal head at synapse
    • Axon in extracellular space (nondirected synapses)
  • From the cell membrane to synapses (axosomatic)
  • From dendrites to synapses (axodendritic)
    • Dendrite stem at synapses
    • Dendrite spines at synapses

Dopamine is released in various ways:1

5.3.1. Axonal release, axonal varicosities

The dopamine formed is transported into dopaminergic cells via nerve tracts (axons). There it is stored in vesicles, which are later brought to the cell membrane and then released in response to electrical impulses, including into the synaptic cleft, which is approx. 20 to 40 nanometers wide and 0.5 nanometers deep. Around 1000 dopamine molecules are released per electrical impulse.24 It is conceivable that axon varicosities release dopamine into the extracellular space even without synapses.2

Axons mediate most of the dopamine transmission. A blockade or knockout of VMAT2 terminates dopamine transmission.
Only around 17 % of varicosities release dopamine.25 Dopamine axons are not myelinated (and therefore conduct slowly) and are highly branched.26 It is therefore possible that not all action potentials of the somatic dopamine neurons reach the dopamine varicosities1

Dopamerminals often form a triad with other axons in close spatial contact. A neuron is connected to both the presynaptic element and the postsynaptic (usually dendritic) target. Triads are widespread in the hippocampus, striatum and mPFC. These triads can contain both dopamine and serotonin or adrenergic terminals.8

5.3.2. Somatodendritic release

Dopamine release in the substantia nigra originates from dendrites.27 The release of dopamine from dendrites is calcium-dependent, vesicular, spontaneous and RIM-dependent. RIM is an important scaffold protein for transmitter release.28 Dopamine release from dendrites is thus similar to that from axons.29 However, the sites at which dendrodendritic transmission occurs have not yet been identified.3031

  • Somatodendritic dopamine release occurs primarily from dendrites, not from cell bodies (soma)12
    • dendrites without recognizable varicosities also released dopamine
    • as well as dendritic branches with bouton structures (similar to axon terminals)
    • dendritic dopamine release appears to be spatially restricted to the immediate vicinity of the release site, unlike axonal release, which spreads over a larger spatial area
  • May also originate from specialized secretory organelles, as dopamine is mainly stored in tubulo-vesicular structures similar to the smooth endoplasmic reticulum in the soma or dendrites32

Somatodendritic dopamine release in midbrain regions (especially in substantia nigra pars compacta (SNc) and VTA), is involved in:12

  • a variety of functions attributed to dopamine neuromodulation:
    • motor control (via SNc)
    • Motivation
    • Learning
  • delaying the onset of Parkinson’s symptoms by compensating for the extensive axonal degeneration of SNc dopamine neurons33

Somatodendritic dopamine release regulates the dopaminergic system via two mechanisms:

  • The dopamine released in SNc and the VTA activates D2 autoreceptors
    • The D2 autoreceptors regulate the excitability of dopamine neurons via GIRK channels (self-inhibition)
      • This self-inhibition of dopamine release in turn regulates
        • dopamine release in distal regions that receive dense axonal innervation from midbrain dopamine neurons (especially striatum and PFC)
        • the release in SNc and VTA
          • in the VTA e.g. relevant for induction of behavioral sensitization to amphetamine by activation of local D1 receptors
  • Dendritic projections of VTA in substantia nigra pars reticulata (SNr)
    • activate D1 receptors
    • regulate / activate the release of the primary GABAergic neurons of the SNr
      • via D1/D5 receptors
      • could activate feedback signals for dopamine regulation between substantia nigra pars compacta and substantia nigra pars reticulata
      • which in turn could influence axonal dopamine release32

5.4. Active zone

The active zone is a protein network. It is found in nerve cells and axons presynaptically directly opposite synapses. The active zone of a synapse docks onto synaptic vesicles and stimulates them. As a result, the active zone forms a pool of easily releasable vesicles and positions these vesicles at specific distances from presynaptic Ca2+ channels, thereby controlling the probability of vesicular release. Only a few percent of the vesicles present are part of the ready-to-release pool2

5.4.1. Active zone in nerve cells

Synaptic transmission is characterized by its speed and spatial precision. The fusion of synaptic vesicles with the cell membrane takes place in less than a millisecond after the arrival of an action potential. The release from a vesicle is spatially precise with respect to postsynaptic receptors from the active zone.34 The active zone binds vesicles prepared for release to the presynaptic plasma membrane in the vicinity of Ca2+ channels.35
The active zone consists of the molecular scaffolds:1

