5. Dopamine release (tonic, phasic) and encoding.

• 5.1. Dopamine release
  • 5.1.1. Source of dopamine release
    • 5.1.1.1. Dopamine synthesis and dopamine release from dopaminergic neurons
      • 5.1.1.1.1. VTA: dopamine, GABA, VGLUT2
    • 5.1.1.2. Dopamine release from noradrenergic neurons
  • 5.1.2. Function of vesicles
    • 5.1.2.1. Triggering of synaptic vesicle fusion by SNARE proteins
    • 5.1.2.2. Slow replenishment of dopaminergic vesicles
  • 5.1.3. Forms of neurotransmitter transmission
    • 5.1.3.1. General forms of neurotransmitter transmission
      • 5.1.3.1.1. Endocrine transmission
      • 5.1.3.1.2. Volume transfer
      • 5.1.3.1.3. Synaptic transmission
    • 5.1.3.2. Dopaminergic transmission
  • 5.1.4. Axonal and somatodendritic release
    • 5.1.4.1. Axonal release, axonal varicosities
    • 5.1.4.2. Somatodendritic release: release from dendrites, not from cell bodies
  • 5.1.5. Active zone
    • 5.1.5.1. Active zone in nerve cells
    • 5.1.5.2. Active zone in axons
    • 5.1.5.3. Active zone in dendrites
  • 5.1.6. Function of synapses
    • 5.1.6.1. Dopaminergic synapses
    • 5.1.6.2. Domain overlap model
  • 5.1.7. Trigger of dopamine release
    • 5.1.7.1. Trigger of axonal dopamine release: calcium ions (Ca2+) at N, P/Q, T, R channels
    • 5.1.7.2. Trigger of somatodendritic dopamine release
  • 5.1.7. Area measurements of dopamine release
• 5.2. Tonic dopamine / phasic dopamine
  • 5.2.1. Tonic dopamine firing
  • 5.2.2. Phasic dopamine firing, bursts
  • 5.2.3. Extracellular dopamine
  • 5.2.4. Tonic and phasic dopamine between PFC and striatum
  • 5.2.5. Tonic and phasic dopamine in the striatum
  • 5.2.6. Tonic and phasic dopamine in explanatory models of ADHD
    • 5.2.6.1. Dynamic Development Theory (DDT)
    • 5.2.6.2. Grace, 1991, 2001
• 5.3. Coding of behavioral values by dopamine
  • 5.3.1. Speed of dopamine level change in the brain encodes different behaviors.
  • 5.3.2. 10-Minute range encodes strength of motivation and behavioral activation
  • 5.3.3. Seconds range encodes value of future reward
  • 5.3.4. Subsecond range activates a. reward search and b. movement
  • 5.3.5. Does mesolimbic phasic DA encode the value of work?
  • 5.3.6. Does acetylcholine switch between dopaminergic encoding of reward prediction error and learning?
  • 5.3.7. Different DA neurons in relation to aversive stimuli?
  • 5.3.8. Phasic DA encodes movement in the dorsal striatum, reward in the ventral striatum
  • 5.3.9. Does dopamine encode the utility of a resource expenditure?
    • 5.3.9.1. Dorsolateral striatum: DA encodes the resource movement
    • 5.3.9.2. Dorsomedial striatum: DA encodes the resource of cognitive processes
    • 5.3.9.3. Nucleus accumbens: DA encodes the resource time

5.1. Dopamine release¶

The representations of this paper currently rely to a disproportionate extent on the work of Liu and Kaeser ¹²

5.1.1. Source of dopamine release¶

5.1.1.1. Dopamine synthesis and dopamine release from dopaminergic neurons¶

Dopamine neurons in the VTA and substantia nigra synthesize dopamine. This is transported to dopaminergic cells via axons.

5.1.1.1.1. VTA: dopamine, GABA, VGLUT2¶

Dopamine from the VTA modulates motivated behavior and reinforcement learning.
The other neurotransmitters that VTA neurons release also influence motivation.

VTA neurons are:

