HPN2: NEURONS AND NEURONAL TRANSMISSION
This unit is about Neurons, Neurons are highly specialized cells that transmit impulses within animals to cause a change in a target cell such as a muscle effector cell or glandular cell. Together with neuroglial (glial) cells make up the nervous system. The neuron is the integral element of our five senses and other physical, regulatory and mental faculties including memory and consciousness.
NEURONS AND NEURONAL TRANSMISSION
INTRODUCTION
The human nervous system contains about a trillion neurons and a lot more gill cells. Neurons are the basic building blocks of the nervous system which is one of the two major regulating systems of the body. The regulatory function of the nervous system is exerted over the body’s muscular and glandular activities most of which are directed toward maintaining homeostasis in the body.
Neurons are specialized for rapid integration and transmission of nerve impulses. They are able to initiate, process, code and conduct changes in their membrane potential as a means of transmitting a message rapidly throughout their length. They can also transmit this information through intricate nerve pathways from neuron to neuron, or neuron to muscles and glands through chemical means.
Description of Neurons
Neurons are highly specialized cells that transmit impulses within animals to cause a change in a target cell such as a muscle effector cell or glandular cell. Together with neuroglial (glial) cells make up the nervous system. The neuron is the integral element of our five senses and other physical, regulatory and mental faculties including memory and consciousness.
Neurons have three main purposes:
To gather and send information from the senses such as touch, smell, sight etc.
To send appropriate signals to effector cells such as muscles, glands etc.
To process all information gathered and provide a memory and cognitive ability thus allowing us to take action on information received.
The structure of neurons is essentially the same in all animals, although the human nervous system is much more specialized and complicated than that of lower animals. Neurons are divided into different regions each having a different function. A typical neuron has the following parts:
A cell body (soma) which contains the cell nucleus and the cytoplasmic organelles which are responsible for maintaining the cell
Several short processes called dendrites which are radial extensions of cell membrane of the body which extend to other neurons and increase the surface area available for connecting with other axons from other neurons
A long process extending from the soma, called the axon. The axon can sometimes stretch over a very long distance and is responsible for transmitting signals from the neuron to other cells down stream in the chain. The axon divides into terminal branches each ending in a button like structure called synaptic knobs or terminal buttons.
Specialized cell junctions called synapses between an axon and other cells which allow for direct communication from one cell to another.
Neuroglial or neurilemma cells are associated with axons of neurons. In the central nervous system they are called oligodendrocytes and in the peripheral nervous system, they are the Schwann cells. They associate with the axons by wrapping themselves around portions of the axon.
This forms a segmented sheath around the axon called myelin sheath. Myelin is a lipid (fatty) substance which is pale in colour. It is this colour that leads to the term white matter or grey matter within the nervous system. The white matter contains myelinated axons predominantly whereas the grey matter contains mainly neuronal cell bodies which are non-myelinated.
The function of the myelin is to increase the electrical capacitance of neurons and to insulate against any leakage of nerve impulse. They also assist in nourishing the axon. The higher the capacitance, and the better the insulation, the faster the nerve impulse will travel along the axon.
The gap of about 1mm between segments of myelin sheath (junctions between adjacent neuroglial cells) is known as nodes of Ranvier. These serve important functions in neural transmission of impulses in a very specialized way.
Neurons display a very high level of metabolic activity for some reasons:
They have massive surface areas compared to other cells in the body
They need to generate nerve impulses.
Their high level of activity reflects on the appearance of the cell-the nucleus is large, with prominent nucleolus representing a high degree of cellular activity.
There is abundant endoplasmic reticulum for protein synthesis.
There is a well developed Golgi apparatus to provide secretions especially neurotransmitters.
There are also large numbers of mitochondria to produce the large amount of energy required by the neuron.
The function of the nervous system as a whole depends very much upon the complexity of the network of connections between the various neurons rather than the specific features of any single neuron.