  • large scaffold proteins
    • Bassoon
    • Piccolo
  • Protein complexes of the active zone
    • RIM
    • RIM-BP
    • ELKS
    • Munc13
    • Liprin-α
  • SNARE complex proteins
    • VAMP
    • SNAP-25
    • Syntaxin

This also applies to active zones in axons.12

5.4.2. Active zone in axons

Dopamine axons contain active, zone-like protein scaffolds from1

  • RIM
    • Only 30 % of the varicosities of dopaminergic axons contain RIM. RIM and MUNC13 are essential for the function of an active zone (as in conventional synapses). This could explain why only 20 % to 30 % of the varicosities of axons actively release dopamine.
  • ELKS2
  • Bassoon
    • Deactivation of the bassoon reduces the release of neurotransmitters36
  • Munc13-1 (presumably)

30% of dopamine varicosities contain postsynaptic densities and form GABAergic synaptic structures with presynaptic neurexin and postsynaptic neuroligin-2. Therefore, dopamine could also be released on axons only at synapses. In the substantia nigra, D1 receptors are located at presynaptic sites on small-diameter axons that are not in contact with tyrosine hydroxylase-positive elements and on terminal end-buttons that form symmetrical synapses on tyrosine hydroxylase-positive or -negative dendrites.37

5.4.3. Active zone in dendrites

Somatodendritic dopamine release also appears to function by means of active zones.12 Here too, neurotransmitter release is linked to the existence of bassoon.

5.5. Dopamine release from DAT (efflux)

The DAT can not only (re)absorb dopamine, but also release it (efflux).
The dopamine efflux is controlled by:38

  • Changes in the membrane potential
  • Reduced extracellular Na+39
  • Reduced extracellular Cl-39
  • Changes in the intracellular Na+
  • Activation of an intracellular signal transduction network
    • by e.g.
      • extracellular dopamine39
        • D2 autoreceptors expressed in midbrain dopamine neurons inhibit neuronal firing by opening K+ channels and closing Ca2+ channels. K+ channel-induced hyperpolarization overrides other dopamine-induced currents. D2 antagonists caused low concentrations of dopamine not to slow neuronal firing as usual, but to increase the firing rate three- to fourfold. This increased firing was blocked by the DAT antagonists cocaine or GBR12909, showing that DAT can release dopamine.40
      • AMP39
      • MPH
    • supported by e.g.
      • Protein kinase C (PKC) beta(II)41
      • Calmodulin kinase II (CaMKII) alpha42
        • indicates the involvement of endogenous signaling and phosphorylation mechanisms43
      • increased efflux is mediated by DRD243

5.5.1. AMP-induced efflux

Amphetamine-induced efflux requires N-terminal phosphorylation of the DAT. N-terminal phosphorylation shifts the DAT from a “reluctant” to a “willing” state for AMP-induced dopamine efflux without affecting (re)uptake.44
AMP-induced dopamine efflux is based on the ability of AMP:44

  • increase the availability of DATs that were previously directed inwards
  • to induce uncoupled currents
  • increase intracellular sodium activity
  • increase intracellular kinase activity

The affinity of wild-type DAT for efflux appears to be more than 300 times lower than that for uptake39

Methylphenidate, on the other hand, is said to increase the release of dopamine by facilitating the movement of these transmitters from the storage pools to the functional pools within the nerve endings.45

5.6. Speed and duration of dopamine release

The study results on the latency periods for the dopamine increase to the peak and the degradation in the striatum and midbrain are different.46

View 1: Striatum faster than midbrain

  • Striatum:
    • Peak dopamine concentration reached within ∼200 ms
    • Degradation after a few hundred milliseconds
  • Midbrain:
    • prolonged increase in extracellular dopamine, since
      • Dopamine (re)uptake reduced by DAT
      • increased extracellular volume
    • SNc:
      • Peak of extracellular dopamine concentration 2000-3000 ms after a single stimulus
      • remains increased for several seconds

View 2: Striatum and midbrain approximately identical

  • comparable latency period for the dopamine increase until the peak
  • Half-width of the dopamine transient in the midbrain was less than twice as large as that in the striatum = small difference
    • probably due to DAT increase in the striatum
  • Total amount of dopamine released varies

5.7. Dopamine levels before and during release

The normal basal extracellular dopamine level at rest is approx. 4 nM.47
A normal nerve impulse briefly increases the dopamine level to around 250 nM, which is around 60 times the basal value.
The extracellular dopamine level then falls back to 4 nM, primarily through diffusion and further through reuptake.

