Dopamine's Phasic vs. Tonic Release [116 studies]
Updated: Jan 3, 2022
For dopamine I think you will agree with me when I say: There are WAY too many people who think "increasing dopamine" is enough to solve their dopaminergic deficits. If only it was that simple… If you are serious about fixing your deficits, you need to know the basics of neurotransmitter firing patterns. Namely, phasic firing versus tonic firing.
Otherwise it's like you're insisting on using a wrong key and hoping to open the door to your house with it.
Well today I'm going to educate you on firing patterns and how their perceived effects differ significantly, with emphasis on dopamine in particular. And I even wrote neat summaries after each part if you just want to skim the article. So let's dive right in.
Table of contents:
1. Overview of neurotransmission 2. Phasic firing pattern 3. Tonic firing pattern 4. Overview of the dopaminergic systems 5. On phasic & tonic dopamine release & effects of drugs 6. Dopamine's involvement in post-SSRI sexual dysfunction (PSSD)
7. Conclusion
1. Overview of neurotransmission
First, a neuron has to synthesize a particular neurotransmitter, right? This takes place at various locations within the neuron. This neurotransmitter is then stored into vesicles by transport proteins.
When there is a stimulus significant enough to excite the neuron, it triggers an action potential. Simply put, there is a voltage difference between the interior and exterior of a cell membrane called resting membrane potential.
An action potential is a series of voltage fluctuations of that potential that propagate as a wave along the axon.
It occurs as a response to a sufficient stimulus, following the all-or-none law. If a neuron responds at all, then it must respond completely.
When it finally reaches the axon terminal of this presynaptic neuron, calcium enters causing release/firing of the neurotransmitter into the synaptic cleft.
After that, the neurotransmitter diffuses across the synaptic cleft and binds to receptors on the postsynaptic membrane of another neuron's dendrite.
When that occurs, ion channels on the postsynaptic membrane open up, causing a shift in postsynaptic potential. This leads to generation of a nerve impulse.
Finally, the neurotransmitter unbinds. It's then either degraded by an enzyme, or taken back into the presynaptic terminal (re-uptake) where it can be either re-used or removed.
And that's the basic gist of it [1].
Summary
Synthesis of the neurotransmitter.
Storage of the neurotransmitter in storage vesicles.
Calcium enters during an action potential, causing release of the neurotransmitter.
After its release, the transmitter binds to and activates receptors on membranes.
Deactivation of the neurotransmitter.
2. Phasic firing pattern
Right. So excitable cells like neurons can have different discharging patterns called the oscillatory patterns, which include phasic firing, tonic firing, mixed, and spiking variations [2].
Rhythmic synchronization of neuronal firing patterns is what gives rise to neural oscillations (brainwaves) [3].
Phasic bursting discharge pattern occurs when a neuron undergoes rapid series of action
potential spiking followed by a refractory, quiescent period. Sensory neurons exhibit this as a response to external stimuli [4][5][6].
Some neuronal subtypes, however, exhibit phasic firing spontaneously, without depending on external stimuli.
This is the case with central pattern generators (CPGs). Examples of which are the respiratory, locomotion, and attention circuits [7][8][9].
Phasic receptors:
Rapid adaptation.
Cease activity if strength of continuous stimulus remains constant.
Allow brain to ignore constant unimportant information.
Generally speaking, the central nervous system (CNS) REALLY prefers changing stimuli when it comes to sensory input and pleasure.
When a neuron fires neurotransmitters, the postsynaptic receptors respond maximally but briefly to the stimuli [10].
If the duration of continuous non-changing stimuli is long, the receptors become desensitized and become much less responsive [11].
Basically, this is your brain getting bored.
Summary
An external stimulus triggering rapid series of action potential spiking (large amplitude).
Followed by a refractory, quiescent period.
If maintained: rapid adaptation of receptors.
Responsible for: most behavioral and executive functions in relation to external stimuli. Brain really prefers changing stimuli.
