neurotransmitters and brain function (a really good summary)

Neurons (nerve cells) in the brain form elaborate networks, with each neuron having up to 15,000 connections with neighbouring neurons at contact points called synapses. While the nerve impulse travel through the neuron as an electrical impulse, it does not cross the gap known as the synaptic cleft but rather stimulates the release of a chemical messenger: a neurotransmitter. This crosses the synaptic cleft and is received by neurotransmitter receptors on the target cell. A neurotransmitter with increase (excitatory) or decrease (inhibitory) the probability that the target cell will produce a nerve impulse.

There are three main types of neurotransmitters in the brain: small molecules used for fast signal transmission between neurons, small used for slower modulation of network activity, and large molecules (peptides) used for even slower modulation of cell circuit functions. Most neurons have receptors for most of the neurotransmitters in all three of these categories.

The two main fast acting signal transmission neurotransmitters are the amino acids glutamate and gamma-Aminobutyric acid (GABA). 99% of all neurons in the brain release one of these two chemicals. All the major functions of the brain, including perception, cognition and consciousness involve neurons communicating using these two neurotransmitters.

The neuromodulators are small molecules including acetylcholine and the monoamines dopamine, serotonin and norepinephrine. The neuromodulators account for less than 1% of neurons, but play an important role in activating widespread neural systems or networks that play an important role in emotions, behaviour and other functions (see below).  

The circuit modulation neurotransmitters are peptides (large protein molecules) used for slower modulation of neural functions and include endorphins, cannabinoids, oxytocin and many others.

In this post, I have tried to make a succinct and inevitably simplistic summary and overview of the more important neurotransmitters below, focusing mainly on brain function (not functions in other parts of the nervous system and body).

Glutamate

Glutamate is an amino acid that is the major excitatory neurotransmitter in mammalian central nervous systems. Glutamate is probably best known as “monosodium glutamate” or “MSG” which is the sodium salt of glutamic acid and a white crystalline solid used as a flavor or taste enhancer in food (food additive number E620). The taste of glutamate is described using the Japanese word “umami” which has not English equivalent (roughly corresponds to “savoury”). People taste umami through taste receptors that respond to glutamate. Umami is recognized as one of the five basic tastes as it is detected through its own specific receptors, rather than arising from a combination of taste receptors. The other basic tastes are salty, sweet, bitter, and sour.  

Glutamate has excitatory effects on nerve cells, and that it can excite cells to their death in a process now referred to as “excitotoxicity”. Powerful uptake systems (glutamate transporters) prevent excessive activation of these receptors by continuously removing glutamate from the extracellular fluid in the brain. Additionally, the blood–brain barrier shields the brain from glutamate in the blood.

Glutamate excitotoxicity is believed to be involved in some degenerative brain diseases such as Alzheimer’s disease2 and amyotrophic lateral sclerosis (ALS or Lou Gehrig’s disease, the disease that Stephen Hawking had.) In ALS, there are decreased levels of the main transporter that removes glutamate from the synapse; this leads to increased synaptic glutamate levels and excitotoxicity which affects motor neurons to a greater degree than other types of neurons. The first and so far only approved specific treatment for ALS is riluzole, a drug that modulates glutamate. Glutamate deficiency is associated with insomnia, concentration problems, mental exhaustion and ADHD-like symptoms. PCP and ketamine decrease or block glutamate.

Gamma-aminobutyric acid (GABA)

Gamma-aminobutyric acid or GABA is the chief inhibitory neurotransmitter and is used at the great majority of fast inhibitory synapses in virtually every part of the brain. GABA is primarily synthesized from glutamate via the enzyme glutamate decarboxylase (GAD) with pyridoxal phosphate (the active form of vitamin B6) as a cofactor. This process converts glutamate (the principal excitatory neurotransmitter) into GABA (the principal inhibitory neurotransmitter). GABA largely does not cross the blood-brain barrier.

Although it has depressive effects on the central nervous system, the subjective effects of GABA are the total opposite. GABA helps the mind and body to relax, and it is known to help counter the effects of stress. It also helps to regulate sleep and mood. Sedatives/tranquilizers, general anesthesia, and anti-seizure drugs work by enhancing GABA, which suppresses brain activity. Alcohol, barbiturates (phenobarbital), benzodiazapines (valium etc), GHB all mimic or increase the effect of GABA. GHB is a precursor to GABA in certain brain areas.  Phenibut (available as a nutritional supplement in some countries) is a central nervous system depressant that is a GABA analogue and acts as a GABA_B receptor agonist (an agonist is a chemical that binds to a receptor and activates it).

