-- Brain Neurotransmitters
by Ben Best
CONTENTS:
- INTRODUCTORY REMARKS
- THE CHEMICAL ENVIRONMENT OF THE BRAIN
- GENERAL COMMENTS ABOUT NEUROTRANSMITTERS
- GLYCINE
- ASPARTIC ACID (ASPARTATE)
- GLUTAMIC ACID (GLUTAMATE)
- GAMMA AMINO BUTYRIC ACID (GABA)
- ACETYLCHOLINE
- DOPAMINE
- NOREPINEPHRINE (NORADRENALIN)
- SEROTONIN (5-HYDROXYTRYPTAMINE, 5-HT)
- PEPTIDES
- RELEVANCE TO CRYONICS
I. INTRODUCTORY REMARKS
Most of the previous chapters of this series have emphasized gross organization and structure of the brain. This has been essential in order to gain perspective, but from a cryonicist's point of view preservation of the "the anatomical basis of mind" will ultimately mean preservation of the structures only visible under a microscope. Understanding what structures to look-for and how those structures might best be preserved is the ultimate goal of this series.
As a step in the direction towards understanding finer structure, this chapter will examine the brain from a more chemical point of view than the previous installments -- with particular reference to the gross anatomy and function of neurotransmitters in the brain.
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II. THE CHEMICAL ENVIRONMENT OF THE BRAIN
Skull surface dissectionThe brain has the consistency of firm jelly, and therefore is protectively encased in a thick, bony skull. The brain literally floats in about 150 millilitres (mL) of CerebroSpinal Fluid (CSF) secreted by the choroid plexus. Approximately 500 mL of CSF is secreted daily, which slowly circulates down through the four ventricles, up through the subarachnoid space and exits into the cerebral veins through the arachnoid villi. The brain has no lymphatic system, so the CSF serves as a partial substitute.
Brain ventricles
The dura mater is a tough, protective connective tissue which is tightly bound to the skull, but which encases the cerebral veins. Under the dura mater is the subarachnoid space containing CSF, arteries and web-like strands of connective/supportive tissue called the arachnoid ("spider-like") mater. The pia mater is a permeable membrane of collagen, elastin fibers & fibroblasts on the floor of the subarachnoid space which allows diffusion between the CSF and the interstitial fluid of the brain tissue. The pia mater lies on a membrane that is infiltrated with astrocyte processes. The dura mater, the arachnoid mater and the pia mater are collectively referred-to as the meninges.
Blood-Brain Barrier
While the brain & CSF are separated by the somewhat permeable pia mater, the blood-cerebrospinal fluid barrier and the blood-brain barrier (BBB) represent substantial protection for the brain against undesirable blood substances. These barriers are very permeable to water, oxygen, carbon dioxide and small lipid-soluble substances. They are also somewhat permeable to small electrolytes -- and special transport systems exist for some other specific molecules such as essential amino acids. The barriers are the result of endothelial cells which line capillary walls -- and glial cells called astrocytes which wrap the capillaries with fibers.
The brain is not only a functionally distinct organ, it is a chemically distinct one. 50% of dry brain weight is lipid (in contrast to 6-20% for other organs). Most of the brain lipid is structural (in myelin or membranes) in contrast to the triglycerides and free fatty acids constituting the fat of other organs. The blood-brain barrier creates a protected chemical environment for the brain wherein certain molecules can perform functions independent of the functions those molecules perform in the rest of the body. This is particularly important for the neurotransmitters serotonin (which is highly concentrated in platelets & the intestine) and norepinephrine (which affects blood pressure & metabolism). All of the known amino-acid neurotransmitters are non-essential amino acids. This means that they can be manufactured in the brain, without needing to be supplied from outside the brain. But in the major area of the brain which does not have a blood-brain barrier -- the hypothalamus -- the primary neurotransmitters are peptides.
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III. GENERAL COMMENTS ABOUT NEUROTRANSMITTERS
The three major categories of substances that act as neurotransmitters are (1)amino acids (primarily glutamic acid, GABA, aspartic acid & glycine), (2)peptides (vasopressin, somatostatin, neurotensin, etc.) and (3)monoamines (norepinephrine, dopamine & serotonin) plus acetylcholine. The major "workhorse" neurotransmitters of the brain are glutamic acid (=glutamate) and GABA. The monoamines & acetylcholine perform specialized modulating functions, often confined to specific structures. The peptides perform specialized functions in the hypothalamus or act as co-factors elsewhere in the brain. [For a well-organized categorization of neurotransmitters, see Neurotransmitter (Wikipedia).]