3. Tonic firing pattern
When neurons produce continues action potentials over the duration of the stimulus without a refractory period or adaptation, it's called tonic firing. This resembles pacemaker-like membrane currents and generally occurs spontaneously [12][13].
There are many patterns of tonic firing, but generally, they don't adapt according to the duration of the stimulus.
When presented with a prolonged stimulus the neurons fire a few spikes with short interspike period and then the period increases [14].
Tonic receptors:
Slow or no adaptation.
Continuous action potential transmission for the duration of the stimulus.
Allow brain to monitor parameters that must be continually evaluated, e.g. baroreceptors and pain receptors.
These control crucial continuous brain functions, such as awareness and attention. They mainly respond to changes in stimulus intensity and rate by changing tonic spiking patterns [15].
Summary
Spontaneous pacemaker-like membrane action potentials.
Continuous; no refractory period.
If maintained: tonic receptors exhibits slow or no adaptation.
Responsible for: crucial continuous brain functions, such as awareness, pain sensation, pressure sensation, body orientation, etc.
4. Overview of the dopaminergic systems
Before we move on to the juicy bits, it's important to understand the general neuroanatomy of the dopaminergic system.
It all comes down to brain regions, you see.. dopamine neurons play different roles depending on which brain area its located in and where they project to (pathways).
Alright. So there are mainly 4 important dopaminergic cell centers in the brain that I will discuss in this article (3 major, 1 minor) [16]:
A. Substantia nigra - pars compacta (SNc/SNpc)
The substantia nigra is part of the midbrain.
The black neuromelanin-pigmented dopamine neurons of its pars compacta part project along the nigrostriatal pathway.
Nigrostriatal pathway:
SNc → Dorsal striatum (caudate, putamen).
Functions:
Indirect regulatory role in voluntary movement by regulating the striatum [17].
Goal-directed behaviors and habit learning (i.e. driving a car, syncing an instrument at a concert) [18][19][20][21].
Indirectly increases tonic and phasic dopamine firing in the prefrontal cortex [40]
B. Ventral tegmental area (VTA):
The ventral tegmental area is also located on the midbrain, close to the substantia nigra. It projects to several regions of the brain. I will focus here on two major pathways:
Mesolimbic pathway: VTA → Ventral striatum (nucleus accumbens).
VTA → Amygdala.
VTA → Hippocampus.
VTA → Medial prefrontal cortex (mPFC).
Functions:
Reinforcement learning of both 'rewarding' and 'aversive' stimuli (synaptic plasticity → neurons that fire together wire together, as long as they get a burst of dopamine) [24][25][26][27][28].
Reward prediction error (if a reward is larger than predicted, DA neurons are strongly phasically excited + and the opposite is true) [29].
Mesocortical pathway:
VTA → Frontal cortex.
VTA → Dorsolateral prefrontal cortex (DLPFC).
Functions:
Note: The mesolimbic and mesocortical pathways interact indirectly through glutamatergic neurotransmission.
C. Arcuate nucleus (ARC)
The arcuate nucleus of mediobasal hypothalamus contains a bunch of dopamine neurons named tuberoinfundibular dopamine neuron (TIDA) that project to the adjacent median eminence (ME) [53]
Tuberoinfundibular pathway:
TIDA → ME (which accesses the pituitary).
Function:
Tonic inhibition of prolactin release [54]
D. Zona incerta
The zona incerta is a nucleus present in the subthalamus. It contains a group of dopamine neurons that project to several brain regions [58].
Incertohypothalamic pathway:
Zona incerta → Anterior hypothalamus (paraventricular nucleus).
Zona incerta → Lateral hypothalamus.
Zona incerta → Lateral preoptic area.
Functions:
Extensive excitatory effect on libido and sexual desire. [55][56][57][58]
Stimulation of gonadotropin release [59]
Summary
Nigrostriatal pathway: Movement & habit learning.
Mesolimbic pathway: Pleasure, reward, libido, seeking behaviors, addictions, emotions.
Mesocortical pathway: Cognition, memory, attention, emotional behavior, learning.
Tuberoinfundibular pathway: Hormonal regulation (prolactin).