An administration of 0.5 mg / kg D-AMP changes these values:47

  • approx. 25 nM extracellular basal value
  • approx. 500 nM peak value for nerve impulse

5.8. Trigger of dopamine release

5.8.1. Trigger of axonal dopamine release: calcium ions (Ca2+) at N-, P/Q-, T-, R-channels

Axonal dopamine release is triggered by extracellular Ca2+.1
Somatodendritic dopamine release in the substantia nigra pars compacta (SNc) persists even at such low extracellular Ca2+ levels that would not be sufficient to increase axonal release in the striatum.
The release of dopamine evoked by a single impulse in the dorsal striatum and SNc is independent of regulation by simultaneously released glutamate or GABA. The first impulse releases approximately 60 % of the dopamine from the pool of vesicles ready for release2

Axonal release appears to be channel-dependent. The striatal axonal release of dopamine was:4849

  • completely prevented by N-channel blocker (omega-conotoxin GVIA, 100 nm) (Cav2 channel)
  • reduced by 75 % due to P/Q channel blocker (omega agatoxin IVA, 200 nm) (Cav2 channel)
  • reduced by 25 % due to T-channel blocker (Ni2+, 100 micrometers) (Cav3 channel)
  • reduced by 25 % due to R-channel blocker (SNX-482, 100 nm)
    • different: R channel without influence49
  • not reduced by L-channel blocker (nifedipine, 20 micrometers) (Cav1 channel)
    • different: L-channel with influence49

The different types of calcium channels are:
L-type (“l “onglasting, long-lasting current),
T-type (“t “ransient, low current),
N-type (“n “either L or T, in “N “eurons),
P/Q type (in “P “urkinje cells of the cerebellum) and the
R-type (“r “emaining) VGCCs (voltage-gated Ca2+ channels)

None of these Ca2+ channel blockers affected somatodendritic dopamine release in the substantia nigra, either alone or together (but together shortened the duration of release).

Inhibition of Cav1 channels can promote the survival of dopamine neurons.1

The Ca2+ triggering substances of axonal dopamine release are largely unknown.
On fast synapses:

  • Synaptotagmin 1,2 and 9 trigger rapid release
  • Synaptotagmin 7 and Doc2 mediate Ca2+ sensitivity50
    • asynchronous and spontaneous release
    • the facilitation

Only 8 synaptotagmins bind Ca2+: synaptotagmin 1, 2, 3, 5, 6, 7, 9, and 10

5.8.2. Trigger of somatodendritic dopamine release

Mediate somatodendritic release:51

  • Synaptotagmin 4
  • Synaptotagmin 7

5.8.3. Spontaneous population activity (tonic)

Neurons can have several states

  • silent state
    • low firing
  • spontaneously active state
    • tonic firing
    • Willingness to also fire bursts
  • active state
    • Burst firing

Manipulations that increase the number of cells in the spontaneously active state also change the probability of firing rates from a normal distribution to a biphasic distribution. This is due to the activation of quiescent cells, which can fire at a lower rate than spontaneously active cells; thus, as more cells switch from quiescent to active, the overall firing rate does not change or decreases slightly.52

Translated with (free version) NMDA in the vSub increases spontaneous population activity

NMDA infusion into the ventral subiculum of the hippocampus (vSub) increases the number of spontaneously active dopamine neurons (population activity). This does not directly change the firing rate or average burst activity.53
Infusion of the glutamate receptor antagonist kynurenic acid into the nucleus accumbens abolished the NMDA effect54
Glutamatergic afferents from the vSub to the NAc activate DA neurons in the VTA and influence DA population activity such as regulation of firing54

  • Infusion of tetrodotoxin into the PFC did not affect DA population activity
  • Infusion of kynurenic acid into the NAc or tetrodotoxin into the vSub reduced the firing rate and burst firing of DA neurons without altering the number of spontaneously active DA neurons.

Simultaneous excitation of vSub and PPN causes a significant increase in both dopaminergic population activity and burst firing, quadrupling the number of neurons with high burst activity. Dopamine neuron population activity is apparently not simply associated with the tonic release of dopamine in the forebrain, but rather represents a recruitable pool of dopamine neurons that can be further modulated by excitatory inputs to induce a graded phasic response. The synchronous activity of different afferent inputs to the VTA appears to activate selective populations of dopamine neurons in phases53

Consequently, the vSub controls the number of dopamine neurons that can be activated in phases by the PPN by regulating the number of dopamine neurons that discharge tonically. The PPN therefore provides the “signal” for phasic dopamine release, which is weaker or stronger depending on the level of regulation of the vSub. The vSub is like the volume control of a stereo system, while the PNN provides the music signal that is played softer or louder. The vSub plays a role in context-dependent processing, and its influence can vary depending on the environment. For example, relevant stimuli in a benign context activate the PPN, allowing the moderate proportion of dopamine neurons activated by the vSub to fire in bursts.55 Neuroleptics increase spontaneous population activity and firing