• pure dopaminerg³
  • Activation by positive stimuli such as food, sugar, water or addictive substances
  • Projection to: Nucleus accumbens
    • NAc D1 type-MSN
      • activated when dopamine is released, by enhancing the PKA pathway
      • encode reward/positive stimuli
      • directly inhibit the ventral mesencephalon, which in turn inhibits the thalamus (direct pathway).
    • NAc D2 type-MSN
      • activated when dopamine is low, through activation of the adenosine A2A receptor (A2AR), which increases intracellular calcium levels
      • encode aversive/negative stimuli
      • disinhibit the ventral mesencephalon by suppressing the ventral pallidum (indirect pathway)
• pure GABAergic³
  • GABAergic VTA neurons project to nucleus accumbens, PFC, central amygdala, lateral habenula, and the dorsal raphe nuclei.
  • GABA-A receptors cause hyperpolarization of postneurons by influx of chloride ions
  • GABA-B receptors further induce hyperpolarization by suppressing acetyl cyclase and voltage-gated calcium channels
  • Tasks:
    • Inhibition of dopaminergic neurons in the VTA and inhibition of distal brain regions
    • Aversion and interruption of rewards
    • Response to cues and in reward-associated learning
    • VTA GABAergic neurons become active and suppress VTA DA neurons when mice anticipate a reward such as sucrose or cocaine after exposure to a stimulus unrelated to the reward. GABAergic neurons in the VTA thus control VTA dopaminergic activity by interrupting reward consumption and disrupting responsiveness
    • regulate place preference when projection from caudal GABAergic neurons of the VTA to serotonergic neurons of the DRN is activated
    • GABEergic VTA neurons predict the absence of a reward⁴
• pure VGLUT2 (type 2 vesicular glutamate transporter)³
  • Knockout of glutamatergic VTA neurons reduces motivated behavior
  • VGLUT2-VTA neurons become active during self-administration of drugs, drug-seeking behavior, and reinforcement
  • project into the medial shell of the nucleus accumbens, ventral palladium, and lateral habenula
  • directly excite nucleus accumbens and ventral palladium
  • inhibit lateral habenula
  • Glutamate in the axon terminal binds to N-methyl-D-aspartate receptors (NMDA-Rs), resulting in calcium influx that activates the pERK pathway
  • become active in classical conditioning when exposed to reward or electroshock
    • active firing in response to the conditioned stimulus associated with the reward
  • glutamatergic VTA neurons predict a reward⁴
• VGLUT2/dopamine neurons³
  • release glutamate and dopamine together at the axon terminals
    • Glutamate via asymmetric synapses
    • Dopamine via symmetrical synapses
  • VGLUT2-DA neurons increase survival and axonal arborization of VTA dopamine neurons
  • project to the cholinergic neurons in the medial shell of the nucleus accumbens
  • contribute to switching the behavioral response in tasks with cognitive reinforcement
• VGLUT2/GABA neurons³
  • differ from pure VGLUT neurons on the circuit level
  • are strongly associated with lateral habenula and ventral palladium
  • become active in classical conditioning when exposed to reward or electroshock
    • no active firing in response to the conditioned stimulus associated with the reward
  • VGLUT2-GABA neurons
    • encode the valence itself
    • signal rewarding and aversive outcomes without signaling learned cues related to those outcomes⁴
• GABA dopamine neurons³
  • are strongly focused on nucleus accumbens
  • Release of neurotransmitters is controlled by uptake mechanism, not by classical GAD1/2 pathway
    • VTA-DA neurons synthesize GABA via aldehyde dehydrogenase 1A1
    • GABA vesicles are filled by vesicular monoamine transporter, not by vesicular GABA transporter

Overall, VTA neurons are³

• dopaminergic: > 70 %
• GABAergic: approx. 30
• VGLUT2erg: approx. 30 %

Dopamine release from the VTA follows a 12-hour rhythm. VTA neurons fire highest early in the light cycle and early in the dark cycle. In particular, a small subset of VTA neurons appears to be active at night.⁵
In contrast, neurons of substantia nigra showed no changes across circadian time.

5.1.1.2. Dopamine release from noradrenergic neurons¶

Since dopamine is also reuptaken by NETs in addition to the DAT (see below under degradation of dopamine) and stored by them in vesicles (especially in the PFC), 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, extracellular dopamine and noradrenaline levels in the mPFC decrease.⁶

5.1.2. Function of vesicles¶

Vesicles are roundish to oval vesicles located in the cell, about one micrometer in size, surrounded by a double membrane or a reticular protein envelope. Vesicles form their own cellular compartments in which various cellular processes take place. Vesicles are responsible for the storage / retention of various many 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 become part of the cell membrane after fusion
    • synaptic vesicles for the release of neurotransmitters
• endocytotic vesicles
  • serve for the uptake of substances into the cell and the recycling of membrane proteins

5.1.2.1. Triggering of synaptic vesicle fusion by SNARE proteins¶

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 found in dendrites only where synaptobrevin-2/VAMP-2 was also detected.⁷
  A small fraction of the neurotransmitter-filled vesicles is bound by synapsin to the actin skeleton of the active zone near voltage-gated Ca2+ membrane channels, where it is activated. When an action potential depolarizes the presynaptic plasma membrane, Ca2+ enters through these channels and triggers fusion of the vesicles with the membrane by means of synaptotagmin 1, 2, or 9, which act as Ca2+ sensors. Neurotransmitters then leak from the vesicles into the synaptic cleft to activate postsynaptic receptors.
  Botulinum toxin A and B cleave SNAP-25 and synaptobrevin-2, inhibiting the docking of vesicles to the cell membrane. Tetanus toxin also cleaves synaptobrevin-2, but does not always inhibit dopamine release.¹