Structural and Functional Classification
Neurons exist in many shapes and sizes and their structure affects their functions. The structural classification of neurons depends on the number of processes extending from the soma. Multipolar neurons that have many dendrites and usually have one long axon carrying an impulse away from the cell body. They also tend to have large cell bodies. Majority of the neurons in the spinal cord are multipolar and they serve principally as motor neurons.
Bipolar neurons have only two main processes similar in length a single dendrite and an axon. Bipolar neurons are generally small simple cells that provide local connections within the central nervous system. They can also be found in some sense organs i.e. retina and olfactory cells. Unipolar neurons possess one major process which subdivides into two branches; one running to the CNS (axon) and the other to a part of the body (dendritic in function). They are usually sensory neurons.
The diagram of a Neuron
Functionally neurons are classified as sensory neurons, motor neurons or interneurons. Sensory neurons transform physical stimuli (sensations) such as smell, light or sound into action potentials which are then transmitted to the central nervous system.
They always have their dendrites in a sensory receptor in the body and the axons end within the central nervous system (either the spinal cord or the brain depending on the part of the body in which the sensory receptor is located). Since they send impulses to the central nervous system, sensory neurons are also called afferent neurons.
Motor neurons transmit nerve impulses away from the brain and spinal cord to muscles or glands and are also called efferent neurons.
Interneurons, also called association neurons provide local connections within the central nervous system. They are mostly found in the central nervous system and are responsible for receiving, relaying integrating and sending nerve impulses within the CNS. All neurons whatever their structure or function carry nerve impulses in one direction. That is from dendrite to cell body and from cell body to the axon. Dendrites always carry impulses toward the cell body and axons always carry impulses away from the cell body.
Transmission of Nerve Impulses
The transmission of nerve impulses which is the unique function of nerve cells depends on two properties of nerve cells:
Excitability and Conductivity
Excitability refers to the fact that nerve cells are able to respond to a stimulus, and in fact have a threshold for excitation. The stimulus may be internal or external; electrical, chemical or mechanical. Muscle fibres are also able to demonstrate excitability and this makes them able to contract when stimulated.
Conductivity refers to the property that neurons alone possess which makes them able to transfer their excitability along their length and then on to other neurons or even muscle tissue.
These two properties together allow neurons to deliver appropriate messages to appropriate parts of the body as and when required.
All cells in the body possess a membrane potential which is related to the non-uniform distribution of and differential permeability to Na+, K+ and large intra cellular anions (protein ions). Nerve cells and muscle cells have specialized use for this membrane potential.
They are able to undergo transient, rapid changes in their membrane potential i.e. they can alter their transmembrane potential reversibly because of the differences in the ionic concentration inside and outside the cell and the selective permeability to Sodium (Na+) and potassium (K+). Nerve and muscle cells are therefore said to be excitable tissues because of their ability to produce electrical signals when excited.
In a resting neuron, the concentration of potassium (K+) inside the cells is up to 30 times greater than it is outside whereas the concentration of sodium is up to 14 times less inside than outside. Even in this state of non-conduction of nerve impulses the neuron continuously maintain a balance of sodium-potassium pump across the membrane i.e. Na+ are actively transported out and K+ are actively transported into the cell.
The inside of the cell at rest is negatively charged because K + are though positively charged and are abundant within the cell; there are a large number of negatively charged (protein) ions within cell which cannot diffuse out through the cell membrane. The K+ is not enough to balance out the protein anions within the cell and this leads to an overall negative charge within the cell. Outside the cell the larger quantity of Na+ with no protein anion, leads to an overall positive charge in the extracellular fluid. This state of potential difference in polarity across the membrane is known as the resting membrane potential. It is usually about-70mV.
When a nerve cell is stimulated one of two types of physiochemical disturbance is produced: local, non-propagated potentials called electrotonic potentials or a propagated disturbance called action potential or nerve impulses. All excitable tissues exhibit these electrical responses and these are the main language of the nervous system. When an excitable tissue is sufficiently stimulated, the polarity of the membrane is reversed momentarily with the inside becoming more positive compared to the outside. It is this event (shift) that is referred to as the action potential.