Haloperidol, L-sulpiride, chlorpromazine, clozapine:565758

  • acute administration increases the spontaneous firing of dopamine neurons
    • in substantia nigra (A9) and VTA (A10)
    • Clozapine only in VTA, not in substantia nigra
    • no change with promethazine, d-sulpiride or imipramine
  • chronic administration increases it to such an extent that almost all neurons are depolarized, which almost completely prevents spontaneous firing
    • GABA, dopamine and apomorphine restored firing, but not glutamate Nitric oxide synthase (NOS) in the striatum increases spontaneous population activity and firing

Nitric oxide synthase (NOS) in the striatum regulates the tonic activity and responsiveness of dopamine neurons to cortical and striatal inputs in the substantia nigra59
NOS substrate in combination with intermittent periods of striatal and cortical stimulation increased the mean firing rate of the DA cell population MPFC regulates spontaneous population activity, firing and bursts in VTA and substantia nigra

Lesions of the mPFC caused by local injection of ibotenic acid:60

  • in the VTA
    • reduced population activity (number of spontaneously active neurons)
    • unchanged firing rate or burst activity of dopamine neurons
  • in substantia nigra
    • unchanged population activity
    • increased rate of fire
    • unchanged burst activity

5.8.4. Dopamine bursts (phasic) NMDA in the PPN increases dopamine bursts

NMDA activation of the pedunculopontine nucleus (PPN, also pedunculopontine tegmental nucleus, PPTg) causes a significant increase in dopamine neuron bursts without significantly affecting population activity53

The phasic activation of burst firing in dopamine neurons can only occur in neurons that are depolarized and fire spontaneously. Dopamine neurons hyperpolarized by GABAergic influences61 exhibit a magnesium blockade of the NMDA channel and cannot trigger a burst when stimulated by NMDA.62 NMDA in the lateral mesopontine tegmentum increases population activity and phasic dopamine activity in the VTA

The mesopontine tegmentum is divided into:63

  • Laterodorsal tegmental nucleus
    • provides tonic input for the maintenance of dopaminergic burst firing
  • Pedunculopontine nucleus (PPN/PPTg)
    • regulates transition from single-spike firing to burst firing
  • Rostromedial tegmental nucleus
    • provides inhibitory input for VTA
    • reduces the spontaneous activity of dopamine neurons
  • lateral mesopontine tegmentum
    • adjacent to PPN/PPTg
    • regulates both population activity and burst firing of dopamine neurons in the VTA
    • NMDA activation causes
      • Increase in the number of spontaneously active dopamine neurons
      • Increase in burst firing of dopamine neurons
        • Increase correlated with extracellular dopamine efflux in the nucleus accumbens in vivo

  1. Liu, Kaeser (2019): Mechanisms and regulation of dopamine release. Curr Opin Neurobiol. 2019 Aug;57:46-53. doi: 10.1016/j.conb.2019.01.001. PMID: 30769276; PMCID: PMC6629510. REVIEW

  2. Liu, Goel, Kaeser (2021): Spatial and temporal scales of dopamine transmission. Nat Rev Neurosci. 2021 Jun;22(6):345-358. doi: 10.1038/s41583-021-00455-7. PMID: 33837376; PMCID: PMC8220193. REVIEW

  3. Marinelli M, McCutcheon JE (2014): Heterogeneity of dopamine neuron activity across traits and states. Neuroscience. 2014 Dec 12;282:176-97. doi: 10.1016/j.neuroscience.2014.07.034. PMID: 25084048; PMCID: PMC4312268.

  4. Zhang, Doyon, Clark, Phillips, Dani (2009): Controls of tonic and phasic dopamine transmission in the dorsal and ventral striatum. Mol Pharmacol. 2009 Aug;76(2):396-404. doi: 10.1124/mol.109.056317. PMID: 19460877; PMCID: PMC2713129.

  5. Rillich (2019): Das dopaminerge System im Gehirn des Menschen: molekulare Grundlagen, Anatomie, Physiologie und Pathologie

  6. Keath, Iacoviello, Barrett, Mansvelder, McGehee (2007): Differential modulation by nicotine of substantia nigra versus ventral tegmental area dopamine neurons. J Neurophysiol. 2007 Dec;98(6):3388-96. doi: 10.1152/jn.00760.2007. PMID: 17942622.

