New review: on to dopamine's phasic & tonic release [116 studies]

Updated: Aug 8, 2019

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 were 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
  1. Synthesis of the neurotransmitter.

  2. Storage of the neurotransmitter in storage vesicles.

  3. Calcium enters during an action potential, causing release of the neurotransmitter.

  4. After its release, the transmitter binds to and activates receptors on membranes.

  5. 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
  1. An external stimulus triggering rapid series of action potential spiking (large amplitude).

  2. Followed by a refractory, quiescent period.

  3. If maintained: rapid adaptation of receptors.

  4. 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
  1. Spontaneous pacemaker-like membrane action potentials.

  2. Continuous; no refractory period.

  3. If maintained: tonic receptors exhibits slow or no adaptation.

  4. 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:

  • Motivation and incentive salience (desire for rewarding stimuli - 'wanting') [22][23].

Reward prediction error

  • 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].

  • Learning and long-term memory formation [30][31][32].

  • Emotional processing and regulation [33][34][35].

  • Drug and non-drug related addictive behaviors [36][37][38].

  • Libido [55][56][57]

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
  1. Nigrostriatal pathway: Movement & habit learning.

  2. Mesolimbic pathway: Pleasure, reward, libido, seeking behaviors, addictions, emotions.

  3. Mesocortical pathway: Cognition, memory, attention, emotional behavior, learning.

  4. Tuberoinfundibular pathway: Hormonal regulation (prolactin).

  5. 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. [81]

  • As such, they potentiate phasic dopamine release. Added together to their pro-reward effect on the nucleus accumbens, this triggers euphoria. [82][83]

  • Not all NMDA antagonist are equal. Memantine is an open-channel blocker while classical antagonists are closed-channel blockers. Also, NMDA antagonist are generally non-selective, with some having a plethora of other actions. [84][85]

  • Inhibition of cortical NMDA receptors is responsible for the negative symptoms seen in schizophrenia. NMDA antagonist are psychotomimitcs at high doses. [62]



5. Bupropion:

  • In humans, it's a very weak dopamine reuptake inhibitor due first-pass metabolism by CYP2B6.

  • Nicotine receptor antagonism would generally reduce phasic dopamine release. [86]

  • It acutely increases tonic dopamine release leading to an initially reduce reward discriminability due to lowering of phasic responsivity. [87]

  • Chronic intake would result in an antidepressant effect, however. [88]

  • A formulation of Bupropion/Dextromethorphan (AXS-05) is under development for treatment-resistant depression. Via inhibition of CYP2D6, bupropion slows the metabolism of DXM and thereby increases its levels. [89]


6. Levodopa (Sinemet, mucuna pruriens):

  • Exogenous levodopa (+carbidopa) intake increases dopamine synthesis in neurons.

  • Same effects of MAO-B inhibitors would apply here. Namely, enhancement of tonic firing. [90]

  • However, it was found that exogenous levodopa alters phasic dopamine firing mechanisms, triggering dyskinesias. [91][92]

  • Due to this strange effect of levodopa on phasic dopamine firing, it's often abused by patients. [93][94][95][96]


7. GABA-B agonist (Baclofen, GHB):

  • Low doses of baclofen (20-100 mg) triggers phasic and tonic dopamine release via disinhibition of nigrostriatal and mesolimbic dopamine neurons. They also preferentially inhibit GABA neurons activity. [97][98][99]

  • Moderate doses of baclofen (300-600 mg) triggers manic reaction and addiction. Withdrawal can be quite severe at that dosage range [100]

  • High doses of baclofen (10 grams) inhibit dopamine release altogether via interrupting the nerve impulse flow. [101][102][103][104][105][106]

  • This bi-directional effect is based on a different coupling efficiency between GABA-B receptors, G-proteins, RGS proteins, and GIRK/Kir3. [107][108]


Summary
  1. High tonic release insensitivity to phasic release spikes.

