Dopamine: 256+ Ways To Increase Or Protect This Neuroimmunotransmitter

Your Dopamine Has Been Hijacked By Chronic Inflammation And Instant Rewards

 
facebook twitter snapchat dopamine
 

Dopamine is extremely important for everyday function and plays a much larger role in the body than just bonding, motivation, cognition, emotion, well-being, and movement.

Unfortunately, our environment today is very good at manipulating and hijacking our dopamine system.

In this post we will discuss, how/why dopamine is produced, how chronic inflammation affects dopamine, what are some quick fixes for dopamine, and what are some long lasting dopamine builders, as well how to avoid losing dopamine. 

Contents:

  1. A Brief History Of Dopamine
  2. Who Is Stealing My Dopamine?
  3. Conditions Associated With Dopamine Activity
  4. Roles Of Dopamine In The Body
  5. Caveats
  6. How To Increase And Protect Your Dopamine
  7. What Decreases Dopamine?
  8. Are You Reliant On Dopaminergic Rewards?
  9. Mechanism Of Action
  10. Dopamine Receptors
  11. Genetics
  12. More Research

A Brief History Of Dopamine

Dopamine is a neurotransmitter that was originally synthesized in 1910, then later identified by Peter Holtz (who discovered L-Dopa decarboxylase) and then Hermann Blaschko who discovered dopamine as the precursor for adrenaline and norepinephrine in the catecholamine pathway. R R R

It wasn't until 1952 when the short name dopamine was adopted, as proposed by Henry Dale. R

It is sometimes referred to as the prolactin-inhibiting factor (PIF), prolactin-inhibiting hormone (PIH), or prolactostatin. R

Dopamine has been studied for a long time and should no longer be called a neurotransmitter, but a neuroimmunotransmitter.

This is because is not only commonly associated with the central nervous system and effects such as increased motivation and muscle movement, but dopamine plays a huge role in many other systems such as the immune system, tissues and organs (kidneys, adipose tissue), and vascular system, to name a few. R R R

Who Is Stealing My Dopamine?

Instant Rewards

Probably the manics or schizophrenics.

Seriously, though, anything that creates an instant reward, especially without any effort.

For example, every time we look at a screen (computer, TV, phone, etc) the blue light tells our brain to release dopamine and this acts on the same system as accomplishing a reward in our brain.

We also get dopamine released from likes on Facebook, retweets on Twitter, upvotes on Reddit, etc (oh and by the way, be sure to like this post share it with your friends 😂).

This release of dopamine (specifically in the striatum) reinforces you to go back and play on Facebook again and again and has been studied as one possible root causes of addiction and depression. R R

This can happen subconsciously. R

Having spontaneous fun, accomplishing goals, and planning positive rewards may help these addictive complications.

Chronic Inflammation - Dopamine As A Pro-Oxidant Or An Antioxidant Potentiator

Apart from instant rewards, chronic inflammation is depleting our brains of dopamine.

For example in those with chronic fatigue syndrome and sickness behavior, dopamine becomes depleted as well as the co-factors and rate-limiting enzymes that create catecholamines in this pathway.

In Parkinson's disease, chronic inflammation and oxidative stress (pic seen below) destroys neurons that transport and create dopamine and create harmful byproducts (pro-oxidant) instead of dopamine (anti-oxidant). R

Reducing chronic inflammation and removing the root cause (such as infections and poor environmental exposure) may helps fix this cause of low dopamine.

Conditions Associated With Dopamine Activity

Low Activity Of Dopamine:

  • Addiction (ie drugs, pornography, alcoholism, marijuana, cocaine, etc) - DA is hyper sensitive R R
  • ADHD R R R
  • Aging R R
  • ALS R
  • Alzheimer's Disease R
  • Anhedonia R
  • Bulimia R
  • Cancer (low in colon, high in lung) R
  • Chronic Fatigue Syndrome R
  • Chronic Infections R
  • Chronic or Extreme Stress R
  • Depression R
  • Dwarfism R
  • Erectile Dysfunction R
  • Leaky Blood Brain Barrier R
  • Leaky Gut (endotoxemia) R
  • Low Motivation R R
  • Heavy Metal Toxicity (ie manganese, arsenic, mercury, cadmium) R
  • Insulin Resistance (dysregulates in brain vs periphery) R
  • Mold R
  • Neuroinflammation R
  • Obesity and Overeating R R R
  • Parkinson's Disease R
  • Prolactinoma R
  • Restless Leg Syndrome R R
  • Slow Reaction Speed R
  • Tourette's Syndrome (phasic DA) R
  • Traumatic Brain Injuries R

High Activity Of Dopamine:

  • Aggression (such as seen in Autism Spectrum Disorders) R
  • Anorexia R R
  • Bipolar (switches between high and low DA activity) R
  • Mania R 
  • Migraines R
  • Huntington's Disease R
  • Nausea R
  • Psychosis R R
  • PTSD R
  • Schizophrenia (dysregulation) R R