The Action Potential
The stimulation of an excitable tissue represents the delivery of energy to the cell membrane in some way. For example, the energy from sound waves exciting the neurons in the inners ear; heat energy exciting neurons in the skin etc.
Action potentials are brief reversals of membrane potential brought about by rapid changes in membrane permeability occasioned by physiochemical stimulation. Within nerve cells the action potential has an amplitude of approximately +110mv (millivolts) and lasts for about 1 millisecond (MS).
Action potentials follow the all-or-none law which means that they are not graded responses but are either full sized or absent depending on the strength of the stimulus. i.e. if the stimulus is strong enough the action potential is fired at its full strength of + 110mv. If the stimulus is not strong enough, there is no action potential at all. The action potential is also able to spread throughout the membrane in non-decemental fashion.
Four terms are normally used to describe the processes that occur during action potentials:
Polarization: This refers to the fact that the membrane has potential (difference) i.e. there is a separation of opposite charges with negative charges inside and positive charges outside. This is the state of the membrane at rest.
Depolarization: The membrane potential is reduced from resting potential; it has decreased or moved toward zero. There is a mix up of opposing charges; only few charges are separated. It is shown as an upward deflection on a recording device.
Hyperpolarization: The potential difference has returned and increased or become even more negative than -70mV. A downward deflection is shown on the measuring device.
Depolarization: The membrane potential returns to its normal resting value.
To initiate an action potential there is a triggering event that causes the membrane to depolarize. Depolarization normally proceeds slowly at first until it reaches a critical level known as threshold potential about 55mv. After this initial 15 mV of depolarization, an explosive increase in depolarization occurs.
There is a sharp upward deflection past the zero level to up to +30 to +35mv. This is called the overshoot because the deflection overshoots the zero potential. This is followed again by a rapid decrease towards OmV and a fall rapidly toward the resting level, a process called repolarization.
Often the repolarization to resting potential is driven back too far causing a brief period of hyperpolarization (below -70mv). This period lasts about 40ms, before the membrane finally returns to its resting potential (repolarization).
The action potential fails to occur if the stimulus is sub-threshold in magnitude whereas if the stimulus is at threshold or above threshold intensity it occurs with constant amplitude and form regardless of the strength of the stimulus. (The all or none law).
Although sub-threshold stimuli do not produce an action potential, they do have an effect on the membrane potential. When there is a triggering event of sub-threshold level, there is localized depolarizing potential charge. This change can rise very sharply but also drops off rapidly as it moves away from the initial source of stimulation. These graded potentials or electrotonic potentials function as signals only for short distances and die out as the distance from the initial source of stimulation increases.
Basis of Excitation and Conduction
The nerve cell membrane as has been discussed is polarized at rest with positive charges lined up along the outside of the membrane and negative changes along the inside. During the action potential this polarity is abolished and for a brief period actually reversed.
The cell membranes of nerves like those of other cells contain different types of ion channels or gates. Some are passive (continually open) and some are voltage-gated (i.e. open or close in response to changes in membrane potentials) while some are chemical messenger-gated (ligand-gated). These open or close in response to the binding of a specific chemical messenger for example neurotransmitter, hormone, to a membrane receptor. The voltage-gated channels are the ones mostly involved in action potentials.
At rest Na + is actively transported out of the cell and K+ is actively transported into the cell. However K+ diffuses out of the cell down its concentration gradient and Na+ diffuses back in through their leak channels (passive). However the permeability of the membrane to K+ is much greater (because of the leak channels) therefore passive K+ efflux is much greater than passive Na+ influx.
The resting membrane is 50 to 75 times more permeable to K +. This in addition to the impermeability of the membranes to most protein anions within the cell maintains the membrane in a polarized state with the outside more positive than the inside (- 70mv). When a membrane starts depolarizing toward threshold as a result of a triggering event, some of the voltage-gated Na+ channels open.
