Classical Neurotransmitters and Their Significance within the Nervous System A. Veca and J. H. Dreisbach University of Scranton, Scranton. PA 18510 The heat and humidity are incredible. As the traveler makes lone sweeos with his machete. the entwined veeetation of thekfrican rain forest falls in his path. This is hiifirst trio to such an environment. and the fact that he knows little abbut its dangers adds to hi$ anxiety. The jungle becomes thicker as he progresses. He hears an odd noise. With his next step the source of this noise is revealed. I t is a large snake directly under his descending foot. A Ixdr offearrhonts through hi! tmdy, and henutomnrically retracts his foot. As he runs he is shaking and Sweating, his face is nale and ashen. He realizes that helost the rentile in the underbrush when he feels a bite on his leg. This story may seem dramatic and is of the kind upon which many adventure films are based. I t is a good example of a human being's actions and reactions that are mediated. contrulled, and direcred by a complex biochemical circuitry: This is une of the rules of the nervous svstem. a rumdirared arrangement of cells responsible for transmitting signals to and from the hrain. This paper describes some of the chemical compounds and their roles in transmitting nerve signals. Although enormous amounts of neurochemical research are perfolmed, much remains to be learned about the biochemistry of the nervous system. That which is understood utilizes information from a variety of research areas including physiology and hiochemistry.
The fundamental cell structure in the nervous system is the neuron. This highly cell has the potential to - . svecialized . become excited. Figure 1shows a typical multipolar neuron, and although other t m e s of neurons exist this will serve as a satisfactor; example-& this discussion. The neuron consists of a cell body (which has numerous
DENDRITES
)
-CELL
BODY
The Nervous System
The nervous system is divided into the central nervous system (CNS) consisting of the brain and spinal cord and the peripheral nervous system (PNS) that includes all other nervous tissue. The CNS is further divided into the ascending (to the brain) and the descending (from the brain) pathways of neurons. The PNS is similarly defined. Afferent neurons, often referred to as sensory neurons, direct their information toward the CNS, and efferent neurons, referred to as motor neurons, direct their information away from the CNS.
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((
TERMINAL I FIBERS
A typical multipolar neuron. The length of more than one meter in length.
the axon varies greatly with some
extensions. called dendrites) an axon. and terminal fibers. The excitability o f ~ t h eneu& is related to the cell membrane. Cells. in eeneral. have a charee difference established across the memirane. Neurons mzntain the charge difference (negative inside and positive outside the membrane) by active transport of sodium ions out of and potassium ions into the cell. The transport of these ions is coupled with three sodium ions out for each two pota&m ions pumped in. Passive diffusion of potassium to the outside of the cell and sodium into the cell results in the membrane potential of -70 mV. The charge potential across the membrane can be calculated using the Nernst equation, the concentrations of the ions, and the resistance and capacitance nro~ertiesof the memhrane. The propagation of a nerve impulse involves a change in permeability of the memhrane that results in the free diffusion of the ions across the membrane. This change in ion concentration on each side of the memhrane is called denolarization and the potential across the membrane change; to approximately +40 mV during the event. The impulse travelsfrom the dendrites to the junctionof the cell body and the axon and is summated until a threshold depolarization is reached. Then there is a propagation of the impulse down to the axon to the terminal fibers. The impulse is relayed through the synapse-the specialized contact zone where one neuron communicates with another-to the next neuron where the process begins again. The problem of nerve impulse transmission across the synapse is widely studied. This discussion focuses on the chemicals involved in synaptic transmission and, although not all the chemistry and physiology of each compound is completely characterized, enough is known to present some models.
. .
A neurotransmitter is a substance that is released s.vnaptically by one neuron and subsequently affecrs another cell in a specific manner. For a suhs&ce to be classified as a true neurotransmitter, four criteria must be met. The compound must he synthesized by the neuron; it must he released by the neuron in sufficient amounts to exhibit an effect on another neuron or effector organ; exogenous application in appropriate quantities must mimic the action of the endogenouslv released comnonnd: and a mechanism must exist to remove the nenrotra&nitter from the site of action. Following are eieht chemical compounds known as the classical orcanonick transmitter substances. Acetylcholine
Synthesis of acetylcholine occurs in the cell body of the neuron. The enzyme, choline acetyltransferase, catalyzes the reaction between acetylCoA and choline (eq 1).