Although high/low levels of DA are associated with some pathologies, addressing dopamine receptor function/dysfunction may be equally important. R R R R R

Roles Of Dopamine In The Body

1. Inflammation And Stress

 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3484236/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3484236/

 

Dopamine synthesis is extremely sensitive to inflammation. R R

As a protective/inhibitory neurotransmitter, dopamine can directly reduce inflammation in the body and brain (dependent which receptor dopamine is acting on). R R R

Chronic infections (ie mold/dysbiosis/virus) and chronic oxidative stress (ie ROS/RNS) use up the body's ability to produce catecholamines by depleting the body of rate limiting enzymes (ie BH4 and TH) and antioxidants (ie glutathione). R

This is one the most important pathologies of reduced dopamine as seen in Parkinson's Disease (more discussed below), chronic fatigue syndrome, fibromyalgia, and sickness behavior (more discussed below). R R

Dopamine is very strong at protecting against stress. R

For example, dopamine can protect the heart from severe cold. R

2. Depression, Motivation, And Energy

Low dopamine is commonly seen in major depressive disorder (MDD) and associated disorders (such as anhedonia). R

Dopamine can improve happiness and induce euphoria. R R

For example, one of the ways bright light or sunshine makes us happy is by its ability to increase dopamine in the brain. R

Dopamine also increases motivation and can lower the perceived effort it takes to achieve something. R R

For example, patients that were given levodopa (l-DOPA) to boost dopamine levels made more economic decisions and reported improved happiness. R

As stated before, chronic inflammation (proinflammatory cytokines) reduces the ability for dopamine to be produced, leading to lazy and unwillingness to execute tasks. R R

This is very commonly seen in sickness behavior, where depletion of dopamine and increased inflammatory markers in the basal ganglia and cerebrospinal fluid leads to malaise and reduced reward-behaviors. R

For example, inflammation also in the putamen causes dopamine dysregulation which is a major pathology of chronic fatigue syndrome (CFS). R

3. The Brain And Central Nervous System

 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5442366/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5442366/

 

Dopamine can protect the brain in many neuroinflammatory disorders and is well studied in its role in Parkinson's Disease (PD) and traumatic brain injury (TBI).

Dopamine's ability to inhibit muscle movements in PD is a byproduct of its major antioxidant/neurotrophic function on the substantia nigra and striatum. R R

Dopamine also reduces inflammation of central nervous system (CNS) disorders, by its ability to modulate the immune system via the vagus nerve. R R

Dopamine can protect the brain during hypoxia (loss of oxygen). R

For example after a TBI, dopamine may become significantly depleted, reducing extraversion and preserving energy for repair mechanisms. R

4. Circadian Rhythms And Time Perception

 
http://www.molcells.org/journal/view.html?doi=10.14348/molcells.2017.0065

http://www.molcells.org/journal/view.html?doi=10.14348/molcells.2017.0065

 

Dopamine is responsible for activating circadian rhythms. R

When dopamine signaling from the eye activates the suprachiasmatic nucleus (SCN) helps entrain the master circadian clock and motivational behaviors (to get up in the morning). R

Insomnia is a common problem of Parkinson's Disease. R

Dopamine is dependent on orexin (hypocretin) receptors and adenosine receptors for sleep/wake activity. R R

Dopamine can influence the perception of time. R

Increasing DA in the substantia nigra pars compacta, is able to slow down the perception of time, while decreasing DA in that area did the opposite. R

5. Obsessions, Addiction, Obesity, And Attention

Dopamine is a major player in the reward pathway and every time something "good" happens, dopamine is released in the brain. R

Reward Deficiency Syndrome (RDS) can happen from low dopamine levels and cause people to seek quick dopamine-enhancing rewards. R R

Increased dopamine can help prevent withdrawal and cravings for drugs and comfort foods (helping overeating/obesity/weight gain/sugar cravings, etc). R R

In obesity, dopamine can increase weight loss through enhanced perceived motivation/reward and reduce binge eating, while low dopamine levels may contribute to lower levels of physical activity, leading to possible weight gain. R R R R R

Dopamine can also work directly on fat cells and suppress their expression to grow. R 

This is a double edged sword, as too much dopamine can contribute to not eating at all (anorexia). R R

Increasing dopamine can improve spatial attention in attention deficit disorders (ADHD). R

6. Mitochondrial Function

Dopamine can increase brown fat (fat cells with tons of mitochondria). R

When dopamine becomes oxidized (via stress) it can cause mitochondrial dysfunction and cells to die and plays a large role in the pathology of PD. R R R R

7. Memory And Plasticity

Dopamine can increase synaptic plasticity in the brain (dependent on TGF-beta). R

Dopamine induces neuroplasticity via signaling of the endocannabinoid system. R R