  7. Devoto, Sagheddu, Santoni, Flore, Saba, Pistis, Gessa (2020): Noradrenergic Source of Dopamine Assessed by Microdialysis in the Medial Prefrontal Cortex. Front Pharmacol. 2020 Sep 23;11:588160. doi: 10.3389/fphar.2020.588160. PMID: 33071798; PMCID: PMC7538903.

  8. Myslivecek (2022): Dopamine and Dopamine-Related Ligands Can Bind Not Only to Dopamine Receptors. Life (Basel). 2022 Apr 19;12(5):606. doi: 10.3390/life12050606. PMID: 35629274; PMCID: PMC9147915. REVIEW

  9. Fuxe K, Dahlström AB, Jonsson G, Marcellino D, Guescini M, Dam M, Manger P, Agnati L (2010): The discovery of central monoamine neurons gave volume transmission to the wired brain. Prog Neurobiol. 2010 Feb 9;90(2):82-100. doi: 10.1016/j.pneurobio.2009.10.012. PMID: 19853007. REVIEW

  10. Zhou Z, Misler S, Chow RH (1996): Rapid fluctuations in transmitter release from single vesicles in bovine adrenal chromaffin cells. Biophys J. 1996 Mar;70(3):1543-52. doi: 10.1016/S0006-3495(96)79718-7. PMID: 8785312; PMCID: PMC1225082.

  11. Sulzer D, Cragg SJ, Rice ME (2016): Striatal dopamine neurotransmission: regulation of release and uptake. Basal Ganglia. 2016 Aug;6(3):123-148. doi: 10.1016/j.baga.2016.02.001. PMID: 27141430; PMCID: PMC4850498. REVIEW

  12. Bulumulla, Krasley, Cristofori-Armstrong, Valinsky, Walpita, Ackerman, Clapham, Beyene (2022): Visualizing synaptic dopamine efflux with a 2D composite nanofilm. Elife. 2022 Jul 4;11:e78773. doi: 10.7554/eLife.78773. PMID: 35786443; PMCID: PMC9363124.

  13. Ford CP (2014): The role of D2-autoreceptors in regulating dopamine neuron activity and transmission. Neuroscience. 2014 Dec 12;282:13-22. doi: 10.1016/j.neuroscience.2014.01.025. PMID: 24463000; PMCID: PMC4108583. REVIEW

  14. Hinghofer-Szalkay: Synapsen,

  15. Structure of Chemical Synapses

  16. Uchigashima, Ohtsuka, Kobayashi, Watanabe (2016): Dopamine synapse is a neuroligin-2-mediated contact between dopaminergic presynaptic and GABAergic postsynaptic structures. Proc Natl Acad Sci U S A. 2016 Apr 12;113(15):4206-11. doi: 10.1073/pnas.1514074113. PMID: 27035941; PMCID: PMC4839454.

  17. Staal RG, Mosharov EV, Sulzer D (2004): Dopamine neurons release transmitter via a flickering fusion pore. Nat Neurosci. 2004 Apr;7(4):341-6. doi: 10.1038/nn1205. PMID: 14990933.

  18. Sulzer, Cragg, Rice (2016): Striatal dopamine neurotransmission: regulation of release and uptake. Basal Ganglia. 2016 Aug;6(3):123-148. doi: 10.1016/j.baga.2016.02.001. PMID: 27141430; PMCID: PMC4850498. REVIEW

  19. (Sulzer, Cragg, Rice (2016): Striatal dopamine neurotransmission: regulation of release and uptake. Basal Ganglia. 2016 Aug;6(3):123-148. doi: 10.1016/j.baga.2016.02.001. PMID: 27141430; PMCID: PMC4850498. REVIEW

  20. Scepek S, Coorssen JR, Lindau M (1998): Fusion pore expansion in horse eosinophils is modulated by Ca2+ and protein kinase C via distinct mechanisms. EMBO J. 1998 Aug 3;17(15):4340-5. doi: 10.1093/emboj/17.15.4340. PMID: 9687502; PMCID: PMC1170767.

  21. Staal RG, Hananiya A, Sulzer D (2008): PKC theta activity maintains normal quantal size in chromaffin cells. J Neurochem. 2008 Jun;105(5):1635-41. doi: 10.1111/j.1471-4159.2008.05264.x. PMID: 18248621; PMCID: PMC6589162.

  22. Pereira, Sulzer (2012): Mechanisms of dopamine quantal size regulation. Front Biosci (Landmark Ed). 2012 Jun 1;17(7):2740-67. doi: 10.2741/4083. PMID: 22652810. REVIEW

  23. Hinghofer-Szalkay: Nervenzellen im Verbund; Physiologie des Kortex,

  24. Garris, Ciolkowski, Pastore, Wightman (1994): Efflux of dopamine from the synaptic cleft in the nucleus accumbens of the rat brain. J Neurosci. 1994 Oct;14(10):6084-93. doi: 10.1523/JNEUROSCI.14-10-06084.1994. PMID: 7931564; PMCID: PMC6577011.