Acetylcholine (ACh)

Acetylcholine is the transmitter used at neuromuscular synapses (junctions): motor neurons release this to activate muscles. It is also used in the autonomic nervous system, being the internal transmitter in the sympathetic nervous system and the primary transmitter of the parasympathetic nervous system. In the brain, it acts both as a transmitter and a neuromodulator. The brain contains a number of cholinergic areas that play important roles in arousal, attention, memory and motivation

ACh an ester of acetic acid and choline. It is synthesized from choline by the enzyme choline acetyltransferase, and is metabolized by acetylcholinesterase, an enzyme that is present in the postsynaptic membrane. ACh cannot cross the blood-brain barrier and is synthesised in brain neurons from choline, which does cross the barrier. Choline can be synthesised by the human body, but must be supplemented from food sources. It is found in meat, vegetables and fruit, but is particularly high in organ meats and egg yolks.

ACh plays an important role in alertness, attention, learning and memory. It also promotes REM sleep. Damage to the ACh-producing system in the brain has been shown to be associated with Alzheimer’s disease. Nicotine activates the ACh receptors. As do nerve gases (VX, Sarin). Drugs that decrease or block acetylcholine include atropine, scopolamine, curare, botox.

Dopamine

Dopamine (DA or 3,4-dihydroxyphenethylamine) is a monoamine neurotransmitter which plays a significant role in motivation and reward-motivated behaviour and learning, mood, pain and appetite. It has both inhibitory and excitatory functions.

Dopamine is incapable of crossing the blood-brain barrier and must be synthesised in inside the brain. Its direct precursor L-DOPA is synthesised in the brain and kidneys from either the essential amino acid phenylalanine or the non-essential amino acid L-tyrosine, both of which are found in nearly every protein in food.

All dopamine-containing neurons exist in cell groups in the midbrain (the substantia nigra and the ventral tegmental area). Parkinson’s disease results from the loss of dopamine-secreting cells in the substantia negra (a structure in the mid-brain that plays an important role in reward and movement). The most widely used treatment for parkinsonism is the use of L-DOPA, the metabolic precursor of dopamine. Unlike dopamine, L-DOPA can cross the blood-brain barrier.

Most antipsychotic drugs act as antagonists for the dopamine receptor (many for the D2 subtype). This led to the dopamine hypothesis that schizophrenia was due to hyperactivity of the brain dopamine systems. However, schizophrenia patients do not typically have elevated levels of dopamine and it is now thought that schizophrenia symptoms result from dysregulation of the dopamine receptors in the brain, particularly overactivation of the D2 receptor. Haloperidol (Haldol) is a typical antipsychotic used for the treatment of schizophrenia, Tourette syndrome and various psychoses. It is a dopamine antagonist that binds to the D2 receptor and also to the serotonin 5-HT₂ receptors at a higher dose.

The mesolimbic pathway, sometimes referred to as the reward pathway, is a dopaminergic pathway in the brain that connects the ventral tegmental area in the midbrain to a part of the forebrain that includes the nucleus accumbens. The release of dopamine from the mesolimbic pathway into the nucleus accumbens regulates the motivation and desire for rewarding stimuli and reward-related learning. It may also play a role in the perception of pleasure. The dysregulation of the mesolimbic pathway by addictive drugs plays a significant role in the development and maintenance of an addiction. Addictive substances such as cocaine, alcohol, and nicotine increase extracellular levels of dopamine within the mesolimbic pathway, particularly within the nucleus accumbens. This results in the perception of reward and increased motivation to repeat the behaviour that caused it.

Altered dopamine neurotransmission is implicated in attention deficit hyperactivity disorder (ADHD). The psychostimulants used to treat ADHD (such as Ritalin or Adderall) increase both dopamine and norepinephrine levels in the brain. Wellbutrin is a norepinephrine-dopamine reuptake inhibitor that is used to treat depression.