experiment. Stimulation of the newe was known to stop the heating of the heart. Loewi perfused the region around the frog heart with a physiolog~alsolution, removed the solution, and applied it to another frog heart. The second heart also stopped beating. Acetylcholine was subsequently isolated from the solution and identified as the chemical mediator. Acetylcholine is the transmitter of motor neurons in the spinal cord and is the transmitter a t all of the nerve-skeletal muscle junctions in vertebrates. It is the transmitter for all preaanplionic (a presvnaptic . . - neuron in the PNS) neurons in theaut&omic nervous system and for the parasympathetic postganglionic neurons (postsynaptic neuron in the PNS). Acetylcholine neurons are also located diffusely throughout the brain. Systems that use acetylcholine as a neurotransmitter are called cholinergic neurons or systems. When acetylcholine is released from the presynaptic memhrane. it is released into the svnawtic cleft. Its action on the postsynaptic memhrane involies dinding with a receptor rotei in snecific for acetvlcholine. and a chanee in the ion permeabfiity of the membrane occurs. These cianges in ion permeabilitv are due to modification of ion channels. - A number of research groups have found that patients with Alzheimer's disease have significantly lower concentrations of the enzyme choline acetyltransferase in their brains. This is the enzyme responsible for synthesis of acetylcholine. This was the first consistent hiochemical abnormality ohserved for patients with Alzheimer's disease. The observation that these patients make too little choline acetyltransferase does not indicate one cause for the disease. Attempts to treat the disease hv increasing levels of acetvlcholine have resulted in only minor iniprovement in some patients. Two tvves of acet\,lrholine receDtors hnw heen idenufied to date. T h e responbes of certain ieceptors to acetylcholine are mimicked by nicotine and blocked bv curare and are termed niwtinic~receptors. Others are mimicked by muscarineand hlocked by arn)pineand arerlascified as muscarinic receptors. Nicotinic receptors seem to he directly coupled to the ion channels they control while the muscarinic receptors are indirectly or transiently coupled to the channels. Binding of acetylcholine to the nicotinic receptor causes a direct change in the ion permeahility of the membrane and thus a depolarization of the memhrane. Binding of acetylcholine with the muscarinic receptor produces biochemical responses in the postsynaptic cell that are not observed with the nicotinic receptor. One of the biochemical responses is the elevation of cyclic guanosine triphosphate (cGTP) as a result of increased activity of guanylate cyclase. Since cyclic nucleotides are known to regulate phosphorylation reactions, it has been hypothesized that a cGTP-dependent protein kinase phosphorylates ion channels. These phosphorylation-dephosphorylation reactions may convert the channels from open to closed configurations. Once acetylcholine is released into the synaptic cleft and bound to the receotors. it must be removed so that the postsynaptic neurons are not constantly affected. I t is hydrolvzed to choline and acetate I w acetylcholinesterase teq 2). The majority of the choline is taken into the presynap; tic memhrane and used in the synthesis of acetylcholine.
up
Acetylcholine was the first subscanre identified as a neurotransmitter. Otto l.oewi demonstrated the release of acetylcholine from the vagns nerve in the frog through a clever Volume 65
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Dopamine and Norepinephrine Dopamine and norepinephrine are referred to as catecholamines because of the catechol structure common to both.
Dopamine and norepinephrine are synthesized through a common pathway. In the initial step the amino acid tyrosine is converted to L-dihydroxyphenylalanine &DOPA) by tyrosine hydroxylase. This is the rate-limiting step in the synthesis of dopamine and norepinephrine. The pathway is given in eq 3.
Three types of receptors for serotonin have been designared. One is inhihiwry, that is, when serotonin binds to this category of receptor;nhihition of nerve impulse propagation or other metabolic change in the postsynaptic cell occurs. The second type of receptor is classified as an autoreceptor and is found on the presynaptic memhrane. This involves mediation of the response of the neuron to its own neuroreceptor. The third, an excitory receptor, is the type that causes propagation of an impulse or a change in the metabolism of the postsynaptic cell. Serotonin, like norepinephrine and dopamine, is removed from the synaptic cleft by reuptake. I t is degraded by monoamine oxidase to 5-hydroxyindole acetic acid (eq 4) when present in free form in the presynaptic cell. Histamine Histamine is synthesized from the essential amino acid Lhistidine hy a decarboxylation reaction as shown in eq 5.