  2. Low tonic release over-sensitivity to phasic release spikes.

  3. Psychostimulats: Phasic + tonic release. (Mostly phasic)

  4. MAO-B inhibitors: Tonic release enhancement.

  5. Dopamine agonists: Tonic release mimics.

  6. NMDA antagonists: Attentuation of tonic release + enhancement of phasic release.

  7. Bupropion: Tonic release + lowering phasic release (acute). Weak-ass DRI in humans due to CYP2B6.

  8. Levodopa-carbidopa: Tonic release + peculiar phasic mechanism alteration.

  9. Baclofen: Bi-directional effect on dopamine release (tonic + phasic).

6. Dopamine's involvement in post-SSRI sexual dysfunction (PSSD)


There is a clear dopaminergic dysfunction in post-SSRI sexual dysfunction (PSSD).


However, this part of the article involves my own hypotheses. As such, they are based on my personal experience with patients, their symptoms, and what has helped them through trial-and-error.


Symptoms vary widely between patients, both in quantity and intensity, but generally speaking they can be classified into subtypes.



Pure PSSD involves sexual dysfunction only:

  • Erectile dysfunction.

  • Loss of libido.

  • Orgasmic dysfunction. (Anorgasmia, PE, or orgasmic anhedonia).

  • Gential numbness.

  • Gential shrinkage.



Complex forms of PSSD involve a plethora of symptoms:


A. Sexual dysfunction:

  • Erectile dysfunction.

  • Loss of libido.

  • Orgasmic dysfunction. (Anorgasmia, PE, or orgasmic anhedonia).

  • Gential numbness.

  • Gential shrinkage.

B. Cognitive dysfunction:

  • Lack of mental clarity (brain fog).

  • Poor memory, forgetfulness.

  • Attention deficit and low concentration.

  • Sluggish cognitive tempo.

  • Loss of verbal fluency.

  • Mental fatigue.

  • Insomnia or excessive daytime sleepiness.


C. Emotional & hedonistic dysfunction:

  • Anticipatory anhedonia.

  • Consummatory anhedonia.

  • Blunted or flattened affect.

  • Apathy and avolition.

  • Either loss of capacity to feel anxiety, or severe anxiety and panic.


There is dysregulation of several large scale brain networks, involving all neurotransmitters and various neurobiological functions.


But for the sake of simplicity, I will address the dopaminergic deficits alone in this article.


It's important to understand what type of dopaminergic deficiency is present (phasic vs. tonic), so I conducted a questionnaire of what dopaminergic drugs patients have tried in vain.


My hypothesis:


Note: only affecting a subset of PSSD patients, not all of them.

It's obvious from the symptoms above that there is a mesolimbic, mesocortical and incertohypothalamical dysfunction.

  • If there is an mPFC over-activity, it leads to excessive tonic dopamine release in the limbic system, causing postsynaptic insensitivity to phasic release spikes. [109]

  • Over-activity of the basolateral amygdala (BLA) potently and selectively decreases the number of DA neurons firing [110]. Amygdalar hypofunction could also be implicated in excess tonic dopamine firing and compensatory downregulation.

  • Another cause of excessive tonic dopamine release is ventral pallidum (VP) hypofunction The VP has a rich GABAergic projection to limbic regions, inhibiting dopamine release. Hypofunction would increase tonic dopamine release as well, leading to compensatory downregulation.

This mPFC–amygdala–VP circuit dysfunction model might explain the high tonic dopamine induced postsynaptic insensitivity to phasic release spikes.


What might cause this dysfunction is unknown. It could involve multiple systems, HPA-axis, neurosteroids, and neurotransmitters.


This model can help explain patient's reaction to medications:


Psychostimulants:

Male patients: Since sympathetic system over-activation is detrimental to male libido, patients:

  • Experience improvements across all symptoms (low sympathetic tone baseline).

  • Experience exacerbation in sexual symptoms (high sympathetic tone baseline).

  • Much blunted effects compared to pre-PSSD (insensitivity to phasic release spikes post-PSSD).


