As we recall, neurotransmitters are chemicals found in the nervous system. They allow neurons to talk to one another. After being released from one neuron, they cross the synapse and bind to other neurons.

The first neurotransmitter, acetylcholline, was discovered in 1915.

There are now believed to be over one hundred unique neurotransmitters in the nervous system.

Neurotransmitters can be generally broken down into excitatory or inhibitory. The former passes on neural impulses, the latter subdues them. Some neurotransmitters, like dopamine, can be both excitatory and inhibitory, depending on which region the receptor is found, and what brain circuitry that specific subgroup of receptor is part of. Given this information, it’s more valid to discuss brain activity in terms of receptors, than in terms of the chemicals (ligands) that bind to them.

Also elaborated upon are some of the most prominent, basic sub-types, or subunits, of the receptor that the neurotransmitters bind to, and the effects of binding to these various receptors within receptors.

Firstly, neurotransmitters don’t act in a vacuum. For instance, when nicotine binds to the nicotinic acetlycholline receptors, a slew of other neurotransmitters are released secondarily. These include dopamine, GABA, norepinephrine, acetylcholline, serotonin, and beta-endorphin.

Amines

Acetylcholline is a neurotransmitter, in a class of its own, involved in many aspects of cognition, muscle movement, and initiation of REM sleep. A lot of natural poisons deal with acetylcholline and its receptors, given how much it governs muscle control.

It binds to both ionotropic and metabotropic receptors

  • Nicotinic (ionotropic)
    • Named after the agonist “nicotine”
    • Functions as excitatory
    • Messages transmitted extremely fast
    • Regulates skeletal muscles
    • Heavily involved in muscle control
      • Found at neuromusclular junctions (where two muscles converge)
    • Heavily involved in cognition
      • Memory, learning, motor control
    • Involved in pleasure
      • Help mediate reward and arousal
    • Five types of subunits
      • Alpha (1-10)
      • Beta (2-5)
      • Gamma
      • Epsilon
      • Delta
      • In different combinations, they can be variously classed..
        • Muscle nicotinic receptors
        • Neuronal nicotinic receptors
        • Neuronal and autonomic nicotinic receptors
        • Epithelial and neuronal nicotinic receptors
    • The snake venom “a-bungarotoxin” stops nicotinic ion channels from opening
  • Muscarinic (metabotropic)
    • Named after the agonist “muscarine”
    • Five subtypes (M1-M5), all of which are found in the CNS
    •  M1-M4 are also found elsewhere
      • M1: on gland that secrete proteins
      • M2: on hear tissue
      • M3: smooth muslces and on protein-secreting glands
    • Acts as an inhibito0 (M2, M4) r or proprietor of neurotransmission (M1, M3, M5)
    • Forwards messages much more slowly
    • Do not affect skeletal muscles
    • Largely modulates the rhythm of
      • Circulatory system
      • Smooth muscle
    • Also involved in
      • Urinary tract
      • Respiratory tract
      • Gastrointestinal tract
      • Eyes
      • Exocrine glands
      • Activates sweat glands
    • Apart from seat gland activation, muscarinic activity in the PNS is relegated to the parasympathetic nervous system

Biogenic Amines

Dopamine is the main chemical involved in reward, pleasure, novelty, eager anticipation, satiation, self-esteem, and confidence. Dopamine is the main neurotransmitter involved in addiction. But it also helps regulate fine muscular action, and aids attention and learning.

As stated elsewhere, it’s far too reductive to state that more dopamine=more happiness. If this were true, levodopa, a medication given to those afflicated with parkinson’s disease, would be a controlled/scheduled substance, and have abuse potential.

The dopamine receptor subtypes are D1, D2, D3, D4, and D5. The first two kinds are at least ten times, and perhaps up to 100 times, more prevalent than the others.

D1 and D5 are closely related, and largely deal with how nerves govern muscles. D1 in particular plays a large role in cognition, or, executive function. It’s largely located in the cortical region of our brain.

D2, D3, and D4 are very similar. Consistent with its role in the experience of reward, one of the areas that D2 receptors are most dense is the nucleus accumbens. D3 receptors are also found in the limbic system.