Dopamine plays a role in the elicitation of many behaviors such as locomotor activity, food intake, chewing, stereotypy (abnormal receptive response, purposeless motor behavior), and temperature regulation. Dopaminergic systems have been related to Parkinson syndrome and schizophrenia. Regions of the CNS affected by these diseases contain high concentrations of dopamine neurons and are found in the brain stem, midbrain, and hypothalamus. The two major categories of receptors for norepinephrine are the alpha- and beta-andrenergic receptors. They are called andrenergic because the hormone adrenalin (also known as epinephrine) is an agonist of these receptors. Adrenalin is produced in the adrenal medulla and is not, by definition, a neurotransmitter. ~lpha-adrenergicreceptor-mediated responses are found in smooth muscle contraction, and heta-andrenereic recentors play roles in such responses as ionotropism-in heart tissue. A specific antagonist for alpha receptors is phentolamine, and for beta receptors, propanol. Isoproternol is an agonist for both types of receptors. Both types .. of receptors bind the I. stereoi&ners of a&nists and antagonists p;eferentially, and hinding has been shown to affect cyclic adeno. sinemonophosphate (CAMP) metabolism within the postsynaptic cell. After dooamine or nore~inenhrine are released into the . . postsynaptic clefts, there exist specific mechanisms for their removal. These neurotransmitters can be taken up into the presynaptic terminal and stored in a vesicle or degraded by monoamine oxidase when not stored in a vesicle. Donamine and norepinephrine can also he inactivated before reuptake or metabolized through a series of enzymic reactions. Serotonin Serotonin (5-hydroxytryptamine, 5-HT) is synthesized from tryptophanasshown in eq 4. Serotonin has beenshown to have an effect onsleen induction. Denression is thoueht " to be caused by a deficiency of serotonin.' 110
Journal of Chemical Education
There are two types of histamine receptors designated HI and Hz receptors. When histamine binds to these receptors adenylate cyclase is activated, and an increase in concentration of adenosine 3',5'-cyclic monophosphate (CAMP) results in the intracellular fluid. Binding to the H1 receptor also results in an increase in cyclic GTP levels. Histamine is believed to play a role in such neural responses as thirst, antidiuresis, and hypothermia. Histamine is taken up by the presynaptic cell and is metabolized to yield 3-methylimidazole acetic acid.
Glycine, Glutamate, and Gamma-Aminobutyric Acid Glycine is thought to be an inhibitory transmitter of the spinal cord interneurons; that is, those neurons that connect other neurons, thelower brainstem, and the retina. Comparatively little is known about the glycine systems due the lack of suitable methodologies. Glyciue may he formed from serine by methylation with tetrahydrofolate (eq 6).
Glutamic acid is an excitory neurotransmitter. I t exhibits activity when applied topically to mammalian brain and crustacean muscle cells. Since it has been difficult to isolate glutamate neurons, there exists some controversy as to whether glutamate qualifies as an actual neurotransmitter. T h e argument in favor of classifying is based on the fact that dorsal portions of the spinal cord contain higher concentrations of glutamic acid than ventral regions. This supports the hypothesis that glutamate functions as an excitory transmitter released from afferent nerve endings. Specific receptors for glycine or glutamic acid have not been isolated to date. This indicates that these compounds may bind to neurons that possess little, if any, specificity to these compounds. Gamma-aminobutyric acid (GABA) is found as a normal constituent of mammalian CNS hut is found in no other mammalian tissue (except retina) in more than trace levels. GABA is formed from glutamic acid through a decarboxylation reaction (eq 7). cool
-0OCCHrCHpCH t
7 -OOC-CHICHICH~NHJ'
171
Summary When we left the traveler, he had been bitten by a poisonous snake. The circumstances leading to his predicament and his reaction to the circumstances can he related to the discussion of neurotransmitters. The traveler's nervous system is very active. Movement and thouaht are beine controlled bv this svstem. - processes . Afferent neurons are busy relaying information concerning movement and environmental conditions to the s ~ i n acord. l Part of this information ascends the spinal cord to the brain where it is "proressed". Then, descending neurons relav the information-needed for proper hodily movement and ieaction to the efferent neurons. The message is relayed from neuron to neuron until it reaches its destination. ~ c e t ~ l c h o line is the transmitter a t all neuromuscular junctions. Its hinding to proper receptors followed by its hydrolysis causes the contraction and relaxation of the muscles. "Firing" of certain other neurons in the CNS during the relay of messages to and from the brain may involve glutamate, glycine, and gamma-aminobutvric acid. I?i&ation of body temperature triggers the parasympathetic division of the autonomic nervous system. This results in panting, perspiring, and vasodilation as physiological means to reduce temperature. Rate of heartbeat is reduced