8. Fear And Confidence

Dopamine plays a role in the feeling of fear. R

Activation of dopamine in the nigrostriatal pathway can help with fear extinction and reduce trauma-related anxiety. R

Increased DA can also make you more optimistic (improve expectations about future events). R

Dopamine can reduce approach avoidance and improve confidence. R

9. Bonding And Social Status

 
http://www.cell.com/neuron/fulltext/S0896-6273(17)30604-9

http://www.cell.com/neuron/fulltext/S0896-6273(17)30604-9

 

Dopamine helps with social bonding and feelings of connectedness to others (such as love). R R R

Oxytocin, the love hormone, works in conjunction with DA to strengthen relationships. R

It acts on reinforcing social behaviors. R

Higher dopamine levels (specifically the density of dopamine D2/D3 receptors in the striatum) are associated with higher social status. R

10. Libido

Dopamine enhances libido and can increase sex drive. R

It can help with erectile dysfunction. R

11. Gut

In the digestive system, DA reduces gastrointestinal motility and protects intestinal mucosa. R

12. Exercise Performance

Dopamine can improve exercise performance and tolerance. R

13. Eyesight

 
http://www.sciencedirect.com/science/article/pii/S1350946217300101?via%3Dihub

http://www.sciencedirect.com/science/article/pii/S1350946217300101?via%3Dihub

 

In the eye, dopamine regulates circadian rhythms (as discussed above) and keep homeostasis of the eye (such as retina development, visual signaling, and refractive development). R

Dopamine receptor stimulation from light can help prevent the development of myopia. R

14. Cancer

Dopamine may be beneficial for cancer as it can inhibit angiogenesis and promote cell death. R R R

It also increases the activity of T lymphocytes, myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs) and natural killer (NK) cells. R

14. Blood Pressure, The Heart, And Kidneys

Depending on which receptor DA acts on, it can modulate blood pressure. R

In blood vessels, dopamine inhibits norepinephrine (NE) release and acts as a vasodilator. R

in the kidneys, it increases sodium excretion and urine output. R

15. Diabetes

Increasing dopamine may help with diabetes. R

For example, cabergoline (a dopamine agonist) can lower fasting blood glucose and HbA1C in patients with type 2 diabetes. R

Dopamine receptors in the pancreas reduce insulin secretion. R

16. Pain

Dopamine may play a role in physical pain, as lower dopamine levels decrease the threshold to feel pain. R

For example, patients with Parkinsons's Disease tend to have abnormally heightened sensitivity to pain. R

17. Pregnancy And Development

Dopamine is important for the mother and child during pregnancy. R

For example, infants of high dopamine mothers had better autonomic stability and less excitability. R

Low levels of dopamine during pregnancy may also contribute to postpartum depression. R

Low dopamine activity has also been implicated in infants with less-exploratory behavior. R R

Dopamine is extremely important in the developmental stages of life. R

By affecting executive function, dopamine dysregulation during development may contribute to autism spectrum disorders (ASD), seizures, motor problems, repetitive behaviors, and impaired neurogenesis. R

18. Smell And Taste

Dopamine plays a role in smell and taste perception. R

For example, in patients with Parkinson's Disease (PD) decreased ability to smell is common. R

Olfactory dysfunction may be an early biomarker of PD. R

19. Creativity

Normal levels of dopamine can make you more creative and can play a significant role in verbal fluency. R

For example, moderate (but not low or high) levels of striatal dopamine benefit creative cognition by facilitating flexible processes. R

Moderate (but not low or high) levels of prefrontal dopamine enable persistence-driven creativity. R

20. Teeth

DA may initiate and regulate dental repair by acting on stem cells. R

Caveats

High levels of dopamine may lead to anorexic conditions. R

Dopaminergic supplements (such as amphetamines) may make schizophrenia worse. R R

Increases in dopamine (in NAC) enhances reward-feedback, so it's important to do good habits while increasing dopamine or else it could cause addiction. R R

Too much dopamine can make you hypersexual and compulsive/impulsive. R R R

Dopamine in excess (receptor dysfunction) can also cause mania and psychosis. R R

Dopamine (hypersensitivity) may contribute to headaches and migraines. R R

Dopamine in the infralimbic cortex (IL) or medial prefrontal cortex (mPFC, acting on DRD1/DRD5) may reinstate fear and aversion (must have had the fear before), while DA activation in the amygdala may attribute to fear conditioning. R R R R

Excessive amounts of dopamine may cause pregnancy loss, premature birth, or increased chances of schizophrenia in the offspring (via D2R expression). R R

Dopamine receptors are found on the skin and in hair follicles and may play a role in inhibiting hair growth. R R

Dopamine may be converted by dopamine beta hydroxylase (DBH) into norephinephrine/adrenaline and increase blood pressure and oxidative stress (which is commonly seen in PD), so inhibiting DBH may be useful. R R R

Dopamine may also cause vitamin B6 deficiency, so supplementing it may help prevent that. R

How To Increase And Protect Your Dopamine

My Top 10 Ways To Increase Dopamine:

  1. Bright/Blue Light or Sunlight (not the same thing) and Blue Glasses At Night
  2. Butyrate
  3. Cordyceps
  4. Exercise and Music (this is what I listen to)
  5. Forskolin
  6. Mucuna Pruriens
  7. Priming (15 min version of visualized meditation)
  8. Super Coffee
  9. Tyrosine
  10. Uridine

I also like to do cycle through ways to increase MANFGDNF, and CDNF as they play a pivotal role in repairing the dopaminergic system.