Four dopaminergic pathways exist in the human brain:

  1. Mesocortical: Mostly responsible for executive function, complex rationality
  2. Mesolimbic: Deals with feelings of euphoria
  3. Nigrostriatal: Largely controls and coordinates movements
  4. Tuberoinfundibular: Regulates lactation

Dopamine is one of the monoamine and catecholamine neurotransmitters. On the former, it’s heavily involved in psychiatry and also seems to have a lot of influence relative to its size. On the latter, the grouping is mostly based on structural similarities to the the other two catecholamines, but also mean that it can be very sympathomimetic (activating the central nervous system); they are produced by the adrenal glands in response to stress

Norepinephrine, otherwise known as noradrenaline, is the monoamine neurotransmitter largely associated with mental arousal. Dopamine gets metabolised (broken down into) norepinephrine. Norepinephrine helps us concentrate, make fast decisions, and judge the tone of our setting.

It’s one of the main chemicals involved in the “fight-or-flight” response, when someone senses that they are in physical danger.

Another monoamine and catecholamine, though norepinephrine isn’t the main excitatory neurotransmitter in our body (that title goes to glutamate), it plays a main role in the world’s most popular psychoactive substance: caffeine.

Again, dopamine (but not all dopamine) metabolizes into norepinephrine, which means that much of the time, we experience it without knowing it.

Epinephrine, perhaps better known as adrenaline, is created when norepinephrine is broken down. It has a much more physically simulating effect than its parent compound, which effects are mostly mental.

It’s the other neurotransmitter, along with its cousin, norepinephrine, in the “fight-or-flight” response.

Both norepinephrine and epinephrine decrease hunger. They also affect motivation, attention, confidence, and alertness.

Norepinephrine and epinephrine bind to the alpha-adrenergic and beta-adrenergic receptors. The former are primarily located in blood vessels, smooth muscle sites, and the nervous system. Beta-adrenergic receptors can be found in the same places, but also in the heart.

There are medications to treat high blood pressure that mimic these two excitatory neurotransmitters, but instead of acting as postsynpatic agonists, they act as agonists on the autoreceptors. Autoreceptors are connected to presynaptic neurons. Since they are attached to the far sides of the neuron, chemicals don’t find their way to them until there is such a high concentration of neurotransmitters in the middle area of the synaptic cleft, that some of them drift to the periphery (side). When autoreceptors are saturated with enough neurotransmitters, they tell the presynaptic neuron to either slow down, or stop, the release of neurotransmitters. Hence, a drug that acts selectively as an agonist at an autoreceptor, has the opposite effect of a drug that acts as a typical agonist at the same type of neuron.

The three neurotransmitters thus far discussed, dopamine, norepinephrine, and epinephrine, are the main catecholamine chemicals. Here they are

Below is the metabolism, by monoamine oxidase (MAO) or catechol-o-methyltransferase (COMT), enzymes that break down neurotransmitters, of norepinephrine into various metabolites

Here is a more straightforward map:

Serotonin, also known as 5-hydroxytryptamine, or, 5-HT, oversees our advanced social interactions, probably in concert with indirect GABA activity. It guides hunger, sexuality, and sleep. Serotonin has a large role in processing information, and behaving based on these interpretations. A lack of serotonin may create anxiety, depression, a loss of healthy inhibition, impulsive behavior, an unstable mind-state, aggression, overeating, excessive sexual behavior, overreaction, and even suicide. Despite being such an important chemical, only 2% of the serotonin in a human body is in the central nervous system. There are over 13 different sites that serotonin can bind to. What is known is what is being discussed.

5-HT1 receptors are largely found in the hippocampus, amygdala, and cortex. They influence eating, the development of migraine headaches, body temperature, depression, and anxiety.

5-HT2 receptors also have a dense presence in the amygdala, isocortical region, hypothalamus, cortex, and hippocampus. They mediate depression, anxiety, psychosis, obesity, and depression

5-HT3 receptors, most present in the primitive brain stem, control nauseau. This binding site is unique in that it’s ionotropic, while all other serotonin binding regions are metabotropic.