Since the concentration and electrical gradient of Na+ both favors its movement into the cell, Na + starts to move in, carrying its positive charges with it. This depolarizes the membrane further, thereby opening more Na+ gated channels and allowing more Na+ to enter. This continues in a positive feedback cycle.
There is therefore an explosive increase in Na+ permeability at threshold potential as the membrane becomes 600 times more permeable to Na+ than to K+ Na+ rushes into the cell rapidly eliminating the internal negativity and making the inside even more positive than the outside. This is represented by the steep upward deflection on a measuring device, past the zero potential level and up to an overshoot level of +30 to +35 mv.
The potential does not however become more positive or rise higher than this level. This is because at this peak level of the action potential the Na+ channels slam shut and enter a state called inactivate state until the membrane potential has even restored to its negative resting value a period of a few milliseconds. In addition the direction of the electrical gradient for Na+ reverses and this limits the influx. The cell membrane becomes impermeable again.
At the same time, as the inactivation of the Na+ channels occurs, K+ permeability greatly increases i.e. the voltage-gated K+ channels open and more K+ move out of the cell the opening of the K+ channels is slower but more prolonged than the opening of Na+ channels and can actually be considered a response triggered by the depolarization caused by Na+ influx.
The marked increase in K+ permeability causes K+ to rush out of the cell down its concentration and electrical gradients carrying positive charges back to the outside. At the peak of an action potential the very positive inside of the cell also tend to repel the positive K+ ions so that the electrical gradient for K+ favours outward movement. The outward movement of K+ rapidly restores the internal negatively returning the potential to resting.
This completes the repolarization process and is shown by the downward deflection past the zero potential towards the initial resting potential of -70mv on the measuring device. Because the K+ channels do not close very quickly, more K + can actually leave the cell than is necessary. This slightly excessive K+ efflux makes the interior of the cell more negative than resting potential; and this explains the after hyperpolarization period.
At the end of an action potential, the membrane potential has been restored to its resting condition but the ion distribution had been slightly altered. Sodium has entered the cell during the rising phase while a comparable amount of K+ has left during the falling phase. It is now left for the Na+ – K+ pump to restore these ions to their original locations in the long run.
Depolarization of one part sends an electrical current to neighbouring un-stimulated parts of the membrane, which stimulates adjacent portions of the neuron membrane to also depolarize. This event repeats itself along the membrane of the cell, thereby conveying the nerve impulse along the neuron.
This continuous conduction is the way impulses are transmitted down unmyelinated nerve fibres. In myelinated nerves, the myelin sheath forms an insulating layer around the axon therefore depolarization can only occur at the nodes of Ranvier where there are short sections of non-myelination. Impulses are conducted by sequential jumping from one node to another along the nerve.
This form of impulse conduction is usually quicker than continuous conduction. It is known as saltatory conduction.
Synapses
Impulses are transmitted from one nerve cell to another cell at synapses. A synapse is a junction where the axon of one neuron (the pre-synaptic neuron) meets the dendrite, cell body or even axon of another neuron or in some cases, a muscle or gland cell (the post synaptic neuron or cell).
Functional Anatomy of Synapses
A neuron may terminate at one of three structures; another neuron, a muscle, or a gland specifically the use of the word at this point will be limited to the junction between two neurons. The commonest synapse is formed at the junction between an axon terminal and the dendrites or cell body of a second neuron. Less frequently axon to axon and dendrite to dendrite connections occur. Usually most neuronal cell bodies and their dendrites receive thousands of synaptic input (axon terminals) from many other neurons.
Diagram of a synapse (inset)
The axon terminal of a pre-synaptic neuron is usually slightly enlarged to form button like structures called the synaptic knobs. The synaptic knobs contain numerous synaptic vesicles which store a specific chemical messenger, called a neurotransmitter. These neurotransmitters have been synthesized by the presynaptic neuron.