 
 

Lifestyle:

  • Achieving Goals/Rewarding Habits (crossing off checklists, video games, etc) R
  • Being social and bonding with others increases dopamine (as well as living with others) R R
  • Having a circadian rhythm (good sleep as well) R
  • Cold (plunges, baths, cryotherapy) - strong R R
  • Enriched Environments R
  • Exercise R R R
  • Gambling/Risk Taking R
  • Hypoxia (adaptive response so chronic may lower it) R R
  • Learning Something New (read the blog LOL) R
  • Massage Therapy R
  • Meditation (mindfulness and consciousness) R R 
  • Music R
  • NoFap (not masterbating for men, probably via reduced prolactin)
  • Sex R R
  • Space Flight (increases DA and COMT, decreases MAO and GDNF) R
  • Standing (not sitting) R
  • Sunlight and chronic Tanning R R R
  • Touch, stroking, tickling (hugs?) R R R
  • Yoga R

Diet:

Devices:

  • Acupuncture and Electroacupuncture R R R
  • Blue Light (timed correctly) R
  • Bright Light R
  • Hyperbaric Oxygen Therapy (HBOT, although short term hypoxia reduces, while chronic hypoxia increases it in response to protect the brain) - reduces dopamine release from neurons but protects the neurons R R R
  • LLLT (on head) - increases DA neurons and survival against stress R R
  • Oxygen Concentrator - protects DA in striatum R 
  • TDCS R
  • UVB (may also be useful for activating tyrosinase to produce melanin) R
  • Vagus Nerve Stimulation (possibly) R

Hormones/Neurotransmitters:

  • Adropin - improves Akt in DA neuronsR
  • AgRP - increases LTP R R
  • Alpha-MSH - increases in hypothalamus R R R
  • Dopamine (of course as well as taken intranasally) R 
  • Endomorphin-2 R
  • Estrogen - in females it increases dopamine-motivation for sex and decreases need for feeding R
  • Ghrelin R R
  • Growth Hormone R
  • IGF1 R R
  • Insulin (as well as intranasal insulinR R R
  • Irisin R
  • Kynurenine - in midbrain (can make schizophrenia worse) R R
  • Melatonin - low doses protects DA neurons, decrease DAT activity, and decreases DA acutely, which is good for sleep R R
  • Nefstatin - protects DA neurons R
  • Orexin (hypocretin) R R
  • Pregnenolone R
  • Somatostatin - protects DA neurons from stress R
  • Testosterone - dependent as it increases DAT in cells, increases D2 mRNA, and decreases D3 mRNA in substantia nigra R
  • Tuftsin - protects DA neurons R
  • Vitamin D R R

Supplements

Probiotics:

  • Clostridium - increases DA in gut lumen in germ-free mice R
  • E. Coli - increases DA in gut lumen in germ-free mice R
  • Lactobacillus plantarum (PS128) - reduces anxiety by increasing serotonin and dopamine in the striatum, but not in the prefrontal cortex or hippocampus R
  • Lactobacillus rhamnosus GG - increases DA in frontal cortex R