5.1.2.2. Slow replenishment of dopaminergic vesicles¶

The pool of easily released dopamine vesicles refills only slowly. The depletion of dopamine release after a single stimulus lasts for several tens of seconds. Restoration of release readiness thus takes one to two orders of magnitude longer than for fast synapses. Since the speed of replenishment 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.⁸ The idea that each release releases a fixed amount of the neurotransmitter (the “quantum”) is outdated.

5.1.3. 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

5.1.3.1. General forms of neurotransmitter transmission¶

5.1.3.1.1. Endocrine transmission¶

Endocrine cells usually release hormones as transmitters. The release takes place at the cell surface. The transmitters travel distances of millimeters to meters through the extracellular space and the bloodstream to distant receptors. Endocrine cells often do not show specially designed release sites.²

5.1.3.1.2. Volume transfer¶

In volume transfer, transmitters diffuse over a wider area. The release sites are located a few hundred nanometers to a few millimeters away. Transmitters are usually released from specialized sites similar to the active zone. The distance to the determines receptor activation and is therefore characterized by a steep transmitter concentration gradient.² Volume transmission thus allows the neurotransmitter to spread over a greater distance (more than 10 μm, instead of only 30-40 nm in the classical 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 of the cross-activity of dopamine.⁹
Volume transmission at dopaminergic synapses is sometimes doubted.

5.1.3.1.3. Synaptic transmission¶

In synaptic transmission, there is a very tight spatial coupling of a few tens of nanometers between the transmitter-secreting active zone and the receptor clusters. The active zone and receptor clusters are often aligned at the subsynaptic level. Signal transmission occurs only within the synaptic cleft, resulting in accurate and efficient receptor activation.²

5.1.3.2. Dopaminergic transmission¶

Dopamine is released from synaptic and non-synaptic varicosities.
Most dopamine varicosities are not bound to postsynaptic cells and densities. Several studies suggest a distributed localization.
D1

• broadly localized on D1-MSN
• with somatic, dendritic shaft and dendritic spine localizations
• At times they occur in groups.

D2

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

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

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

Thus, dopamine receptors seem to be partially clustered on MSNs. The majority of dopamine receptors are (so far) not detectable in synapse-like apposition.
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 incorporation of dopamine into the vesicles. Rabbits treated with reserpine became paralyzed. Administration of L-DOPA, a precursor of dopamine, restored locomotor capacity even though VMAT blockade persisted. Thus, in the absence of vesicular dopamine and precise vesicular release in synapses, the brain can metabolize L-DOPA and use it for locomotion.
Vertebrate dopamine receptors are exclusively G protein-coupled receptors, which are orders of magnitude slower than ionotropic receptors. Dopamine is therefore able to transmit signals even without precise synaptic communication: the so-called volume transmission.²

5.1.4. Axonal and somatodendritic release¶

In principle, neurotransmitters can be transferred in several ways:¹⁰

• From the axon (axoaxonal)
  • Axon stem 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 trunk at synapses
  • Dendrite spinous processes at synapses

Dopamine is released in a number of ways:¹

5.1.4.1. Axonal release, axonal varicosities¶

The dopamine formed is transported via nerve tracts (axons) into dopaminergic cells. There, it is stored in vesicles, which are later brought to the cell membrane and there, in response to electrical impulses, release the dopamine 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.¹¹

Axons mediate most of the dopamine transmission. Axonal dopamine varicosities are densely packed with clusters of small, clear vesicles. Quantitative events reminiscent of single vesicular dopamine packets can be sensed by dopamine axons or cell bodies. Blockade or knockout of VMAT2 terminates dopamine transmission.
Only about 17% of varicosities secrete dopamine.¹² It is conceivable that axon varicosities also secrete dopamine without synapses.²

Dopaminterminals often form a triad with other axons in close spatial contact. In this case, a neuron is connected to both the presynaptic element and the postsynaptic (usually dendritic) target. Triads are widely distributed in hippocampus, striatum and mPFC. These triads may contain both dopamine and serotonin or adrenergic terminals.⁹

5.1.4.2. Somatodendritic release: release from dendrites, not from cell bodies¶

• Somatodenritic dopamine release occurs primarily from dendrites, not soma⁷
  • also dendrites without recognizable varicosities secreted dopamine
  • as well as dendritic branches with bouton structures (resembling 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 stored mainly in tubulo-vesicular structures resembling the smooth endoplasmic reticulum in the soma or dendrites¹³