The membrane of the synaptic knobs (of the presynaptic neuron) does not come into direct physical contact with the membrane of the post-synaptic cell, rather a small gap of about 20 nanometers separate the two. This space is called the synaptic cleft. This space makes it difficult for electrical signals (action potentials) to pass directly between the two cells; the presynaptic and the post synaptic neurons-thereby necessitating the action of a mediator.
In most synapses transmission is by chemical means requiring the chemical mediators neurotransmitters. At some synapses however transmission is electrical while in a few synapses it is conjoint i.e. both chemical and electrical being possible. In any case, transmission across a synapse is not a simple jumping of action potentials from the presynaptic to the postsynaptic cell.
Synapses operate in one direction only i.e. the presynaptic neuron brings in the signal to the synapse and stimulates the postsynaptic neuron which then carries signals away from the synapse.
Transmission across a Synapse
When an action potential in a presynaptic neuron reaches the synaptic knob, it triggers the opening of the voltage-gated calcium ion (Ca++) channels in the the synaptic knobs. This allows Ca++ which is more in the extracellular fluid (outside the cell) to enter inside the cell.
The presence of Ca++ inside the cell causes the vesicles inside the knob to move towards the cellmembrance at the synaptic cleft. Vesicles fuse with the membrane and release their neurotransmitters by exocytosis into the synaptic cleft. The neurotransmitters diffuse across the space and bind to receptors in the membrane of the post-synaptic cell. The amount of neurotransmitter released is proportionate to Ca++ influx.
The binding of neurotransmitters to receptors in the postsynaptic cell membrane opens ion channels in the post-synaptic cell membrane. This is an example of a chemical messenger-gated channel. With the opening of the channels there is a change in the permeability of the post synaptic membrane, resulting in a change in the membrane potential. If the excitation is strong enough it results in the generation of a nerve impulse.
The neurotransmitter molecules left in the synaptic cleft are usually broken down by enzymes, reabsorbed by pre-synaptic cell where they are resynthesized (using energy from ATP generated by the nearby mitochondria) and packaged once again into vesicles.
Synaptic Excitation and Inhibition
There are two types of synapses depending on the permeability changes induced in the post synaptic neuron by the combination of transmitter substances with receptor sites: excitatory synapses and inhibitory synapses.
At an excitatory synapse, the response to the receptor neurotransmitter combination is an opening of the Na+ and K+ channels in the post synaptic membrane, increasing the permeability to both of these ions. Na+ moves into the cell in large numbers, reducing the potential difference in the cell by making the inside of the cell less negative than at rest. This produces a small depolarization of the post-synaptic neuron.
The effect of just one synapse is usually not enough to stimulate the post-synaptic membrane to a firing level (threshold). Before a post-synaptic membrane can fire an action potential, it must be stimulated by several synapses at once. Each synapse produces a small depolarization and each depolarization contributes to bringing the membrane nearer to threshold and increase the likelihood of firing an action potential.
This post synaptic potential change occurring at an excitatory synapse is called an excitatory post-synaptic potential (EPSP). The small rises contributed by depolarizations at each synapse add together, raising the EPSP to a level high enough to trigger a nerve impulse (fire an action potential).
It is called spatial summation when stimulation occurring at the same time at several synapses add together to reach threshold level. However if the same synapse supplies impulses to the post-synaptic neuron in quick succession before the previous ones have died out, the stimulations add together in what is called temporal summation.
Certain synapses however have opposite effects. The effect of the neurotransmitter receptor combination instead of opening the Na+ channels rather opens the K+ or Cl– channels. The result is that the membrane becomes hyperpolarized and the inside of the post synaptic membrane becomes more negative.
What happens is that if it is the K+ channels that open, more positive charges leave the cell via K+ efflux, leaving more negative charges behind inside the cell or in the case of increased Cl– permeability negative charges enter the cell in the form of Cl–ions because Cl– concentration is higher outside the cell.