Drugs

  • Agomelatine R
  • Amantadine R
  • Amfonelic acid R
  • Apipiprazole R
  • Atomoxetine R
  • Barbiturates R
  • BPC-157 - protects DAS from stimulants R
  • BRF-110 - protects DAS, especially in the midbrain R
  • Bromantane (Ladasten) R
  • Bromocriptine R
  • Bupropion (more effective in females) R
  • Cabergoline (used to counteract alcohol) R
  • Carbenoxolone R
  • Cocaine (using coca leaves may not be that bad) R R
  • Deferoxamine R
  • DETQ R R
  • Dextroamphetamine (amphetamines...adderall, vyvanse) - increases DAT long term and cause DA depletion, may be able to be prevented by NAD R R R R
  • D-512 (strong) R
  • Fluoxetine R
  • Gabapentin R
  • GHB R
  • L-Dopa R
  • Lipitor - normalizes DA in the hippocampus R
  • Losartan R
  • LSD (also binds to 5HTRs) R
  • Marijuana (THC increases DA via CB1, while CB2 protects DA neurons, but withdrawal from marijuana decreases DA) R R R
  • MDMA R
  • Melanotan II (Bremelanotide...melanocortins) R R
  • Memantine R
  • Mercury (inorganic mercury increases striatal DA release up to 2658%, probably causing depletion) R
  • Metformin R
  • Methylphnidate (Ritalin) - increases DA but causes DA neuron loss R R
  • Modafinil R R
  • Morphine (also Apomorphine...opioids) - although chronic opioid use significantly decreases in DAT, DA, TH and DA receptors R R R
  • Nicotine R R
  • Nortilidine R
  • Nortriptyline R
  • Nilotinib (150 or 300 mg once daily) - restores DA in brain R
  • Pentothal R
  • Phenylpiracetam R
  • Piracetam (weak) R
  • Pregabalin R
  • PRL-8-53 R
  • P6/P21?
  • Ropinirole R
  • RTI-111 (and RTI-121 and RTI-126, 20x stronger than cocaine) R
  • Selegeline (Deprenyl, low doses) R
  • Selank R
  • Semax R
  • Sertraline (zoloft) R
  • Spice (JWH-018) - may create higher dependence than MJ R
  • Testosterone Propionate (intransally) R R R
  • Tianeptine R
  • Tricor (Fenofibrate) R
  • Tolcapone R
  • Trihexyphenidyl R
  • Venlafaxine R
  • Vinpocetine R
  • 9-ME-BC - increases DA in hippocampus and possible regeneration of DA neurons via Shh R R

Pathways:

What Decreases Dopamine?

Diet

  • High Saturated Fat Diet (significantly can reduce DA signaling/functioning, also eating a high fat diet during pregnancy can alter dopamine receptor in offspring) - brown rice (γ-oryzanol) may reverse some problems with a high fat diet on DA R R R R
  • High Tryptophan Diet R
  • Low Iron Diet R

Lifestyle

  • Aging - DA levels reduce with age R
  • Chronic inflammation (ranging from infections such as Ochratoxin A or T. Gondii, brain injuries, leaky blood brain barrier, improper light usage, etc) R R R R
  • Chronic stress - increases DA release to the point where it causes dopamine dysfunction R
  • Forest Bathing R 
  • Insulin Resistance R
  • Noise Pollution (at night) R
  • Physical Inactivity - results from altered dopamine receptors rather than excess body weight, meaning you're not fat because you don't workout/lazy, but that dopamine dysfunction causes you to be lazy and not workout R
  • Sleep Deprivation R R

Hormones/Neurotransmitters:

  • Acetylcholine - not directly and not a simple inverse correlation R
  • Amylin R
  • Cortisol - chronically secreted leads to DA dysfunction R R
  • DHEA R
  • GABA R
  • Histamine - H3 receptor agonists significantly decreases the affinity of D2 receptors R R R
  • Leptin - leptin inhibits DA neurons, leptin resistance may also cause a problem R R
  • Obestatin (in hypothalamus) R
  • Prolactin R
  • Serotonin - not directly and not a simple inverse correlation R R

Supplements:

Probiotics:

Drugs/Chemicals:

  • Ambien R
  • Ammonia R
  • Arsenic R
  • Cadmium R
  • Deuterium (possibly) R
  • GSK598809 R
  • Lithium R R
  • Naltrexone (normal doses) R
  • Sulpiride R
  • Valproic Acid R

Pathways:

  • KOR R R R
  • M5 mACHR R

Are You Reliant On Dopaminergic Rewards?

It's easy to become addicted to dopaminergics as it affects the reward system. 

To counteract this, create normal routines (as described above) and pair dopaminergics with good habits. 

Also being able to choose which dopamine receptor and which part of your brain dopamine works on would be nice.

There may also be some pathways we can use to get ourself out of a drug-induced dopamine addiction.

CaMKII

Ca2+/calmodulin-dependent protein kinase (CaMKII) is also necessary for dopamine addition in some drugs, as it phosphorylates the downstream transcription factor cyclic AMP response element binding protein (CREB) and it starts the glutamatergic activation into synaptic plasticity during learning and memory formation. R

Inhibiting CaMKII may be very promising in making dopaminergics less addictive. R

For example, in animal models CaMKII inhibition has been shown to have a protective effect against nicotine and cocaine dependence. R R

Some CaMK inhibitors are:

Stay away from CaMK inducers:

mTOR

Another way to stop over excitation of dopaminergics is by inhibiting mTOR activation. R

Some mTOR inhibitors:

Rho Kinase

Inhibiting Rho kinase (ROCK) may be able to promote the goal-seeking action of dopamine and neuroplasticity without the creating addictive habits. R 

Some ROCK inhibitors:

When coming off dependence of dopamine agonists, to prevent dopamine agonist withdrawal syndrome (DAWS), it may be a good idea to taper. R

Mechanism Of Action

Simple:

  • Increases AgRP R
  • Increases AMPK R
  • Increases Ang(1-7) R
  • Increases Dynorphin R
  • Increases GH R R
  • Increases HO-1 R
  • Increases NPY R
  • Increases NRF2 R R
  • Increases Orexin R
  • Increases Oxytocin R
  • Reduces a-MSH R
  • Reduces beta-Endorphins R
  • Reduces COX-2 R 
  • Reduces CRP R
  • Reduces ERK1/2 R 
  • Reduces GABAAR R
  • Reduces HbA1C R
  • Reduces HMGB1 R
  • Reduces IFN-alpha R
  • Reduces IL-1β R
  • Reduces IL-6 R
  • Reduces iNOS R
  • Reduces KC R
  • Reduces KOR R
  • Reduces MIP-2 R
  • Reduces mTOR R
  • Reduces NF-κB R
  • Reduces POMC R
  • Reduces Prolactin R R
  • Reduces p38 R
  • Reduces Survivin R
  • Reduces TNF-α R
  • Reduces Tregs R
  • Reduces TSH R
  • Reduces VEGF R R

Advanced:

 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5067323/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5067323/

 
  • Dopamine has a hard time crossing the blood-brain barrier. R
  • There are a few ways to make dopamine: R R
    • L-phenylalanine via PAH -> L-tyrosine via TH -> L-DOPA via DDC -> Dopamine
      • Dopamine can then turn into NA via DBH (in presence of L-ascorbic acid and molecular oxygen), which NA is converted into adrenaline via PNMTase (SAMe as a cofactor) R
    • L-phenylalanine via DDC -> phenylethylamine via PAH -> tyramine via p-450 CYP2D6 -> Dopamine
    • L-tyrosine via DDC -> tyramine via p-450 CYP2D6 -> Dopamine
  • How To Break down dopamine:
    • DAT brings dopamine back from the synaptic cleft into storage vessicles via vesicular amine transporter (VAT2)
    • Excess dopamine is then catalyzed by MAO (A/B), ALDH, ADHs, ARs, and COMT: R
      • DA via COMT -> 3MT via MAO (A or B) -> 3-methoxy-4-hydroxyacetaldehyde via ALDH -> HVA
      • DA via MAO (A or B) -> DOPAL via ALDH -> DOPAC via COMT -> HVA
      • MAO-B is mainly found in astrocytes, whereas MAO-A predominates in catecholaminergic neurons like the cells of the SN. R
    • Dopamine can also be oxidized (bad) by cyclooxygenases, peroxidases, cytochromes, oxidases, and oxygenases (as seen in PSTs and PAPS) R
      • For example: DA via COX -> prostaglandin H -> dopaminochrome
      • Can also form other ROS byproducts such as DOPA quinone, dopamine quinone, and 6-hydroxydopamine quinone
        • Ie lead to neuromelanin in the brain
  • Most DA circulates as dopamine sulfate (DA-S), which can be de-conjugated to bioactive DA by arylsulfatase A (ARSA). R
  • For example, nerve-derived DA chiefly maintains plasma DA level, whereas plasma DA consists of only approximately 1% in its free form and the remaining part exiting in an inactive sulfate, and DA in circulation is mainly stored in platelets. R
  • Nigrostriatal pathway - associated with voluntary movement, reward processing, acquisition of spatial learning, memory, cognitive function, executive function, and attention R
    • substantia nigra (SN) and striatum (includes NAcc and caudate putamen)
      • projects to the dorsolateral PFC (DLPFC) in executive function and working memory R
      • projections from the caudate to the frontal lobes are disrupted and result in significant motor, attentional, and executive dysfunction R
      • In HD, striatal DA receptor subtype 2 (D2) binding is decreased and is sensitive to cognitive performance on a variety of tasks including executive function, attention. R
      • DA and cAMP-regulated phosphoprotein mKDa 32 (DARPP-32) - PP1 and PKA tightly regulates protein transcription related to numerous important cellular functions including neurotrophic factor production, regulation of synaptic plasticity, and cell homeostasis R
      • DA acts through D1 receptor mediated increases in PKA to promote DARPP-32 phosphorylation at its T34 site, which leads to an inhibition of PP1 R
  • Mesocorticolimbic pathway - consists of the mesocortical and mesolimbic pathways
    • Mesocortical
      • connects the ventral tegmentum to the prefrontal cortex
      • involved in cognitive control, motivation, and emotional response
    • Mesolimbic
      • involved in reward (incentive salience, motivation, reinforcement learning/addiction, and fear) and pleasure perception
      • ventral tegmental area (VTA) - consists of dopaminergic, GABAergic, and glutamatergic neurons; Cacna1c regulates normal DA neurotransmission. R 
      • prefrontal cortex (PFC)
      • hippocampus - DA receptors in the hippocampus receive projections from the SN and facilitate the maintenance of long-term potentiation (LTP) and blockade of D1/D5 receptors inhibits LTP formation R R R
      • amygdala
      • nucleus accumbens (NAcc)
      • olfactory tubercle
  • Tuberoinfundibular Pathway
    • projects from the arcuate nucleus in the tuberal region of the hypothalamus to the median eminence
    • regulates the secretion of prolactin from the anterior pituitary gland
  • In the immune system, (dopaminergic proteins expressed in immune cells) dopamine is a potent activator of resting effector T cells (Teffs), via two independent ways: direct Teffs activation, and indirect Teffs activation by suppression of regulatory T cells (Tregs) - dopamine "suppresses the suppressors" R R
    • T cells express functional dopamine receptors (DRs) D1R-D5R, but their level and function are dynamic and context-sensitive
    • DR membranal protein levels do not necessarily correlate with DR mRNA levels
    • different T cell types/subtypes have different DR levels and composition and different responses to dopamine
    • autoimmune and pro-inflammatory T cells and T cell leukaemia/lymphoma also express functional DRs
    • dopamine (~10(-8) M) activates resting/naive Teffs (CD8(+) >>>CD4(+) )
    • dopamine affects Th1/Th2/Th17 differentiation
    • dopamine inhibits already activated Teffs (i.e. T cells that have been already activated by either antigen, mitogen, anti-CD3 antibodies cytokines or other molecules)
    • dopamine inhibits activated Tregs in an autocrine/paracrine manner
  • Reward is also controlled by DA's ability to interact with opioid receptors via the endocannabinoid system. R
  • Midbrain dopamine neurons innervate the SCN and accelerates circadian entrainment. R
  • ARSA activity in adipocyte increases after differentiation. R
  • DA at nM concentrations suppresses cAMP, stimulates cGMP, and activates MAPK in adipocytes. R
  • In the entopeduncular nucleus (EP) of the basal ganglia (BG), dopamine modulates striatal and pallidal GABAergic inputs. R
  • In the eye, dopamine controls circadian rhythms by controlling tight junctions and GABA release. R
  • In the nose, dopamine cycles DOPAC/DA ratios are shown to be highest during ZT 0-12 (lights turned on) and lowest during ZT 13-24 (lights turned off). R