Somatodendritic dopamine release in midbrain regions (especially substantia nigra pars compact (SNc) and VTA), is involved in:⁷

• of 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 neurons¹⁴

Somatodendritic dopamine release uses two mechanisms for this purpose:

• Dopamine released in SNc and in the VTA activates D2 autoreceptors
  • 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
        • relevant in VTA e.g. for induction of behavioral sensitization to amphetamine by activation of local D1 receptors
• Dendritic projections of VTA in substantia nigra pars reticulata (SNr)
  • activates D1 receptors
  • regulates / activates the release of the primary GABA-ergic 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 DA release¹³

5.1.5. 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 synaptic vesicles and stimulates them. As a result, the active zone forms a pool of readily releasable vesicles, and positions these vesicles at specific distances from presynaptic Ca2+ channels, thereby controlling the vesicular release probability. Only a few percent of the vesicles present are part of the pool ready for release²

5.1.5.1. Active zone in nerve cells¶

Synaptic transmission is characterized by its speed and spatial precision. The fusion of synaptic vesicles with the cell membrane occurs in less than a millisecond after the arrival of an action potential. Release from a vesicle occurs spatially precisely opposite postsynaptic receptors from the active zone.¹⁵ The active zone binds vesicles primed for release to the presynaptic plasma membrane near Ca2+ channels.¹⁶
The active zone consists of the molecular scaffolds¹

• 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.⁷

5.1.5.2. Active zone in axons¶

Dopamine axons contain active zonelike protein scaffolds composed of¹

• RIM
  • Only 30% of varicosities of dopaminergic axons contain RIM. RIM and MUNC13 are essential (as in conventional synapses) for the function of an active zone. This may explain why only 20% to 30% of varicosities of axons actively secrete dopamine.
• ELKS2
• Bassoon
  • Deactivation of the bassoon reduces neurotransmitter release¹⁷
• Munc13-1 (probably)

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 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.¹⁸

5.1.5.3. Active zone in dendrites¶

Somatodendritic dopamine release also appears to function by means of active zones.⁷ Here, too, neurotransmitter release is linked to the existence of Bassoon.

5.1.6. Function of synapses¶

Fundamental to the function of synapses: German: Hinghofer-Szalkay.¹⁹ English: Synapseweb.²⁰

Chemical synapses consist of

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

Gray type:

• Gray type I
  • Asymmetric synapse
• Gray type II
  • Symmetrical synapse

5.1.6.1. Dopaminergic synapses¶

Dopamine synapses are commonly found in dendritic shafts and spines of medium-sized spiny projection neurons (MSNs), the principal neurons in the striatum.
Midbrain dopamine neurons project densely into the striatum and form so-called dopamine synapses at MSNs. 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 those farther away. The exact organization of dopamine receptors in relation to release sites is not yet known.²

5.1.6.2. Domain overlap model¶

A growing body of 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 in which release and receptors are arranged in micrometer-sized structures relative to each other may be relevant. This is based on rapid release followed by diffusion with a micrometer-sized release-receptor organization.
This model is thought to allow 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 switching firing modes supports a broad and dynamic role of dopamine and can lead to marked modulation of signaling pathways.²

5.1.7. Trigger of dopamine release¶

5.1.7.1. 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 substantia nigra pars compacta (SNc) persists even at extracellular Ca2+ so low that it would be insufficient to increase axonal release in the striatum.
Dopamine release evoked by a single pulse in the dorsal striatum and SNc is independent of regulation by simultaneously released glutamate or GABA.

The first pulse releases approximately 60% of the dopamine from the vesicle pool ready for release²

Axonal release appears to be channel dependent. The striatal axonal dopamine release was:²²²³

• by N-channel blocker (omega-conotoxin GVIA, 100 nm), completely prevented (Cav2 channel)
• by P/Q channel blocker (omega agatoxin IVA, 200 nm), reduced by 75% (Cav2 channel)
• reduced by 25 % by T-channel blockers (Ni2+, 100 microns) (Cav3 channel)
• reduced by 25 % by R-channel blocker (SNX-482, 100 nm)
  • different: R channel without influence²³
• not reduced by L-channel blocker (nifedipine, 20 microns) (Cav1 channel)
  • different: L channel with influence²³

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

Inhibition of Cav1 channels may promote survival of dopamine neurons.¹

The Ca2+-triggering agents of axonal dopamine release are largely unknown.
At fast synapses:

• Synaptotagmin 1,2 and 9 trigger rapid release
• Synaptotagmin 7 and Doc2 mediate Ca2+ sensitivity²⁴
  • the asynchronous and spontaneous release
  • the facilitation

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

5.1.7.2. Trigger of somatodendritic dopamine release¶

Mediate somatodendritic release:²⁵

• Synaptotagmin 4
• Synaptotagmin 7

5.1.7. Area measurements of dopamine release¶

Previously, dopamine could only be measured at a single point. This only allowed the detection of a quantity value at a single point.
In the meantime, methods have been developed to measure and record dopamine release at the area level.
One method describes the observation of whole cell dopamine release,²⁶ another describes the areal observation of dopamine release down to the dendrite level.⁷
These new techniques will enable significant gains in knowledge.