Incertohypothalamic pathway: Libido and sexual behaviors.
5. On phasic & tonic dopamine release & effects of drugs
Now that you are more familiar with dopamine nuclei and pathways, it's time for the juicy bits.
Dopamine neurons fire in both phasic and tonic patterns:
Phasic dopamine release:
Occurs either in response to behaviorally relative stimuli (depolarization-mediated, calcium ion-dependent) [60], or under glutamatergic and cholinergic control in locomotion [61]
Characterized by being a transient, large amplitude pulse releasing dopamine to postsynaptic receptor. [62]
Dopamine is rapidly removed from the synaptic cleft through re-uptake by dopamine transporters before triggering homeostatic responses [63].
Responsible for most of dopamine's behavioral effects.
Tonic dopamine release:
Occurs either spontaneously or through afferent control (NMDA, glutamate), depending on brain regions. [64][62]
Characterized by releasing a steady-state, background level of dopamine that would determine the baseline level of receptor stimulation and regulation. [65]
Homeostasis allows for limited baseline activation by tonic dopamine. It sets the level of responsivity of the system to more rapid phasic stimuli [62][66]
To put things into perspective, if you decrease tonic dopamine, homeostatic responses will endeavor to upregulate postsynaptic dopamine receptors to restore the minimal allowed activation. Decreased tonic release would enhance phasic release further through reduced autoreceptor activation.
The opposite is correct: if you increase tonic dopamine, homeostasis will endeavor to downregulate postsynaptic dopamine receptors to restore the minimal allowed activation. Increased tonic release would blunt phasic release further through autoreceptor activation. [67]
In other words:
High tonic dopamine → increased autoreceptor activation + decreased postsynaptic receptor responsivity → insensitivity to phasic release spikes.
Low tonic dopamine → decreased autoreceptor activation + increased postsynaptic receptor responsivity → over-sensitivity to phasic release spikes.
Dopaminergic medications & drugs of abuse:
1. Psychostimulants (Amphetamines, methylphenidate, modafinil, cocaine, etc):
They act either to inhibit or reverse the function of the dopamine transporter (DAT), or both.
This causes dramatically enhanced phasic dopamine release and, to a lesser extent, tonic release. [68][69]
Amphetamine, by releasing vesicular stores through interaction with VMAT2, has been found to increase tonic release more so than a DAT-inhibiting stimulant. [70][71]
2. MAO-B inhibitors (Rasagiline, Selegiline):
They prevent breakdown of dopamine by inhibiting the MAO-B enzyme isoform.
As such, they increase the stores of dopamine for the neuron to fire in a tonic pattern, activating both autoreceptors and postsynaptic receptors. [72]
Chronic intake would cause desensitization of dopamine autoreceptors, improving tonic release. [72]
Since they don't enhance phasic release drastically, they show no potential for abuse. [73][74][75]
Overall, they are tonic-enhancers that have little effect on mood and, therefore, have no meaningful antidepressant effect in doses that do not inhibit MAO-A. [76]
3. Dopamine agonists (Pramipexole, ropinirole, quinpirole, cabergoline, bromocriptine, etc):
These agents directly bind to both presynaptic and postsynaptic dopamine receptors, mimicking a tonic-firing pattern.
Most of these agents have high affinity to D2-family (D2/D3/D4), without activating D1-family to any meaningful degree (D1/D5). [77]
Desensitization of presynaptic and postsynaptic receptors after chronic intake. [78]
As tonic firing mimics, they show no potential for abuse. [79][80]
Tonic postsynaptic dopamine receptors activation leads to an imbalance between the ‘on’ and ‘off’ pathways of the reward-related circuit, thereby promoting impulse control disorders (ICDs: compulsive shopping, gambling addiction, sexual compulsion, etc). [97][98]
4. NMDA antagonists (Ketamine, Memantine, Amantadine, PCP, Dextromethorphan, etc)
Cortical glutamate neurons expressing NMDA receptors control tonic dopamine firing of the limbic system. [62]
NMDA antagonism causes tonic dopamine inhibition of the limbic system.