  25. Elizarova, Chouaib, Shaib, Hill, Mann, Brose, Kruss, Daniel (2022): A fluorescent nanosensor paint detects dopamine release at axonal varicosities with high spatiotemporal resolution. Proc Natl Acad Sci U S A. 2022 May 31;119(22):e2202842119. doi: 10.1073/pnas.2202842119. PMID: 35613050; PMCID: PMC9295782.

  26. [Matsuda W, Furuta T, Nakamura KC, Hioki H, Fujiyama F, Arai R, Kaneko T (2009): Single nigrostriatal dopaminergic neurons form widely spread and highly dense axonal arborizations in the neostriatum. J Neurosci. 2009 Jan 14;29(2):444-53. doi: 10.1523/JNEUROSCI.4029-08.2009. PMID: 19144844; PMCID: PMC6664950.)](

  27. Condon AF, Robinson BG, Asad N, Dore TM, Tian L, Williams JT (2021): The residence of synaptically released dopamine on D2 autoreceptors. Cell Rep. 2021 Aug 3;36(5):109465. doi: 10.1016/j.celrep.2021.109465. PMID: 34348146; PMCID: PMC8351352.

  28. Robinson BG, Cai X, Wang J, Bunzow JR, Williams JT, Kaeser PS (2019): RIM is essential for stimulated but not spontaneous somatodendritic dopamine release in the midbrain. Elife. 2019 Sep 5;8:e47972. doi: 10.7554/eLife.47972. PMID: 31486769; PMCID: PMC6754207.

  29. Gantz SC, Bunzow JR, Williams JT. (2013): Spontaneous inhibitory synaptic currents mediated by a G protein-coupled receptor. Neuron. 2013 Jun 5;78(5):807-12. doi: 10.1016/j.neuron.2013.04.013. PMID: 23764286; PMCID: PMC3697754.

  30. Cragg SJ, Rice ME (2004): DAncing past the DAT at a DA synapse. Trends Neurosci. 2004 May;27(5):270-7. doi: 10.1016/j.tins.2004.03.011. PMID: 15111009.

  31. Wiencke K, Horstmann A, Mathar D, Villringer A, Neumann J (2020): Dopamine release, diffusion and uptake: A computational model for synaptic and volume transmission. PLoS Comput Biol. 2020 Nov 30;16(11):e1008410. doi: 10.1371/journal.pcbi.1008410. PMID: 33253315; PMCID: PMC7728201.

  32. Zhou FW, Jin Y, Matta SG, Xu M, Zhou FM (2009): An ultra-short dopamine pathway regulates basal ganglia output. J Neurosci. 2009 Aug 19;29(33):10424-35. doi: 10.1523/JNEUROSCI.4402-08.2009. PMID: 19692618; PMCID: PMC3596265.

  33. González-Rodríguez, Zampese, Stout, Guzman, Ilijic, Yang B, Tkatch, Stavarache, Wokosin, Gao L, Kaplitt, López-Barneo, Schumacker, Surmeier (2022): Disruption of mitochondrial complex I induces progressive parkinsonism. Nature. 2021 Nov;599(7886):650-656. doi: 10.1038/s41586-021-04059-0. Epub 2021 Nov 3. Erratum in: Nature. 2022 Mar;603(7899):E1. PMID: 34732887; PMCID: PMC9189968.

  34. Biederer, Kaeser, Blanpied (2017): Transcellular Nanoalignment of Synaptic Function. Neuron. 2017 Nov 1;96(3):680-696. doi: 10.1016/j.neuron.2017.10.006. PMID: 29096080; PMCID: PMC5777221. REVIEW

  35. Südhof (2012): The presynaptic active zone. Neuron. 2012 Jul 12;75(1):11-25. doi: 10.1016/j.neuron.2012.06.012. PMID: 22794257; PMCID: PMC3743085. REVIEW

  36. Altrock, tom Dieck, Sokolov, Meyer, Sigler, Brakebusch, Fässler, Richter, Boeckers, Potschka, Brandt, Löscher, Grimberg, Dresbach, Hempelmann, Hassan, Balschun, Frey, Brandstätter, Garner, Rosenmund, Gundelfinger (2003): Functional inactivation of a fraction of excitatory synapses in mice deficient for the active zone protein bassoon. Neuron. 2003 Mar 6;37(5):787-800. doi: 10.1016/s0896-6273(03)00088-6. PMID: 12628169.