and respiratory passages constrict due to parasympathetic stimulation. Thoughts and memory may involve dopamine action, though this mechanism is not characterized with certaintv. ~ h i r i reaction t is mediated in part by histamine. As t i e traveler sights the snake, his pupil accommodates by focusing. Acetylcholine acts as a neurotransmitter for the pupilar muscles. Once our explorer senses impending danger, he undergoes a noticeable change. The automatic retraction of his foot is called a spinal reaction. It is very fast since the signals are relayed through the spinal cord with no contribution from the brain. he attack-by the snake causes intense sympathetic nervous system arousal known as the "fight or flight" reaction. His reactions require a longer time than retraction of his foot since the brain is involved. The\ shaking and perspiration reactions are also sympathetic arousal reactions. His paleness is due to internalization of blood as a defense reaction. If he is injured, he will not bleed as severely. The increase in the rate of heartbeat results in an increased supply of oxygen required in the response. Acetylcholine is the preganglionic transmitter and norepinephrine is the postganglionic transmitter. Some snake venoms contain alpha-bungarotoxin, which binds tightly with nicotinic receptors in the CNS interfering with neural transmission. Assuming this particular encounter passes with no serious injury, the explorer's anxiety will pass. During sympathetic arousal, the parasympathetic system is inhibited, possibly in the spinal cord by one of the hiogenic amines. Under nonstress conditions, the parasympathetic and sympathetic systems are in fine balance. Now with strong excitation withdrawn.. the oarasvm-svm~athetic . . pathetic system "slingshots" hack, often overshooting the normal level. This is known as the "rebound effect" and often results in reactions such as fainting or tears. There are many more neurochemicals that may be involved in such a story. The classical neurotransmitters are those compounds for which most information is available. More will he identified and characterized as research in the neurosciences continues. General References Bjorkiund. A : Hokfe1t.T.; Kuhsr, M. J. Hondbook ofChemirolNeuroonotomy:Elsevier: New York, 1984:Vol. 3. Barnan, W. B.N~umfmnsmitfsra,Rec~toraodDrugAclion;SPMediur(andScientilie: New York. 1980.
York, 1981. Kolata, G. B. Science 1981,211,1032. Larnble, J. W. Towords Understonding Recepton; Els~iermarth-Holland: N
~ W~
ork,
,OR,
Larnble, J.W.More About Receptors; Elsevier,%rth-Hollsnd: New Yark, 1982. aoth, R. H.; Blmm, F.E.; Cooper, J. R. The f l i o c h e m i d flosra 01 Neurophormoeology: Oxford Univenitv: Oxford, 1982.
Symposium on High-Temperature Superconductors: Structure and Microstructure Symposium April 21-22,1988 in Bad Nauheim (FRG)
A symposium on High-TemperatureSuperconductors:Structure and Microstructurewill be held April 21-22,1988, in Bad Nauheim, West Germany. The aim of this symposium and discussion meeting is to provide an up-to-date and comprehensiveevaluation of recent progress and unsolved problems of structure and microstructure of high-temperature superconductors. The conference is intended to bring together researchers in material sciences, physics, chemistry, and crystallography to an exchange of knowledge and experiences but also speculative ideas to stimulate the scientific and technological effort in this field. It is the intention of the organizing committee to present the latest results as posters that will be discussed in two plenary sessions.Those who wish to contribute should submit one copy of a photo-ready typescript extended abstract (one Daee. 16 cm X 24 em. beeinnine with the title. the author's name and affiliation. includinefieuresand tables) in Endish to ihe Conference secmtkiat b; March 31, 1988. Further information can be obtainld Trom: conference secretariat Deutsche Gesellschaftfur Metallkunde e.V., Adenaueralle 21, D-6370 Oherursel (FRG),Tel.: 0617114081.
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