Although there are many neurotransmitters in the central nervous system, the peripheral nervous system has only two: acetylcholine and norepinephrine. Why are there so many brain neurotransmitters? Because the functions performed by brain neurotransmitters are not as uniform as they might superficially appear. Some (like glutamate) are excitatory, whereas others (like GABA) are primarily inhibitory. In many cases (as with dopamine) it is the receptor which determines whether the transmitter is excitatory or inhibitory. Receptors can also determine whether a transmitter acts rapidly by direct action on an ion channel (eg, nicotinic acetylcholine receptors) or slowly, by a second-messenger system that allows for synaptic plasticity (eg, muscarinic acetylcholine receptors). Speed & mechanism of transmitter inactivation after the signal has been sent is also a factor. There are probably also costs & benefits involved in synthesizing, transporting and recycling various neurotranmitters in the differing chemical mileus of the brain.
Many of these issues will become more clear in discussing the synthesis, distribution and function of the major brain neurotransmitters.
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IV. GLYCINE
GlycineGlycine is the simplest of amino acids, consisting of an amino group and a carboxyl (acidic) group attached to a carbon atom. Glycine's function as a neurotransmitter is also fairly simple. When released into a synapse, glycine binds to a receptor which makes the post-synaptic membrane more permeable to Cl- ion. This hyperpolarizes the membrane, making it less likely to depolarize. Thus, glycine is an inhibitory neurotransmitter. It is de-activated in the synapse by a simple process of reabsorption by active transport back into the pre-synaptic membrane.
Glycine is a neurotransmitter only in vertebrate animals. The glycine receptor is primarily found in the ventral spinal cord. Strychnine is a glycine antagonist which can bind to the glycine receptor without opening the chloride ion-channel (ie, it inhibits inhibition). The resultant spinal hyperexcitability is what makes strychnine a poison. Quoting from the ENCYCLOPEDIA BRITANNICA:
"Symptoms of poisoning usually appear within 20 minutes, starting with stiffness at the back of the neck, twitching of the muscles, and a feeling of impending suffocation. The patient is then seized with violent tetanic convulsions in which the body is arched and the head bent backward. After a minute the muscles relax, and the patient sinks back exhausted, heightened perceptiveness being perceived throughout due to sensory cortex stimulation. A touch, a noise or some other stimulus causes the convulsions to recur; or they may recur spontaneously, often at intervals of a few minutes. Strychnine poisoning is ultimately the result of suffocation or exhaustion."
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V. ASPARTIC ACID (ASPARTATE)
AspartateLike glycine, apartate is primarily localized to the ventral spinal cord. Like glycine, aspartate opens an ion-channel and is inactivated by reabsorption into the pre-synaptic membrane. Unlike glycine, however, apartate is an excitatory neurotransmitter, which increases the likelihood of depolarization in the postsynaptic membrane. Aspartate & glycine form an excitatory/inhibitory pair in the ventral spinal cord comparable to the excitatory/inhibitory pair formed by glutamate & GABA in the brain. Interestingly, the two exitatory amino acids -- glutamic acid & aspartic acid -- are the two acidic amino acids found in proteins, insofar as both have two carboxyl groups rather than one.
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VI. GLUTAMIC ACID (GLUTAMATE)
GlutamateGlutamate is the most common neurotransmitter in the brain. It is always excitatory, usually due to simple receptors that increase the flow of positive ions by opening ion-channels. Glutamate stimulation is terminated by a (chloride-independent) membrane transport system that is only used for re-absorbing glutamate & aspartate across the pre-synaptic membrane. Glutamate & aspartate re-enter the cell by a transporter driven by the high extracellular concentrations of Na+ and the high intracellular concentrations of K+. Soduim enters the cell along with the amino acids and potassium leaves the cell -- much the way a pulley couples the lifting of a light weight with the fall of a heavier weight. Thus, glutamate/asparate entry is indirectly powered by the ATP-driven Na+-K+-ase (sodium pump) which creates the high ion concentration gradients.