5.2. Tonic dopamine / phasic dopamine¶

Tonic firing refers to sustained activity of a dopamine neuron at 0.2-10 Hz mediated by cell autonomic pacemaker impulses.
Burst firing is characterized by brief bursts of action potentials (3-10 spikes, >10 Hz) from a dopamine neuron. They are usually caused by activation of NMDA receptors via excitatory inputs and represent the response to environmental stimuli. Burst firing is sometimes referred to as phasic firing, emphasizing the synchrony of activity of dopamine neurons due to common inputs.²

Tonic and phasic firing should be distinguished from tonic and phasic release.
Firing rates of somatic dopamine neurons are not linearly translated into axonal dopamine release because release is subject to strong short-term depression. In addition, nearly one-third of tonic release occurs without somatic firing.²

5.2.1. Tonic dopamine firing¶

50-98% of dopamine neurons exhibit tonic firing in vivo.² Midbrain dopamine neurons show spontaneous clock firing from 0.2 to 10 Hz.¹ The usual tonic firing frequency of dopaminergic neurons in rats is about 4 Hz.²⁷²⁸ Tonic dopamine firing occurs particularly at varicosities, extrasynaptically, in the extracellular space. From there, dopamine diffuses to autoreceptors or to (extrasynaptic) receptors of the patient’s own neuron or of other, sometimes relatively distant, neurons (volume transmission). Dopamine is degraded in the extracellular space by COMT.²⁹
Since tonic dopamine is not released into the synapse, it does not trigger a signal at postsynaptic receptors. It only activates presynaptic autoreceptors (also from neighboring nevus cells), which in turn can slow down the phasic dopamine release of their neuron (negative feedback).

Tonic dopamine in the nucleus accumbens is likely to be regulated by glutamatergic afferents from the PFC.³⁰

Switching a response strategy due to changing criteria to achieve goals requires a decrease in tonic dopamine.³¹ Sustained elevated tonic dopamine therefore causes rigidity³² and is therefore likely to promote task switching problems.

Sometimes extracellular dopamine is inaccurately referred to as tonic dopamine; however, extracellular dopamine can come from other sources, such as diffusion of dopamine from the synaptic cleft. Phasic dopamine contributes more to extracellular dopamine than tonic dopamine.³³

Tonic release produces short-lived dopamine transients of a few milliseconds at a small, variable subset of release sites. Dopamine is released into the extracellular space where it rapidly disperses. The basal dopamine level (approximately 2 to 20 nM) is the result of a balance between tonic release and DAT (and NET) reuptake. The basal dopamine level is below the activation threshold of most dopamine receptors. Presumably, the basal dopamine level is composed of a large number of small, short-lived dopamine spikes. Tonic signaling is likely mediated by these short-lived dopamine signals near the release sites, not by the basal dopamine level itself²
The basal level of dopamine develops:

• up to 70 % by firing action potentials
• to 30% independent of action potentials and the active zone proteins RIM and Munc, for example, explained by spontaneous vesicular fusion.

In experimental paradigms, low-frequency stimulation is often used to mimic tonic release. However, this does not mimic the stochastic feature of activation of release sites that is typical of tonic release, but rather recruits many axons simultaneously, thus mimicking the essential feature of phasic release.

5.2.2. Phasic dopamine firing, bursts¶

Phasic dopamine signaling is relevant to synaptic plasticity, reward processing, and behavioral learning.³⁴³⁵
Phasic release on the one hand and bursts (phasic firing) on the other hand correlate with each other but are to be distinguished²