  37. Caillé, Dumartin, Bloch (1996): Ultrastructural localization of D1 dopamine receptor immunoreactivity in rat striatonigral neurons and its relation with dopaminergic innervation. Brain Res. 1996 Aug 19;730(1-2):17-31. doi: 10.1016/0006-8993(96)00424-6. PMID: 8883884.

  38. Mazei-Robison MS, Bowton E, Holy M, Schmudermaier M, Freissmuth M, Sitte HH, Galli A, Blakely RD (2008): Anomalous dopamine release associated with a human dopamine transporter coding variant. J Neurosci. 2008 Jul 9;28(28):7040-6. doi: 10.1523/JNEUROSCI.0473-08.2008. PMID: 18614672; PMCID: PMC2573963.

  39. Itokawa M, Lin Z, Uhl GR (2002): Dopamine efflux via wild-type and mutant dopamine transporters: alanine substitution for proline-572 enhances efflux and reduces dependence on extracellular dopamine, sodium and chloride concentrations. Brain Res Mol Brain Res. 2002 Dec;108(1-2):71-80. doi: 10.1016/s0169-328x(02)00515-6. PMID: 12480180.

  40. Sulzer D, Galli A (2003): Dopamine transport currents are promoted from curiosity to physiology. Trends Neurosci. 2003 Apr;26(4):173-6. doi: 10.1016/S0166-2236(03)00063-8. PMID: 12689764.

  41. Johnson LA, Guptaroy B, Lund D, Shamban S, Gnegy ME (2005): Regulation of amphetamine-stimulated dopamine efflux by protein kinase C beta. J Biol Chem. 2005 Mar 25;280(12):10914-9. doi: 10.1074/jbc.M413887200. PMID: 15647254.

  42. Fog JU, Khoshbouei H, Holy M, Owens WA, Vaegter CB, Sen N, Nikandrova Y, Bowton E, McMahon DG, Colbran RJ, Daws LC, Sitte HH, Javitch JA, Galli A, Gether U (2006): Calmodulin kinase II interacts with the dopamine transporter C terminus to regulate amphetamine-induced reverse transport. Neuron. 2006 Aug 17;51(4):417-29. doi: 10.1016/j.neuron.2006.06.028. PMID: 16908408.

  43. Bowton E, Saunders C, Reddy IA, Campbell NG, Hamilton PJ, Henry LK, Coon H, Sakrikar D, Veenstra-VanderWeele JM, Blakely RD, Sutcliffe J, Matthies HJ, Erreger K, Galli A (2014): SLC6A3 coding variant Ala559Val found in two autism probands alters dopamine transporter function and trafficking. Transl Psychiatry. 2014 Oct 14;4(10):e464. doi: 10.1038/tp.2014.90. PMID: 25313507; PMCID: PMC4350523.

  44. Khoshbouei H, Sen N, Guptaroy B, Johnson L’, Lund D, Gnegy ME, Galli A, Javitch JA (2004): N-terminal phosphorylation of the dopamine transporter is required for amphetamine-induced efflux. PLoS Biol. 2004 Mar;2(3):E78. doi: 10.1371/journal.pbio.0020078. Epub 2004 Mar 16. PMID: 15024426; PMCID: PMC368172.

  45. Wise RA, Bozarth MA (1987): A psychomotor stimulant theory of addiction. Psychol Rev. 1987 Oct;94(4):469-92. PMID: 3317472.

  46. Ford CP, Gantz SC, Phillips PE, Williams JT (2010): Control of extracellular dopamine at dendrite and axon terminals. J Neurosci. 2010 May 19;30(20):6975-83. doi: 10.1523/JNEUROSCI.1020-10.2010. PMID: 20484639; PMCID: PMC2883253.

  47. Seeman P, Madras BK (1998): Anti-hyperactivity medication: methylphenidate and amphetamine. Mol Psychiatry. 1998 Sep;3(5):386-96. doi: 10.1038/ PMID: 9774771. REVIEW

  48. Chen, Moran, Avshalumov, Rice (2006): Limited regulation of somatodendritic dopamine release by voltage-sensitive Ca channels contrasted with strong regulation of axonal dopamine release. J Neurochem. 2006 Feb;96(3):645-55. doi: 10.1111/j.1471-4159.2005.03519.x. PMID: 16405515.

  49. Brimblecombe, Gracie, Platt, Cragg (2015): Gating of dopamine transmission by calcium and axonal N-, Q-, T- and L-type voltage-gated calcium channels differs between striatal domains. J Physiol. 2015 Feb 15;593(4):929-46. doi: 10.1113/jphysiol.2014.285890. PMID: 25533038; PMCID: PMC4398530.