Possibly the most complicated of all neurotransmitter receptors is the NMDA glutamate receptor. N-Methyl-D-Aspartate is a synthetic chemical not naturally found in biological systems, but it binds specifically to the NMDA glutamate receptor (receptors are frequently named for artificial substances that bind to the receptor with higher specificity than their natural neurotransmitter ligands). The NMDA receptor is the only known receptor which is regulated both by a ligand (glutamate) and by voltage. There are at least 5 binding sites which regulate NMDA receptor activity, ie, sites for (1)glutamate (2)glycine (3)magnesium (4)zinc and (5)a site that binds the hallucinogenic substance phencyclidine (PCP, "angel dust"). Phencyclidine can induce psychosis -- an NMDA effect that is difficult to explain. NMDA receptors have a capacity for an activity-dependent increase in synaptic efficiency known as LTP (Long-Term Potentiation), which may be crucial to some forms of learning & memory. Inhibition of NMDA activity (and LTP) is believed to be an important part of the way ethanol affects brain functions.
NMDA receptors are most densely concentrated in the cerebral cortex (hippocampus, especially -- particularly the CA1 region), amygdala, & basal ganglia. They are particularly vulnerable to glutamic acid excitotoxicity, ie, damaging effects due to excessive excitatory neurotransmitter release. Both aspartic acid & glutamic acid (the two amino acids having 2carboxyl groups -- the "acidic amino acids") have the capacity for destroying neurons when released in excessive amounts (although calcium seems to be more of a cause than acidity). Monosodium glutamate(MSG), a major component of soya sauce, has been shown to destroy nerve cells when fed to young animals. Insofar as glutamate does not normally cross the blood-brain barrier, it is open to question whether this is relevant to a human adult. Increased alertness (or anxiety) due to caffeine may be mainly due to blockage of adenosine receptors which normally inhibit glutamate release.
Glutamate released into synapses is either reabsorbed directly into neurons by the ion-exchange transport system described above, or is soaked-up by astrocytes (glial cells) which convert the glutamate into glutamine (a molecule which cannot cause excitotoxicity). The glutamine can then be safely transported back to neurons for re-conversion into glutamate. One of the damaging effects of mercury poisoning is swelling of astrocytes, which are rendered unable to soak-up glutamine from synapses (contributing to excitotoxicity). Excitotoxicity due to glutamic acid is a major destructive process seen in stokes and other forms of brain ischemia (see Ischemia and Reperfusion Injury in Cryonics).
Nitric oxide can act as neuromodulator when glutamate stimulation of NMDA receptors results in nitric oxide synthesis & release -- enhancing neurotransmitter release from adjacent synapses. Granule cells of the dentate gyrus of the hippocampus are rich in nitric oxide synthetase. Nitric oxide may contribute to LTP.
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VII. GAMMA AMINO BUTYRIC ACID (GABA)
GABA BiochemistryGABA is the major inhibitory neurotransmitter of the brain, occurring in 30-40% of all synapses (second only to glutamate as a major brain neurotransmitter). It is most highly concentrated in the substantia nigra & globus pallidus nuclei of the basal ganglia, followed by the hypothalamus, the periaqueductal grey matter ("central grey") and the hippocampus. The GABA concentration in the brain is 200-1000 times greater than that of the monoamines or acetylcholine.
GABA is somewhat unique among neurotransmitters insofar as it is commonly inactivated (after release into the synapse) by active transport into the astrocyte glial cells that are closely associated with synapses. Both glutamate and GABA are synthesized in the brain from the Krebs citric acid molecule alpha-keto glutarate -- a reaction known as the "GABA shunt". GABA is synthesized from glutamic acid and is catabolized back into the citric acid cycle. The vitamin B6 derivative pyridoxal phosphate is a cofactor in the synthesis of GABA, which is why seizures occur in Vitamin B6 deficiency. GABA levels rise when the citric acid cycle activity is low (ie, when cell energy usage is low), and the resultant generalized GABA inhibitory effect on the brain neurons can be protective during hypoxia or ischemia.