• Phasic release depends on the simultaneous recruitment of a population of dopamine neurons and relies on synchrony between dopamine neurons. Phasic release does not require burst firing of individual neurons.
• Burst firing is the result of a single synchronous activation of a large number of dopamine releases. In general, burst firing is synchronized across all dopamine neurons. The first spike efficiently increases dopamine levels, whereas subsequent activity releases less dopamine due to less synchrony and the presence of refractory sites. Subsequent burst spikes therefore increase dopamine levels only slightly, but serve to maintain the elevated levels caused by the first spike, thus prolonging the dopamine’s residence time.
• Phasic dopamine release (bursts) occurs from vesicles into the synapse. Stimuli such as reward or other stimuli activate short bursts of action potentials from dopaminergic neurons. These dopamine bursts occur at around 20 Hz or more³³, last less than 200 ms, and release large amounts of dopamine from storage vesicles in the presynapse into the synaptic cleft. This phasically released dopamine crosses the synaptic cleft and activates receptors at the postsynapse. After release by the receptors, dopamine is taken up from the synaptic cleft back into the presynapse by dopamine transporters (reuptake). In smaller amounts, it diffuses out of the synapse into the extracellular space or is degraded (albeit secondarily) by COMT located in the synaptic cleft.²⁹³⁶

Dopamine release occurs robustly in response to an initial activation, but then quickly tapers off for several tens of seconds. It follows that even tonic firing leads to the depletion of the respective dopamine release site for seconds, and dopamine release in response to each action potential is largely determined by the recovery of these release sites. Neurons with lower spontaneous activity therefore contribute more to phasic release because their release-ready vesicle pool is less depleted when the synchronizing stimulus arrives. In burst firing, only the first few action potentials result in significant dopamine release from a single axon. Thus, it is the synchrony of group firing, rather than the firing pattern of individual neurons, that dominates signaling during phasic release. This view is supported by the fact that in mice lacking NMDA receptors, burst firing is severely impaired, but phasic dopamine transients and the behaviors they mediate persist. Phasic release is the result of simultaneous activation of a large number of dopamine release sites. Dopamine reuptake mechanisms are temporarily overdriven. This results in significant crosstalk between dopamine signaling areas and causes prolonged dopamine dwell times. In phasic signaling, the rapid increase in dopamine over spatial ranges of several micrometers can result in the activation of dopamine receptors that are somewhat distant from the release sites. A prerequisite for phasic release and signaling is synchrony of release across dopamine neuron populations.²

In the dorsolateral striatum, increasing the burst length from 1 to 10 pulses (at 20 Hz) only moderately enhanced the dopamine signal, whereas in the nucleus accumbens, dopamine release increased sharply with increasing burst length (even more so in the NAc shell than in the NAc nucleus).²⁷

5.2.3. Extracellular dopamine¶

Phasic dopamine is released into the synaptic cleft. Unless it is reabsorbed there, as in DAT-KO rats, for example, it diffuses very slowly into the extracellular space.
Tonic dopamine, on the other hand, is released directly into the extracellular space. Tonic dopamine therefore leads directly to extracellular dopamine, which is why “tonic dopamine” is sometimes used - although not entirely correctly - as a synonym for extracellular dopamine.
Tonically released dopamine from a nerve cell thus becomes extracellular dopamine. This can regulate the dopamine release of the transmitting neuron via autoreceptors of the presynapse. It is not only limited to the immediate presynapse, but can also control neighboring neurons.

5.2.4. Tonic and phasic dopamine between PFC and striatum¶

Both tonic and phasic dopaminergic signals originate from dopamine neurons in the substantia nigra pars compacta and VTA, both located in the midbrain. These innervate, among other areas, the entire dorsal to ventral region of the striatum and the PFC³³
Substantia nigra dopaminergic projections to the dorsal striatum influence voluntary movements and habit learning, and VTA projections to the ventral striatum influence reward and motivation.³⁷

Tonic dopamine mediates the regulatory (inhibitory) control of the PFC on the ventral striatum, thus inhibiting the (phasic) activity of the striatum. In response to reward stimuli, the striatum fires phasically dopaminergically and activates dopaminergic postsynaptic receptors. Thus, tonic control is inhibitory and modulates excitatory phasic firing to reward stimuli.³⁸

5.2.5. Tonic and phasic dopamine in the striatum¶

The ratio of phasic to tonic dopamine within the striatum varied with average ongoing firing frequency, and was generally higher in the nucleus accumbens than in the dorsolateral striatum. Blockade of DAT or D2 receptors predominantly enhanced tonic dopamine. Blockade of nicotinic acetylcholine receptors containing β2-subunits suppressed tonic dopamine. Suppression of tonic dopamine release increased the contrast between phasic and tonic dopamine.³³

In ADHD sufferers, one study found decreased dopamine release at rest (“tonic dopamine”) and increased dopamine release during a flanker task (“phasic dopamine”) in the caudate nucleus. In other parts of the striatum, this tended to be similar but not significant. This supports the hypothesis of overactive DAT ³⁹

5.2.6. Tonic and phasic dopamine in explanatory models of ADHD¶

5.2.6.1. Dynamic Development Theory (DDT)¶

According to this, ADHD has a hypo-dopaminergic cause:

• Decreased tonic firing rate impairs extinction of previously reinforced behaviors⁴⁰
• Flattened phasic dopamine bursts impair reinforcement learning⁴⁰⁴¹

In silicio, a neuronal basal ganglia model of decreased tonic and phasic dopamine showed:⁴²⁴³⁴⁴

• Dopamine modulated
  • the Go- and NoGo-paths in the striatum
  • the average reaction time
  • however, not (alone) the increased reaction time variability

5.2.6.2. Grace, 1991, 2001¶

Tonic dopamine release in the basal ganglia is regulated by afferents from the PFC. Transient phasic dopamine release is regulated by the firing of dopaminergic neurons.⁴⁵

A decrease in tonic dopamine activity correlates with an increase in phasic bursts,⁴⁶ as was also found by a PET study in adults with ADHD in the right caudate nucleus.⁴⁷
This imbalance

• was the result of impaired presynaptic regulation of dopamine at the terminal level, not the consequence of centrally reduced tonic dopamine activity as suspected in chronic stress⁴⁸⁴⁹
• causes oversized reward reinforcements. From this followed
  • Impulsivity⁵⁰
  • Preference for smaller immediate rewards over larger delayed rewards⁵¹

Véronneau-Veilleux et al showed in a computer model that this theory also models the increased reaction time variance.⁵²

5.3. Coding of behavioral values by dopamine¶

Phasic dopamine encodes:

• The presence of an aversive or high-intensity stimulus⁵⁴
  Aversive stimuli cause dopamine output in only a few dopamine neurons.
  Aversive or high-intensity stimuli evoked a three-phase sequence of activation-suppression-activation over a period of 40 to 700 ms:
  • Startup phase: activation at short latencies (40-120 ms)
    • Encodes the sensory intensity
  • Middle phase: (between 150 and 250 ms)
    • Codes the motivational value
      • Activation during appetitive stimuli
      • Suppression during aversive and neutral stimuli.
      • Reward prediction error⁵⁵
        • Activity increased for 100 to 200 ms when reward or reward prediction stimulus is better than predicted
        • Activity unchanged when events have same reward value as predicted
        • Activity briefly dampened when events have lower reward value than predicted
  • Late stage:
    • Moderate “rebound” after strong suppression
    • Strong activation by high reward is often followed by supression
• The quantitative reward prediction error⁵⁶⁵⁷ dopamine neurons in the midbrain, and a subpopulation of dopamine neurons in the striatum, amygdala, and PFC
  • Fire dopaminergically when a reward is higher than expected
  • Remain unchanged if the reward corresponds to the expectation
  • Decrease their dopaminergic activity when the reward is less than expected
• Learning a response strategy to reinforcement
  • Occurs via phasic dopamine in the nucleus accumbens via D1 receptors³¹

5.3.1. Speed of dopamine level change in the brain encodes different behaviors.¶

The rate of dopamine level change in the brain encodes different behaviors.

Encode dopamine level changes

• In the 10-minute range: the strength of motivation and behavioral activation
• In seconds: the value of a future reward
• In the subsecond range: the search for the reward

Phasic dopamine encodes a stimulus/reward that exceeds expectation.⁵⁶

5.3.2. 10-Minute range encodes strength of motivation and behavioral activation¶

Encode dopamine level changes

• In the 10-minute range: strength of motivation and behavioral activation

Tonic activations are mediated by changes in dopamine levels in the nucleus accumbens (part of the basal ganglia in the striatum, part of the mesolimbic system) when the changes in dopamine levels occur at a (slow) rate in the 10-minute range. Slow dopamine level changes over time units of 10 minutes correlate with reward rate, strength of motivation, and behavioral activity.⁵⁸⁵⁹

5.3.3. Seconds range encodes value of future reward¶

Phasic activations are mediated by changes in dopamine levels in the nucleus accumbens when the changes in dopamine levels occur at a (rapid) rate in the seconds range. Rapid (relative) dopamine level changes on a second-by-second basis mediate the valuation of a future reward. Thus, with value changes of dopamine in the seconds range, the value of an event that lies in the future is estimated and encoded.⁵⁸ This is tangential to the ADHD and stress symptoms that follow from the devaluation of more distant rewards.

5.3.4. Subsecond range activates a. reward search and b. movement¶

Even more short-term changes in dopamine levels in the range of fractions of a second (subseconds) were found in rats trained to respond to a signal upon which they could request sugar or cocaine. The corresponding signal triggered an extremely rapid increase in dopamine levels in animals trained in this way (time ranges below one second). Only in the animals trained in this way could a dopamine administration in the nucleus accumbens, which occurred at the appropriate speed, also trigger the search for the reward.⁶⁰⁶¹

Specifically, other axons in the striatum respond to fast phasic dopamine signals to encode movement initiation.⁶²

Distinguishing the effect of dopamine according to speed of level increase on the one hand (seconds and subseconds range) and changes in the direction of the absolute level dimension on the other hand (10-minute time measure) may explain why dopamine is relevant for (short-term) motivation and (long-term) learning simultaneously.