The slight hyperpolarization moves the membrane potential even farther away from threshold making it more difficult for excitation to threshold level to occur. The membrane is said to be inhibited under these circumstances, and the small hyperpolarization is called inhibitory post-synaptic potential (IPSP). Both spatial and temporal summation of inhibitory potentials can also occur.
The transmission of an electrical signal across a synapse, for a presynaptic neuron takes time, an interval of at least 0.5ms (0.5 – Ims). This is called synaptic delay, and corresponds to the time it takes for the neurotransmitter to be released and to act on the post-synaptic membrane. Therefore it is faster to transmit electrical signals through a pathway with fewer synapses than a complex pathway with multiple synapses. The more complex (polysynaptic) the pathway, the more synaptic delays and therefore the longer the time required to respond to a particular electrical event.
The generation of an action potential (nerve impulse) in the post-synaptic neuron is therefore the result of a constant interplay of excitatory and inhibitory activity of thousands of presynaptic neurons on the postsynaptic neuron. This produces a flunctuating membrane potential i.e the algebraic sum of the hyperpolarizing and depolarizing activity. The cell body of the neuron performs an integrating function. When the net effect of excitatory and inhibitory activities at synapses produces 10 – 15mv of depolarization, which is sufficient for an action potential to fire, an action potential results i.e an impulse is transmitted.
Neurotransmitters
Many different chemicals are known or suspected to act as neurotransmitters in the nervous system. Neurotransmitter substances vary from synapse to synapse and the same transmitter is always released at a particular synapse. One particular neurotransmitter will always induce EPSP while another will always induce IPSP. Yet another neurotransmitter may even induce an EPSP in one synapse and an IPSP in another synapse. The response of a given transmitter B receptor combination at a given synapse is always constant. A given synapse is either always excitatory or always inhibitory.
In the human nervous system some neurotransmitters are simple chemical ions such as calcium, others are more complex chemicals such as Dopamine, Serotonin (SHT), gamma-amino-butyric acid (GABA), Acetyloline, etc. Identified neurotransmitters can be divided into broad categories based on their chemical structure.
Some are amines e.g. dopamine, Norepinephrine, epinephrine etc, others are amino acids, e.g. glutamate, aspartate, glycine etc, others are purines e.g. adenosine, and many are polypeptides e.g. somatostatin, Endothelins, Endorphins, motilin, Glucagon, Gastrin, angiotensin II etc.
Some of these substances in addition to acting locally as neurotransmitters in the synaptic cleft can also function as hormones at other sites distant from where they are produced or act as paracrine regulators. It is also known that many neurons contain more than one transmitter i.e. they contain co transmitters. Often the amines exist with one or more polypeptides.
Neurotransmitter Inactivation, Removal and Recycling
Neurotransmitters are quickly inactivated from the synaptic cleft once it has produced the appropriate response in the post-synaptic neuron so that the post-synaptic neuron can get ready for other presynaptic inputs. As long as neurotransmitters remain bound to their receptors, EPSP or IPSP which they produce continue, thus it is necessary that they are removed and their responses terminated. This removal can be achieved in the following ways:
They may be inactivated by specific enzymes within the membrane of the post-synaptic neuron or they may be actively taken up back into the axon terminal by transport mechanisms in the presynaptic membrane (reuptake). Once the neurotransmitter is inside the synaptic knob, (following reuptake) it can either be (1) Stored and released another time (recycling) or (2) Destroyed by enzymes in the synaptic knob.
Neurotransmitters and Their Receptors
Receptors are protein substances on the surface of the cell or in some instances in the cytoplasm or nucleus which act as binding sites for chemical messengers (hormones, neurotransmitters and other ligands). There are three facts that must be noted about receptor.
Every lagans (chemical messenger e.g. neurotransmitter) has many sub types of receptors. For example, nor epinephrine binds to α1, α2, ß1 and ß2 There are also different kinds of α1 and α2 receptors. This makes the possible effects of a particular lagans more specific and more selective.