Serotonin

Serotonin (or 5-hydroxytryptamine (5-HT)) is a monoamine neurotransmitter and neuromodulator  produced in the gastrointestinal nervous system and the brainstem. It has both inhibitory and excitatory functions and plays a significant role in the sleep/wake cycle, mood, pain and appetite. Serotonin deficiency is associated with depression and anxiety. Most antidepressants act on serotonin, and sometimes also on norepinephrine.

Serotonin deficiency leads to depression and/or anxiety. Excess serotonin results in increased relaxation, decreased libido, increased non-REM sleep, suppressed REM sleep, and high levels can cause serotonin syndrome (which can be fatal).

Serotonin does not cross the blood-brain barrier but its precursors do:
Tryptophan –> 5-Hydroxytryptophan (5-HTP) –> Serotonin –> Melatonin

Serotonin levels can also be raised by taking selective serotonin reuptake inhibitor drugs (SSRI) such as Zoloft (sertraline) and citalopram. Tricyclic antidepressants also block the reuptake of serotonin and norepinephrine. Amphetamines such as MDMA (ecstasy), MDA, MDEA, act as serotonin-norepinophrine-dopamine releasing agents and are also agonists for the serotonin 5-HT_2B receptor. Cocaine, LSD and other psychedelics also interact with serotonin receptors, as well as dopamine and other receptors.

Norepinephrine

Norepinephrine (also called noradrenaline) is a monoamine neurotransmitter in both the peripheral and central nervous systems. It is synthesised mainly within the neurotransmitter vesicles from dopamine (see diagram earlier for the dopamine pathway).

It is the main neurotransmitter used by the sympathetic nervous system, where it can modify organs throughout the body to facilitate active body movement, often at the cost of increased energy use and wear and tear.  Norepinephrine in the brain is the neurotransmitter for the noadrenergic neurons whose activation results in alertness, arousal and readiness for action. The norepinephrine system is important in attention (alerting, focusing, orienting), appetitive behaviours, the hedonic (pleasurable) properties of natural and drug-related reinforcement, mood, and regulation of blood pressure.

ADHD drugs, cocaine, and amphetamines activate dopamine and norepinephrine receptors. Many drugs that inhibit the reuptake of norepinephrine into presynaptic terminals (tricyclic antidepressants such as desipramine) or the metabolism of norepinephrine in the presynaptic terminals (MAO inhibitors such as iproniazide) are used to treat clinical depression.

Epinephrine (Adrenaline)

Epinephrine (also known as adrenaline) is a monoamine hormone and neurotransmitter, which is synthesized from norepinephrine in the adrenal glands and by a small number of neurons in the medulla oblongata (in the lower brainstem). It plays an important role in the fight-or-flight response, a role in sleep, and with ones ability to stay or become alert. Adrenaline is a key factor in enabling the extreme muscle contraction involved in feats of extreme strength, often occurring in times of crisis. Eddie Hall has described how he used hypnosis to create what he called a “very dark mental scenario” which enabled him to summon the strength needed to become the first person ever to deadlift 500 kg.

Cannabinoids

Cannabinoid receptors were only discovered relatively recently in the 1980s. The two main cannabinoid receptors are termed CB1 and CB2. The endocannabinoid system uses endogenous cannabinoid neurotransmitters that bind to the cannabinoid receptors. This system regulates multiple aspects of neural functions, including the control of movement and motor coordination, learning and memory, emotion and motivation, addictive-like behavior and pain modulation, among others. THC, the primary psychoactive component of the cannabis plant (marijuana, hasish) produces its effects by binding to the CB1 receptor in the brain.

Opioid peptides

This system consists of widely scattered neurons that produce three opioids: beta-endorphin, the met- and leu-enkephalins, and the dynorphins. These opioids act as neurotransmitters and neuromodulators at three major classes of receptors, termed mu, delta, and kappa, and produce analgesia. Opioid peptides have been reported to inhibit the release of acetylcholine, dopamine, and norepinephrine in both the brain and the peripheral nervous system. The addictive opiate drugs exert their effects primarily as functional analogs of opioid peptides, which, in turn, regulate levels of dopamine, and norepinephrine. In addition, opioid peptides can increase as well as decrease the release of serotonin and GABA in the brain. Brain opioid peptide systems are known to play an important role in motivation, emotion, attachment behaviour, the response to stress and pain, and the control of food intake.