5-HT4 is largely in the hippocampus, and is involved in cognitive dysfunction and anxiety.

The jury is out on the function of 5-HT5 receptors, though we know where they’re found (the cortex and hippocampus).

5-HT6, prevalent in the striatum and cortex, plays a great role in cognitive deficits.

Finally, 5-HT7, found in the thalamus and hippocampus, is heavily implicated in depression, and possibly in cognition.

Dopamine, norepinephrine, epinpehrine, and serotonin are termed monoamine neurotransmitters. They are synthesized from the same amino acid, though serotonin is not a catecholamine, it’s an indolamine. Monamines are theorized to be heavily involved with a host of mental illnesses, particularly depression. This is called the chemical imbalance theory. While that may be so, recent research has suggested other, perhaps more salient, physical abnormalities in the brains of the mentally ill more directly mediate mental illness.

Below is an illustration of how the monoamine chemicals interact to produce various qualitative states.

Trace amines are closely related to the monoamine neurotransmitters in structure and function. Generally speaking, they interact most with dopamine. Trace amines tend to be stimulating (sympathomimetic). Oftentimes, they co-localize their receptors with monoaminergic neurons, and can directly inteact with their transporters and auto-receptors.

The “trace” aspect comes from:

  1. They have a half life of about 30 seconds, meaning that they only exist for less than three minutes after being released
  2. Other, more well-known neurotransmitters outnumber them by hundreds of times

There are some notable trace amines

  • Beta-phenylethylamine (PEA)
    • Structurally similar to the catecholamines (dopamine and nor/epinephrine)
    • Widely considered to be the human brain’s “endogenous amphetamine”
    • Increases activation of the brain’s reward pathway (centered in the limbic system)
  • Tryptamine
    • Structurally more similar to serotonin (both of which are indolamines
    • Structurally related to serotonin (both of which are classified as indolamines)
    • Has an inhibitory effect on the brain’s reward system

There are seven trace amine-associated receptor (TAAR) subtypes. The most well-known is TAAR 1, which, activated, increases synaptic concentrations of monoamine neurotransmitters through reputake inhibition and release. Beta-phenylethylamine, followed by tyramine, is the most potent agonist of TAAR 1. Interestingly enough, a slew of other chemicals also act as ligands for TAAR 1:

  • Some thyroid hormones
  • LSD
  • The catecholamine neurotransmitters
  • MDMA
  • Serotonin
  • Methamphetamine
  • Amphetamine

TAAR 1 can be found in many structures throughout the limbic systems. It also exists in the prefrontal cortex, thus, making its presence in the primitive, as well as the executive, regions of our brain.

It appears that some trace amines also facilitate reverse transport. Other trace amine receptors are not well-studied. In studies with rats, TAAR 4 was only activated by beta-phenylethylamine and tyramine.

Their function is thought to be swift balancing agents. They help regulate synaptic concentrations of the monoamine neurotransmitters, but they also interact with the GABAergic and chollinergic systems.

 

Histamine

In the past, scientists theorized that histamine acted mostly peripherally, playing a small role in inflammation. While it does this, it is now understood to have a greater magnitude of effect, and to oversee other bodily processes

  • Increases the efficiency of immune activity
  • General arousal
  • Partly presides over the release of hormones
  • Plays a role in allergies
  • Modulates our blood pressure and sense of pain
  • Controls inflammation

An influx of histamine induces itching. Mentally, histamine helps regulate emotion and appetite, and staves off the desire to sleep. It’s involved in complex cognition such as learning, and various forms of memory.