Dopamine Receptors

Dopamine receptors have a circadian rhythm and change with the seasons (as a regulatory process you have ~2x more dopamine receptors during the winter than during the summer). R

Dopamine receptors are categorized in two groups: R R

  • D1 receptors (DRD1 and DRD5), which are stimulatory (alpha-type) on cyclic amp (cAMP)
  • D2 receptors (DRD2, DRD3, and DRD4) which are inhibitory (beta-type) on cAMP

cAMP function depends on the coupling of its receptor (DR) to the heterotrimeric G proteins Gα-s/olf and Gα-i/o.

 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2806224/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2806224/

 

It's important to note that dopamine activation on receptors have separate functions, for example, some will increase inflammation, while others will decrease it. R

For example, DRD1 and DRD2 are coupled to anti-inflammatory mechanisms, thereby dampening inflammation, while DRD3 and DRD5 have been found consistently to promote inflammation. R

D1 Receptors

 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3948488/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3948488/

 

DRD1:

  • Localized on post-synaptic dendrites of both pyramidal and non-pyramidal neurons. R
  • Activates adenylate cyclase (AC) and subsequent activation of cAMP, activate phosphoinositide hydrolysis, and inhibit arachidonic acid release (inhibits the inflammatory response). R
    • Dopamine inhibits cytokine production via dopaminergic type-1 receptors R
      • DRD1 signaling negatively regulates NLRP3 inflammasome via a second messenger cyclic adenosine monophosphate (cAMP), which binds to NLRP3 and promotes its ubiquitination and degradation via the E3 ubiquitin ligase MARCH7. R
  • Along with DRD5 regulates long-term depression (LTD) and LTP in the hippocampus and spatial learning. R R R R
  • In adipose tissue DA suppresses leptin and stimulates adiponectin and IL-6 release (also in DRD5). R
  • Inhibits NADPH oxidase activity via protein kinase A and protein kinase C R
  • Upregulates mRNA expression of steroidogenic enzymes in adrenal glands R
  • Plays a role in "zombie-like" responses from amphetamine usage R
  • Found in Effector T cells, Regulatory T cells, B cells, macrophages, and dendritic cells. R

DRD5:

  • Stimulates TH1/TH17, making autoimmunity worse R
  • Suppresses cancer/tumor formation (inhibits mTOR) via increase of T lymphocytes, myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs) and natural killer (NK) cells. R R
  • Activates (dose dependently) AC R
  • Improves learning via BDNF/PAkt in PFC (as well as DRD1) R R
  • Decreases NADPH oxidase (via inhibition of phospholipase D2) and increases HO-1 expression R
  • Found in Effector T cells, Regulatory T cells, B cells, NK cells, macrophages, dendritic cells, and neutrophils. R

D2 Receptors

DRD2:

  • D2Sh (short) - pre-synaptic autoreceptors - synthesis, storage, and release of DA into the synaptic cleft R
  • D2Lh (long) - post-synaptic - transmit exitatory/inhibitory information R
  • Inhibits G-proteins that lead to an inhibition of AC and cAMP or or independently of cAMP pathways. R R
    • Inhibit phosphoinositide hydrolysis and subsequent Ca2+ mobilization R
    • Activates Akt and downstream GSK3B, similar to insulin secretion 
  • Forms heterodimers with adenosine A2a receptors and metabo-tropic glutamate-5 (Mglut-5) receptors R R R
    • Via A2a and Mglut-5 DRD2 regulates striatal LTP and LTD R
  • Suppresses innate immunity (and neuroinflammation) through αB-crystallin (CRYAB). R
  • In fat cells, DA and DA-S inhibit PRL gene expression and release. R
  • Increases PARK7 or (DJ-1), paraoxonase 2 (PON2), and heme oxygenase 2 (HO-2) R
  • D2 in left lobe is tied to positive reinforcement learning, whereas D2 receptor density being higher in the right lobe was tied to negative reinforcement learning. R
  • Found in Effector T cells, Regulatory T cells, B cells, NK cells, monocytes, macrophages, dendritic cells, and neutrophils. R

DRD3:

  • Increases pro-inflammatory Th1/TH17, and suppresses TH2 response in chronic inflammation R R
  • D3 dopamine receptor may contribute to motivation to use drugs R
  • Inhibits AC type V R
  • In neuropathic pain, there may be higher extracellular dopamine levels and reduced expression of D2, but not D1, receptors and TH in the nucleus accumbens. R
  • Affects reward/movement R
  • May exert a tonic inhibition on DA neurons in the ventral tegmental area projecting to the NAcc by stimulating GABA release at accumbal neuron terminals or by an autoreceptor control R
  • Systemic injection of the D3 receptor agonist 7-OH-DPAT has been shown to trigger ejaculation in rats without affecting arousal, even when anesthetized (also works on DRD2/4) R
  • Found in Effector T cells, Regulatory T cells, B cells, NK cells, monocytes, macrophages, dendritic cells, and neutrophils. R

DRD4:

  • Inhibits AC and cAMP R
  • Found in Effector T cells, B cells, NK cells, macrophages, dendritic cells, and neutrophils. R

TAAR

TAAR1:

  • Increases intracellular levels of cAMP and intracellular calcium concentration. R

Genetics

    DRD1

    • SNPs, rs265981, rs4532 and rs686, has been associated with autism in families having only affected males R

    DRD2  

    rs6277 (C957T)

    • C allele
      • 1.6x higher schizophrenia risk R
      • C allele associated significantly (p = 0.021) with post-traumatic stress disorder in a sample of (assumedly Australian) 127 war veterans w/ 228 controls R
    • CT allele
      • 1.4x higher schizophrenia risk R
    • T allele
      • normal schizophrenia risk, learns NoGo faster R

    rs2283265

    • significantly associated with improvements during working memory training R

    rs1799978

    • Association between ADORA2A and DRD2 polymorphisms and caffeine-induced anxiety R

    rs4648317

    • T allele
      • prone to higher nicotine dependence, more impulsive/sensation seeking R

    rs1076560

    • A allele
      • influences working memory R R
      • 1.3 fold more associated with Alcoholism than the rs1076560(C) alleles R

    rs1801028

    • CG allele
      • 1.4x risk for schizophrenia R

    rs1800497 (Taq1a)

    • T allele
      • genotype displays a 30– 40% reduction in D2 DA receptor density in the striatum R
      • reduced response to errors and increased addictive behavior R
      • T allele may play a role in nicotine addiction by causing an "understimulated" state that can be relieved by smoking R
      • individuals were significantly associated with all advanced adenoma recurrence R
    • A allele
      • recover slower from traumatic brain injury by memory and attention tests R
      • relationship between conduct disorder, the behavioral phenotype of impulsivity, and problematic alcohol/drug use among adolescents R

    DRD3 

    rs6280

    • CC allele
      • showed significantly (p = 0.002) poorer performance than TT carriers on executive functioning tasks in a somewhat small Caucasian sample R
      • better response to olanzapine R
    • TC allele
      • 23% more preservative errors on the WCST compared to TT homozygotes in a small (216) healthy Han Chinese sample R

    DRD4

    rs1800955

    • CC allele
      • increased susceptibility to novelty seeking R
    • CT alleles
      • increased susceptibility to novelty seeking R

    rs747302

    • Association between dopaminergic polymorphisms and borderline personality traits among at-risk young adults and psychiatric inpatients R

    rs11246226

    • A allele
      • increased risk of schizophrenia while CC has reduced risk R

    DRD5

    rs6283

    • association with bruxism R

    More Research

    • Dopamine is present in very high concentrations in some algal blooms. R