Receptors can exist on the presynaptic as well as post-synaptic neurons. The presynaptic receptors usually act to inhibit further secretion of the ligand (by feedback control). For example noradrenaline binding to α2 presynaptic receptors can inhibit norepinephrine secretion.
The subtypes of receptors tend to group in large families as far as structure and function is concerned. Thus some families of receptors in combination with their lagans function by changing the lagan-gated channels thereby altering membrane permeability and ionic fluxes across the postsynaptic membrane.
Another mode of synaptic transmission used by the transmitter-receptor complex involves the activation of second messengers within the postsynaptic neuron such as cyclic AMP which can then perform the function of opening the ion channels or other functions as may be necessary.
Acetylcholine as a Neurotransmitter and its Receptors
Acetylcholine is an amine neurotransmitter that exists commonly and in high concentrations in terminal buttons of cholinergic neurons. Neurons which release acetylcholine are known as cholinergic neurons.
Acetylcholine receptors are divided into two main types due to their pharmacologic properties muscarinic and nicotinic receptors depending on the action of acetylcholine on the different parts where they function. Muscarine has stimulatory action on smooth muscles and glands, thus the muscarinic actions of acetylcholine are stimulatory on smooth muscles and glands. The receptors here are called muscarinic receptors.
They are blocked by the drug atropine. In autonomic ganglia, large amounts of acetylcholine block transmission of impulses from pre-to post-ganglionic neurons. These are nicotine-like actions. Thus these actions of acetylcholine are nicotinic actions, and the receptors for such actions are called nicotinic receptors.
Acetylcholine nicotinic receptors have 5 sub-units 2 alpha, one beta, one gamma and one delta subunits. Acetylcholine binds on alpha subunits when it does, it opens ionic channels for Na+ and other cat ions, resulting in the influx of Na+ and a depolarizing potential Muscarinic receptors also have four types identified and they seem to act through a second messenger system.
Acetylcholine is removed from the synaptic cleft through the catalytic activity of acetylcholinesterase which hydrolyzes acetylcholine to choline and acetate.
Catecholamine and Their Receptors
Norepinephrine is the neurotransmitter found at most sympathetic ganglionic endings. Together with its methylderivative epinephrine they are secreted by the adrenal medulla, however epinephrine is not a mediator at preganglionic sympathetic nerve endings. The neurons secreting norepinephrine are called adrenergic neurons. Sometimes, the termadrenergic is used to refer to both of them. The third catecholamine in the body is dopamine and dopamine secreting neurons are called dopaminergic neurons. The catecholamines are formed by hydroxylation and decarboxylation of the amino acids phenylalanine and tyrosine.
Epinephrine and norepinephrine both act on alpha and ß receptors, with norepinephrine having greater affinity for X adrenergic receptors and epinephrine for ß adrenergireceptors. Both α and ß receptors work through the action of cyclic AMP as second messenger.
Dopamine which is a step in the formation of norepinephrine and epinephrine (catecholamines can be secreted as a neurotransmitter in certain parts of the brain and autonomic ganglia. There are the D1 and D2 receptors at sites where dopamine is released. Their action is by activating dopamine sensitive adenylate cyclase (second messenger system).
Catecholamines are recaptured by active reuptake mechanism and inactivated by monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT).
Other classical neurotransmitters of the amine type include serotonin, and histamine.
Amino Acids and Polypeptides as Neurotransmitters
Other transmitters of the amino acid and polypeptide group differ from the classical transmitters in that they are larger molecules containing sometimes from two to forty amino acids. They also bring about slower and more prolonged responses. Some of these substances released at synapses function as true neurotransmitters but some as neuromodulators.
Neuromodulators are chemical messengers that bind to neuronal receptors at non-synaptic sites and by so doing bring about long-term changes that depressesorenhances effective synaptic transmission, often by activating second messenger systems.
For example a neuromodulator may influence the level of an enzyme critical in the synthesis of a neurotransmitter by a presynaptic neuron or alter the sensitivity of a post synaptic neuron to a neurotransmitter.