Its subtypes are H1, H2, H3, and H4

H1 is known for increasing appetite

H3 has recently gained widespread attention in the psychiatric field, as inverse agonists or antagonists may be very useful. It indirectly affects

  • Apoptosis (the controlled destruction of cells)
  • Parkinson’s
  • Diabetes
  • Ischemia (when a tissue is cut off from nutrients)
  • Alzheimer’s
  • Neuronal plasticity.
  • Obesity
  • Epilepsy
  • Perception of pain

H3 autoreceptors largely control the production and release of histamine. Phase I, II, and III, trials involving chemicals that interact with the H3 subtype are being conducted for…

  • Narcolepsy
    • Four drugs in trials
  • Alzheimer’s
    • Three drugs in trials
  • Schizophrenia (for cognition)
    • Two drugs in trials
  • Parkinson’s
    • One drug in trials

H4 acts as an important mediator between the immune system, and the central nervous system. One study suggested that it might be involved with movement and anxiety. If antagonized, it may be useful as treatment for respiratory diseases. This subtype also appears to be effective in restraining excess microglia action, thereby reducing inflammation.

Amino acids 

GABA (gamma-aminobutyric acid) is the main inhibitory neurotransmitter of the brain. GABA activity is heavily associated with a reduction in anxiety. GABA also plays a significant role in impulse, relaxation of muscles, and sleep. It tones down our emotional responses to positive and negative circumstances, including both pleasure and agitation.

Standard drinking alcohol (ethanol) is a GABAergic (works by GABA) agonist.

There are several important sub-units on GABA neurons. They can be generally be broken down into GABA-A and GABA-B.

There have been 17 different possible receptor sites found on GABA-A neurons, which are ionotropic. The most important ones are elaborated on.

The α1 subunit is responsible for feeling a hypnotic effect. The “z” drugs, including Ambien (zolpidem), Lunesta (eszoiclone), and others, termed “non-benzodiazepines”, are fairly selective for this subunit. They are rationally dispensed for insomnia.

α2, and to a lesser extent, α3, cause anxiolysis, a reduction in anxiety.

α5 is most associated with amnesia. The last three subunits are found in abundance throughout the central nervous system.

The role of GABA-B receptors is poorly understood, but they are theorized to be involved in relaxing skeletal muscles and inhibiting the cough reflex.

GABA-C receptors, found largely in the hippocampus, are now thought to be a type of GABA-A receptors.

Since GABA is such a prominent inhibitory neurotransmitter, those who are addicted to non-prescribed GABAergics can go into seizures and die if they are suddenly cut off from usage of the drug. This includes alcohol, benzodiazepines, and others.

Glutamate, also called glutamic acid or glutamine, is present in 80% of our brain’s neurons, is an excitatory neurotransmitter, interesting because it also serves as a precursor to the inhibitory GABA. Our body creates it when glucose is broken down. It greatly facilitates our cognitive capacities (largely in memory) and sensory-motor functions. Glutamate regulates damage caused by heart attacks and strokes. Levels of glutamate increase when ischemia (blood supply being cut off) occurs, perhaps as a warning sign that something it wrong.

Glutamate binds to AMPA, NMDA, and kainate receptors. These are ionotropic receptor that leads to fast neurotransmission, and regulate neuronal change involved in memory and learning.

Additionally, glutamate binds to three groups of metabotorpic receptors. Things get a bit complicated with this one!

Glycine is another inhibitory neurotransmitter. Mostly found in the brainstem and spinal cord, this chemical aids the synthesis of protein. It’s involved in relaxing our muscles that involve circulatory, respiratory, and facial movements.

Here we can see some glycine and (mainly) glutamate neurotransmission, and how the latter can interact with glial cells, not just neurons.

Aspartate, the fourth, and final, amino acid neurotransmitter, hasn’t been studied much. It appears to be excitatory.

Peptides

These are long chains, up to 36, of amino acids linked together. For the sake of a bit of review, one of the ways in which peptides differ from other neurotransmitters is that they don’t just act locally. They also affect blood flow, activity of glial cells, and gene expression (through the first and second messenger system detailed in the Advanced Neurotransmission explanation).

Opiate Peptides

It may be most helpful to begin with the opiate receptors, which are found in all regions of the body that deal with pain. The chemicals act exclusively on G-protein coupled receptors.

Firstly, the µ (pronounced mew) opiate receptor is heavily associated with euphoria, partly because its activation leads to less GABAergic activity that would otherwise inhibit dopamine release. µ activation may be more salient in causing feelings of reward than dopaminergic (dopamine activity) release. Most drugs that are known to produce a high or buzz, from caffeine to marijuana to  alcohol, partly function to make the µ receptor receptor fire. Activation of the µ site also causes respiratory depression and physical dependence. This receptor subtypes mostly populates the thalamus and brainstem. Because the brainstem controls so many of our bodily processes that keep us alive, inhibitory opioid activity in this region can cause respiratory failure, and death.