Like glycine, the GABA receptor is connected to a chloride ion channel, allowing more chloride ion to enter the cell and thus making the membrane less likely to depolarize. A closely associated receptor site will bind to benzodiazepines (such as diazepam) to increase the frequency of channel opening. Caffeine can neutralize the effects of benzodiazepine tranquilizers such as diazepam (Valium®). Benzodiazepines act by enhancing the effect of GABA on GABAA receptors, whereas caffeine has an opposite effect by inhibiting GABA release. Barbiturates slightly decrease the frequency of opening, but prolong the duration. The benzodiazepine receptor site is thought to be the natural site of action of a yet-unidentified peptide. By potentiating the effects of GABA, the benzodiazepines function as so-called "minor tranquilizers" (to be distinguished from the anti-psychotic "major tranquilizers"). Anxiety is the most frequently diagnosed psychiatric disorder -- affecting 10-30% of people -- which is why diazepam (Valium) was for many years the most frequently prescribed drug in North America. Alcohol & barbiturates have similar effects on the GABA receptor. In fact, potentiation of chloride influx into neurons is a major mechanism in the effect of ethanol on the brain. Some of the effects of benzodiazepines are probably due to GABA synapses on monoamine-producing neurons. GABA receptors can also be blocked, and the insecticide dieldrin is used for this purpose.
Prolonged use of benzodiazepines results in adaptation of the receptors to their use. Receptors may increase in number and/or sensitivity to GABA. (An increase or decrease in receptor number or sensitivity due to receptor alteration by drugs is known as upregulation or downregulation, respectively. A larger dose of benzodiazepine may be needed to produce the same result -- a phenomenon known as tolerance. Withdrawal of the drug can result in GABA receptor hypoactivity producing symptoms worse than the ones that the patient originally sought treatment for. Such symptoms are called withdrawal. The phenomenon of receptor adaptation and drug dependence is seen with most drugs that act at synapses, including ones that are excitatory or potentiating as well as inhibitory or deactivating.
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VIII. ACETYLCHOLINE
AcetylcholineAcetylcholine was the first neurotransmitter discovered and is the major neurotransmitter in the peripheral nervous system (the only other peripheral neurotransmitter being norepinephrine). Acetylcholine is usually (but not always) an exitatory neurotransmitter -- in contrast to the monoamine neurotransmitters, which are nearly always (with a few exceptions) inhibitory. Acetylcholine in the brain is produced from acetyl-CoA, resulting from glucose metabolism, and from choline, which is actively transported across the blood-brain barrier. Most dietary choline comes from phosphatidyl choline, the major phospholipid in the membranes of plants&animals (but not bacteria). The acetyl-CoA & choline are independently synthesized in the neuron cell body and independently transported along the axon to the synapse where they are conjugated into acetylcholine.
There are comparatively few acetylcholine receptors in the brain, but outside the brain acetylcholine is the major neurotransmitter controlling the muscles. Body muscles can be divided into the skeletal muscles system (under voluntary control) and the smooth muscles of the autonomic nervous system (controlling heart, stomach, etc. -- not under voluntary control). The autonomic nervous system is further subdivided into sympathetic and parasympathetic divisions. Direct innervation of skeletal muscles is due to acetylcholine, as is the innervation of smooth muscles of the parasympathetic nervous system. Direct innervation of the sympathetic nervous system (except for sweat glands) is due to norepinephrine (or both epinephrine & norepinephrine in the case of the adrenal medulla).
The sympathetic nervous system innervates body organs in "fight or flight" situations, so the role of norepinephrine as the end-organ neurotransmitter should not be surprising. End-organ stimulation by acetylcholine in the parasympathetic nervous system is more "vegetative", eg, assisting digestion. Acetylcholine receptors are of two types: (1)a fast-acting ion-channel controlled receptor and (2)a slow-acting receptor that acts through a G-protein (Guanine nucleotide-binding protein) that stimulates second-messengers (often cyclic AMP) to indirectly open ion-channels. Direct ion-channel controlling receptors can respond in microseconds, whereas indirect second-messenger controlling receptors take milliseconds to produce a response. Only indirect, second-messenger controlling receptors have the capacity for plasticity. The two acetylcholine receptor classes are named for artificial toxins that selectively activate them. The fast-acting receptor is named nicotinic, because it is specifically activated by the toxin found in tobacco. The slow-acting receptor is named muscarinic, because the toxin muscarine (found in poisonous mushrooms) and acetylcholine will activate it, but nicotine will not.