5.3.5. Does mesolimbic phasic DA encode the value of work?¶

One view proposes that mesolimbic phasic dopamine encodes the value of work required to achieve a goal, that is, the need to invest time and effort to obtain the reward.⁶³ Dopamine levels increase only in response to signals prompting movement, but not in response to signals prompting rest, even if these indicate a similar future reward.⁶⁴

5.3.6. Does acetylcholine switch between dopaminergic encoding of reward prediction error and learning?¶

Several reports show that dopamine encodes the reward prediction fallacy on the one hand and value signals on the other. It is possible that dopamine-receiving circuits can actively switch how they interpret dopamine. Circumstantial evidence suggests that acetylcholine, among others, may have such a switching function.
Whereas dopamine cells respond to unexpected signals with phasic spike bursts, cholinergic interneurons in the striatum exhibit brief pauses of approximately 150 ms during which they do not fire, and do not scale with reward prediction error values.
These pauses of cholinergic interneurons can be triggered by GABAergic neurons of the VTA as well as by “surprise” cells in the intralaminar thalamus. For example, GABA-releasing neurons of the VTA that project to the nucleus accumbens are able to inhibit cholinergic interneurons in the accumbens to enhance learning of stimuli and outcomes. It is possible that these pauses act as an association signal that enhances learning. During pauses in cholinergic interneurons, the absence of muscarinic blockade of synaptic plasticity appears to encode dopamine as a signal for learning. If the cholinergic interneurons fire, the release of dopamine terminals is controlled locally to influence ongoing behavioral performance. However, this is not yet certain.^65666768

5.3.7. Different DA neurons in relation to aversive stimuli?¶

One study reported different dopaminergic neurons, one excited by rewards and inhibited by aversive stimuli and the other activated by both types of stimuli. The DA neurons that were excited by aversive stimuli or stimuli that predicted them were more likely to be found in the dorsolateral substantia nigra pars compacta, whereas neurons that were inhibited by this were more likely to be found ventromedially, including in the ventromedial VTA.⁶⁹

5.3.8. Phasic DA encodes movement in the dorsal striatum, reward in the ventral striatum¶

One study found evidence that phasic dopamine in the dorsal striatum encodes movement and phasic dopamine in the ventral striatum (nucleus accumbens) encodes reward and motivation, respectively.⁷⁰ This has been confirmed many times in the meantime.

5.3.9. Does dopamine encode the utility of a resource expenditure?¶

Berke⁶⁵ sheds light on the hypothesis that dopamine encodes the utility of consuming a limited resource, viz

• economic (distribution of resources) and
• motivational (whether it is worth spending resources:⁷¹

5.3.9.1. Dorsolateral striatum: DA encodes the resource movement¶

In Berke’s dorsolateral striatum, dopamine encodes the resource of movement, which is limited due to energy expenditure and the incompatibility of multiple actions at the same time.⁷⁴ An increase in dopamine increases the likelihood that an individual will consider the energy expenditure for a movement to be worthwhile.^7570717677 At the same time, if higher dopamine encodes a “movement is worthwhile,” there is a correlation between dopamine and movement itself, but it is not directly causal.

5.3.9.2. Dorsomedial striatum: DA encodes the resource of cognitive processes¶

In the dorsomedial striatum, dopamine encodes the resources of cognitive processes such as attention (which is limited by definition)⁷⁸ and working memory according to Berke.⁷⁹ Dopamine encodes attention to salient external cues. Conscious activation of cognitive control processes is effortful.⁸⁰ Dopamine encodes - especially in the dorsomedial striatum⁸¹ - that it is worth the effort, for example, whether the effort of cognitively more demanding, model-based decision strategies is worth the effort.
Dopamine deficiency, on the other hand, causes such cues, which normally trigger orientation movements, to be neglected - as if they deserved less attention⁸²

5.3.9.3. Nucleus accumbens: DA encodes the resource time¶

In the nucleus accumbens, dopamine encodes the resource time according to Berke. Some rewards require a long preparatory work of in detail unrewarded actions, e.g., searching for food. A decision to engage in such time-intensive work implies foregoing other beneficial ways of spending time. A high mesolimbic dopamine level encodes that it is worthwhile to engage in time-extensive, effortful work for a temporally distant goal. If mesolimbic dopamine levels decrease, interest in long-term reward decreases.
Simple actions with quick rewards do not require mesolimbic dopamine.⁸³