We now understand that there are µ1 and µ2 receptors. µ1 is the main type of receptor being stimulated when the user experiences euphoria. µ2 is mostly involved in respiratory depression.

Next, the δ (delta) opiate receptor, which is also implicated in euphoria, though to a lesser extent. Arguably, the delta subtype makes up for this disparity in eliciting well-being by acting as a sustainable antidepressant and anxiolytic (anxiety-reducer). That is to say, the dos does not have to be regularly increased to benefit mood, unlike the transient high that µ  activation causes. The delta subtype also lowers the seizure threshold (seizures are more likely to happen).

Finally, the κ (kappa) opiate receptor is most linked to sedation, dysphoria, and hallucinogenic effects. Antagonists produce an antidepressant effect. But agonists may be helpful for users whom are trying to break addiction to other drugs.

Endorphin is the most well-known endogenous (created by the body) opiate. The hypothalamus orders the pituitary gland to begin its creation. Endorphin is released during times of abnormal stress (mental as well as physical). It also plays a big role in the pleasure of orgasm, indirectly causing sex hormones to become active. As would follow, endorphin plays a role in obesity, diabetes, and many mental illnesses. It binds to the µ receptor most, then δ, and finally κ.

Enkephalin is another endomorphine (endogenous morphine-like) neurotransmitter. It is largely responsible for regulating bodily pain, and mostly binds to the δ receptor.

Following these peptides, we have dynorphin. It’s produced in many regions of the body, including the spinal cord, hypothalamus, and hippocampus. Dynorphin controls the activity of oxytocin, the “love chemical”. It also helps control appetite, pain, bodily temperature, and out sleep cycle. Dynorphin (as in dys-phoria) preferentially binds to the κ opiate receptor.

Then we have  endomorphin, which is found in a large variety of areas, including the spinal cord, brainstem, hypothalamus, striatum, amygdala, and nucleus accumbens. It comes in tow forms: endomorphin1 and endomorphin2. Endomorphin1 has the most affinity of all for the µ receptor. It mediates arousal, response to stress, sedation, reward, and cognition.

Morphine itself is now known to be produced by the brain, but in quite small amounts.

Receptors for opioids are most concentrated in the ventral tegmental area. This region of the brain has strong connections both to the nucleus accumbens (the center of euphoria), and the frontal cortex (the center of cognition).

One of the main ways by which opioids act is through reduction of GABA neurotransmission. GABA prevents excitatory dopaminergic activity in some regions of the brain. By reducing GABA activity, opioids indirectly increase dopamine levels, leading to euphoria.

Want to increase those endogenous pleasure chemicals? One recent study suggests that this can be done by watching a movie with a significant amount of drama.

Here we have a useful, if outdated, chart relaying the binding profiles of various (but not all) endogenous opiates to the three subtype categories of the receptor (µ, δ, 0).

Another main crux by which opioids work is by inhibiting excitatory neurotransmission of the monoamines, acetylcholline, and substance p, and generally preventing sense of pain from reaching the brain.

So less Ca influx means that excitatory neurotransmitters that otherwise would be released, are not. Increasing the polarization of the postsynaptic neuron means that it will less likely fire and release excitatory neurotransmitters into the next synapse. Things get very complicated when opioid receptors are activated, partly because opiates are so large, and facilitate volume nuerotransmission as a result (they have effects far beyond where they’re released).

Tachykinins

These chemicals are termed as such for their ability to cause swift muscle contraction. As are endomorphines, tachykinins affect groups of neurons, and have wide-reaching influence.