  50. Kaeser, Regehr (2014): Molecular mechanisms for synchronous, asynchronous, and spontaneous neurotransmitter release. Annu Rev Physiol. 2014;76:333-63. doi: 10.1146/annurev-physiol-021113-170338. Epub 2013 Nov 21. PMID: 24274737; PMCID: PMC4503208. REVIEW

  51. Mendez, Bourque, Fasano, Kortleven, Trudeau (2011): Somatodendritic dopamine release requires synaptotagmin 4 and 7 and the participation of voltage-gated calcium channels. J Biol Chem. 2011 Jul 8;286(27):23928-37. doi: 10.1074/jbc.M111.218032. PMID: 21576241; PMCID: PMC3129174.

  52. Marinelli M, McCutcheon JE (2014): Heterogeneity of dopamine neuron activity across traits and states. Neuroscience. 2014 Dec 12;282:176-97. doi: 10.1016/j.neuroscience.2014.07.034. PMID: 25084048; PMCID: PMC4312268. REVIEW

  53. Lodge DJ, Grace AA (2006): The hippocampus modulates dopamine neuron responsivity by regulating the intensity of phasic neuron activation. Neuropsychopharmacology. 2006 Jul;31(7):1356-61. doi: 10.1038/sj.npp.1300963. PMID: 16319915.

  54. Floresco SB, Todd CL, Grace AA (2001): Glutamatergic afferents from the hippocampus to the nucleus accumbens regulate activity of ventral tegmental area dopamine neurons. J Neurosci. 2001 Jul 1;21(13):4915-22. doi: 10.1523/JNEUROSCI.21-13-04915.2001. PMID: 11425919; PMCID: PMC6762358.

  55. Véronneau-Veilleux F, Robaey P, Ursino M, Nekka F (2022): A mechanistic model of ADHD as resulting from dopamine phasic/tonic imbalance during reinforcement learning. Front Comput Neurosci. 2022 Jul 18;16:849323. doi: 10.3389/fncom.2022.849323. PMID: 35923915; PMCID: PMC9342605.

  56. Chiodo LA, Bunney BS (1983): Typical and atypical neuroleptics: differential effects of chronic administration on the activity of A9 and A10 midbrain dopaminergic neurons. J Neurosci. 1983 Aug;3(8):1607-19. doi: 10.1523/JNEUROSCI.03-08-01607.1983. PMID: 6135762; PMCID: PMC6564520.

  57. Bunney BS, Grace AA (1978): Acute and chronic haloperidol treatment: comparison of effects on nigral dopaminergic cell activity. Life Sci. 1978 Oct 23;23(16):1715-27. doi: 10.1016/0024-3205(78)90471-x. PMID: 31529.

  58. White FJ, Wang RY (1983): Differential effects of classical and atypical antipsychotic drugs on A9 and A10 dopamine neurons. Science. 1983 Sep 9;221(4615):1054-7. doi: 10.1126/science.6136093. PMID: 6136093.

  59. West AR, Grace AA (2000): Striatal nitric oxide signaling regulates the neuronal activity of midbrain dopamine neurons in vivo. J Neurophysiol. 2000 Apr;83(4):1796-808. doi: 10.1152/jn.2000.83.4.1796. PMID: 10758092.

  60. Shim SS, Bunney BS, Shi WX (1996): Effects of lesions in the medial prefrontal cortex on the activity of midbrain dopamine neurons. Neuropsychopharmacology. 1996 Nov;15(5):437-41. doi: 10.1016/S0893-133X(96)00052-8. PMID: 8914116.

  61. Floresco SB, West AR, Ash B, Moore H, Grace AA (2003): Afferent modulation of dopamine neuron firing differentially regulates tonic and phasic dopamine transmission. Nat Neurosci. 2003 Sep;6(9):968-73. doi: 10.1038/nn1103. PMID: 12897785.

  62. Mayer ML, Westbrook GL, Guthrie PB (1984): Voltage-dependent block by Mg2+ of NMDA responses in spinal cord neurones. Nature. 1984 May 17-23;309(5965):261-3. doi: 10.1038/309261a0. PMID: 6325946.

  63. Chen L, Lodge DJ (2013): The lateral mesopontine tegmentum regulates both tonic and phasic activity of VTA dopamine neurons. J Neurophysiol. 2013 Nov;110(10):2287-94. doi: 10.1152/jn.00307.2013. PMID: 24004527; PMCID: PMC3841868.

Diese Seite wurde am 13.04.2024 zuletzt aktualisiert.