Female patients: Since sympathetic system activation plays a positive role in female libido, patients:

  • Experience enhancement of libido.


MAO-B inhibitors:

  • Acute, initial boost in libido (autoreceptor activation → lower tonic release → better phasic release + postsynaptic sensitivity to phasic spikes).

  • After adaptation, this effect is lost. (presynaptic desensitization → higher tonic release → postsynaptic desensitization → worse sensitivity to phasic spikes).

  • Chronic intake would cause small improvement in anhedonia, mood, and energy owing to autoreceptor desensitization → higher tonic release → postsynaptic bombardment.


Dopamine agonists:

  • Similar to MAO-B inhibitors, except they don't activate D1/D5 receptors, making them useless for other non-sexual symptoms. D1-family activation induces glutamate release and cAMP activation. This improves anhedonia and energy. Dopamine agonists, being selective to D2-family, do the opposite: sedation and somnolence. Useless for PSSD.


NMDA antagonists:

Although NMDA antagonism would inhibit tonic release + facilitate phasic release, they are usually pretty 'dirty' drugs (non-selective). Often with effects that directly counteracts that phasic enhancement, such as nicotinic antagonism and tonic activation of D2 receptor. Being open-channel blockers also doesn't help. It's hard to predict what happens.


Bupropion:

  • Initial worsening in anhedonia. (typical reaction to tonic release enhancement)


Baclofen:

Since it disinhibits dopamine release (phasic and tonic), it is like a stimulant minus the sympathetic over-activation. It also triggers serotonin release to postsynaptic 5HT1A receptors. [111]

  • Several patients report significantly improved anhedonia and emotional reactivity, with tolerance often close to follow. (Dopamine/serotonin postsynaptic activation).

  • Enhancement of nicotine's and caffeine's euphoria on baclofen.

  • Memantine, by inhibiting tonic dopamine firing + sensitizing/upregulating postsynaptic dopamine receptors, prevents tolerance to baclofen's effects and augments the phasic release.

  • However, baclofen doesn't improve sexual symptoms in some people due to the fact that it doesn't target the incertohypothalamic pathway. If there is a mesolimbic dysfunction, it can improve libido. [112]

The dopamine neurons of the incertohypothalamic pathway project to the medial preoptic area (mPOA). Lesions of mPOA results in complete loss of copulatory behaviors. [113][114]


In male rats, estradiol has direct stimulatory effect on the incertohypothalamic pathway in the absence of circulating prolactin. In both sexes, mu opioid activation has a stimulatory effect on the incertohypothalamic pathway. [115][116]


Summary
  1. mPFC–amygdala–VP circuit dysfunction high tonic dopamine release.

  2. High tonic release postsynaptic downregulation insensitivity to phasic release spikes.

  3. Insensitivity to phasic release spikes loss of response to stimulants + loss of libido + negative symptoms (anhedonia, apathy, avolition, etc) + cognitive dysfunction.

  4. Incertohypothalamic pathway dysfunction blunted medial preoptic area (mPOA) phasic activation profound sexual dysfunction.


7. Conclusion:

In this article, I have outlined the neurobiological basics needed to understand phasic vs. tonic dopamine release. Now you also have a grasp on the major dopaminergic nuclei and pathways in the brain and sufficient knowledge on their functions.


With my explanation of how drugs modulate phasic and tonic neurotransmission, you now have sufficient understanding to apply that knowledge onto other neurotransmitter systems, such as serotonin or norepinephrine. Hopefully.


My hypothesis regarding a subset of PSSD patients is up for debate. However, it's still a fact that multiple dopamine pathways have to be targeted for symptomatic relief. Hopefully, my hypothesis would open up more options for trialing.


It took an entire week of hard work for me to review all these studies (116!) and write this article. If you like what I'm doing, please support The Research Zone so I can continue investing time in researching and helping you out. Alternatively, you can now book a consultation with me. I've added the option to my Patreon page. Thanks for your support.

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