Endorphins are produced and stored in the pituitary gland and inhibit the communication of pain signals. Endorphins can also produce a feeling of euphoria very similar to that produced by other opioids. Runners high is due to the release of endorphins. I recall the first time I was shown how to correctly do a deadlift and proceeded to do multiple sets of heavy deadlifts. I was high on endorphins for several hours afterwards, and hooked on powerlifting.

Oxytocin

Oxytocin is a peptide hormone and neurotransmitter. It is normally produced in the hypothalamus and released by the posterior pituitary. As a hormone, it is involved in childbirth and breast-feeding. It is also associated with empathy, trust, sexual activity, and relationship-building. It is sometimes referred to as the “love hormone,” because levels of oxytocin increase during hugging and orgasm.

Its neurotransmitter actions in the central nervous system are mediated by specific oxytocin receptors. Its complex influence on behaviour includes not only prosocial effects facilitating trust and attachment between individuals, but it also modulates fear and anxiety, as well as mood more generally, as well as social behaviours such as empathy and generosity, and in-group versus out-group behaviour.

Melatonin

Melatonin is a monoamine hormone and neurotransmitter primarily released by the pineal gland at night, and plays a key role in synchronizing the circadian rhythm and control of the sleep–wake cycle. Melatonin is biosynthesised from serotonin as shown in the diagram below.

Creatine

Creatine is synthesized in the liver from the amino acids glycine and arginine, and stored in the major muscles. Once inside the muscle cells, creatine is phosphorylated to form creatine phosphate (CP), which, as a high energy substrate for the universal energy molecule adenosine triphosphate (ATP), assists in the contraction of the muscle fibers. Creatine phosphate is utilized to maintain higher levels of ATP during exercise. Creatine phosphate maximizes physical performance and reduces exercise fatigue by absorbing hydrogen ions released by muscles in the form of lactic acid.

Intense anaerobic exercise, such as weight lifting and sprinting, depletes ATP and greatly increases the demand for creatine. I take creatine as a supplement during powerlifting training cycles to facilitate training at higher volume and intensity. It is one of the few supplements for strength training with good evidence for effectiveness. Creatine crosses the blood-brain barrier and is also thought to enhance energy levels in the brain. There are several double-blind studies that suggest that creatine can enhance various cognitive skills. The evidence is complex (see here for a discussion). Perhaps the best study is an Australian study of 45 young adult vegetarian subjects followed for 18 weeks in a double-blind, placebo-controlled cross-over study. The level of creatine supplementation was 5 g per day, similar to the level athletes use.

The study results showed clear improvements on creatine supplementation in working memory and general intelligence. This is in line with results of previous studies showing that brain creatine levels correlate with improved recognition memory and reduce mental fatigue.

In conclusion

Neurons expressing certain types of neurotransmitters sometimes form distinct systems, where activation of the system affects large volumes of the brain, called volume transmission. Major neurotransmitter systems include the noradrenaline (norepinephrine) system, the dopamine system, the serotonin system, and the cholinergic system, among others.  The brain, the volume transmission systems and the various brain-body networks have quite complex interconnections and feedback mechanisms.

A good example of this is stress. Most of the physiological effects of stress are regulated by the endocrine system, and in particular cortisol. The brain controls the endocrine system through the a circuit called the HPA axis (Hypothalamus-Pituitary-Adrenal). This allows the brain to recognize a threat and trigger the flight and fight response throughout the body.

However, those same hormones have a wide range of effects on the brain, altering brain function: including on the amygdala and hypothalamus, which are responsible for regulating stress to begin with (and do so in manners depending heavily on timescale, intensity, and a host of external factors). These sorts of feedback loops are common in the brain, so saying that one is cause and one is effect misses a lot of the complexity. Previous stress effects current neurotransmitter levels, which affects our current perception of stress and so on and so forth.

So, in summary, emotions and brain chemistry are interconnected to each other in complex and in many times inconsistent ways, depending on a wide range of other factors. Similarly, the relationship between neurotransmitters, brain waves and states of consciousness is also complex and cannot be reduced to a simple mechanistic cause and effect relationship.

reposted from Mountains and rivers Explorations by Colin Mathers 15 June 2021