Substance P is a tachykinin neurotransmitter found in sensory neurons, mostly in the amygdala, nucleus accumbens, hypothalamus, pineal gland, and limbic regions in general. It sends messages of pain from the peripheral nervous system to the central nervous system, and reduces blood pressure. It increases saliva and histamine release, while decreasing insulin release, and can cause nausea and vomiting. It mostly binds to the neurokinin-1 (NK1) receptor, which induces pain, depression, and anxiety. Opioids, both endogenously created (made by the body), and exogenously created (made outside of the body) reduce physical pain partly by stopping the release of substance p. This is a mechanism they share with gabapentin and pregabalin, which one might argue justifies these two chemicals as sometimes effective at treating heroin addiction.

Neurokinin A is quite present in the nucleus accumbens and amygdala, as is substance p, but also finds its home in many peripheral regions. It has most affinity for the neurokinin-2 (NK2) receptor. Blocking this receptor leads to less stress, and may also conduce to the creation of new neurons in the hippocampus.

Neurokinin B is largely found in the cortex, spinal cord, and several limbic areas, and has a preference for the neurokinin-3 (NK3) receptor, which we know the least about. It is theorized to possibly lower dopaminergic activity.

Hormones

Oxytocin is a peptide, and hormone, produced by the hypothalamus, and deposited directly by the pituitary gland into the bloodstream and in the brain. It promotes uterine contractions, and may improve autism, but is best known for its pro-social, emotional, mood-elevating effects. It largely facilitates what we think of as “female” behavior.

Vassopressin plays a large role in “male” behavior. It may lead to anxiety and depression.

Orexin is highly associated with appetite.

Endocannabinoids are, as inferred, endogenous neurotransmitters that bind to cannabinoid receptors. Anandamide binds to CB1, the cannabinoid receptor most associated with psychoactive effects, which is widely found throughout the central nervous system, such as in the striatum and amygdala. Activation leads to the impairment of many cognitive functions. It also activates the CB2 receptor, which is less found in the central nervous system, and mediates pain and immune system function. These receptors are located largely in the limbic system. They also have a presence in regions that deal with the creation of emotions based on sensory data, learning, memory, and pain.

2AG is a more recently discovered endocannabinoid.

Endocannabinoid activity has been linked to a reduction in GABAergic activity, as is endomorphines, but also less glutamtergic action. They also indirectly prompt acitivuty of various amine neurotransmitters.

The pituitary peptide corticotropin controls stress, healing, and immune function.

Nitric oxide, a gas, sends messages to various organs, mainly the intestines. It also regulates sexual behavior and agression.

Adenosine is a hormone that regulates cell activity.

hormones, and nitric oxide 

GHB

DMT

Orexin

Melatonin

Sources: Abnormal Psychology: An Integrative Approach, Uppers, Downers, All Arounders: Physical and Mental Effects of Psychoactive Drugs, www.medicinenet.com, www.news-medical.net, Encyclopedia of the Human Brain, Curriculum Connections Psychology: The Brain, Changes in Cortical Dopamine D1 Receptor Binding Associated with Cognitive Training, The European Bioinformatics Institute, Phylogenetic Analysis and Selection Pressures of 5-HT Receptors in Human and Non-Human Primates: receptor of an Acnient Neurotransmitter, pharmacorama.com, Endogenous Opioids: Their Physiological Role and Receptors, Encyclopedia of Psychopharmacology, Endocannabinoid Regulation of Monoamines in Psychiatric and Neurological Disorders, Handbook of Biologically Active Peptides, Biopsychology, http://www.guidetopharmacology.org, Dr. Kevin Davis, Trace Amines and the Trace Amine-Associated Receptor 1: PHarmacology, Neurochemistry, and Clinical Implications, Histamine Pharmacology and New CNS Drug Targets, http://onlinelibrary.wiley.com/doi/10.1111/j.1755 5949.2010.00212.x/full, http://www.ingentaconnect.com/content/ben/mrmc/2013/00000013/00000001/art00005, http://wholesomeemotionalrecovery.com/wp-admin/post.php?post=1522&action=edit, https://www.atsdr.cdc.gov, https://www.ebi.ac.uk/interpro/potm/2005_11/Page2.htm, https://image.slidesharecdn.com/glutamateschizophrenia-141117062742-conversion-gate02/95/glutamate-schizophrenia-3-638.jpg?cb=1421566746