Drugs and Synaptic Transmissions
Many drugs are able to interfere with neurotransmitter processes and this has resulted in their use as legitimate drugs for treatment of mental health problems or as illegal or recreational drugs.
The vast majority of drugs that influence the nervous system perform their function by altering synaptic mechanisms. Hence they can be used to block an undesirable effect or to enhance a desirable one. Specifically some of those drugs may act in the following ways:
Altering the synthesis, axonal transport, storage or release of a neurotransmitter;
Modifying neurotransmitter interaction with the post synaptic receptor,
Influencing neurotransmitter reuptake or destruction; or
Replacing a deficient neurotransmitter with a substitute transmitter.
For example, the illegal drug cocaine blocks the reuptake of the neurotransmitter dopamine at presynaptic terminals by competitively binding with the dopamine reuptake transporter which picks up released dopamine from the synaptic cleft and shuttles it back to the axon terminal for reuptake.
When cocaine occupies the dopamine transporter, dopamine remains longer in the synaptic cleft, and continues to interact with its receptor sites in the post synaptic neuron. This results in prolonged activation of the neural pathways that use dopamine as neurotransmitter, such as those pathways that play a role in emotional responses like feelings of pleasure.
Drugs that alter neurotransmitter functions are called psychoactive drugs. They can be divided into six major pharmacological classes based on their desired behavioural or psychological effect: alcohol, sedative hypnotics, opiate analgesics, stimulant euphoriants, hallucinogens, and psychotropic agents.
Hallucinogens are pscychedelic drugs such as LSD (Lysergic acid diethylamide), mescaline etc. they are serotonin agonists that produce their effects by activating and binding to 5HT2 receptors. They are usually taken illegally to alter perception and thinking patterns. They have little known medical use.
Psychotropic drugs like the phenothiazine tranquilizers are effective in the relief of symptoms of schizophrenia. Their antipsychotic activity parallels their ability to blockD2 dopamine receptors.
Disease and Synaptic Transmission
Synaptic transmission is also vulnerable to a number of disease processes including defects at presynaptic and post-synaptic sites.
Parkinson’s disease for example is attributable to a deficiency of dopamine in a particular region of the brain involved in controlling complex movements called the substantial nigra. The cells have their axons ending in the basal nuclei of the brain. A gradual destruction of the dopamine secreting cells in the substantial nigra and the resultant loss of basal nuclei function are responsible for Parkinson’s disease.
The basal nuclei is another region of the brain involved in the coordination of slow, sustained movements, inhibition of muscle tone and suppression of useless patterns of movement. As dopamine activity slowly diminishes, symptoms begin with involuntary tremors at rest, such as involuntary rhythmic shaking of hands and head. Symptoms of increasing stiffness and rigidity ensue as disease worsens.
Treatment of Parkinson’s disease is an example of a deficient neurotransmitter being replaced with a substitute transmitter. Patients with this disease are given Levidopa (L-dopa) a closely related precursor of dopamine. The drug can be taken up by the dopamine deficient synaptic knobs, thereby substituting for the lacking, naturally occurring dopamine. It alleviates the symptoms associated with dopamine deficit.
Strychnine and tetanus toxin act at different synaptic sites to block inhibitory impulses while leaving excitatory inputs untouched. Strychnine competes with the inhibitory transmitter glycine at the post synaptic receptor sites. It takes up receptor sites without affecting the cells potential, making the receptors not available for binding with glycine when it is released. In such nerve pathways that use glycine as neurotransmitter, post-synaptic inhibition is abolished. Unchecked excitatory pathways lead to convulsions and muscle spasticity.
Tetanus toxins also prevent the release of another inhibitory transmitter, Gamma aminobutyric acid (GABA) from presynaptic inputs terminating on motor neurons supplying skeletal muscles. Unchecked excitatory inputs to these neurons result in uncontrolled muscle spasms. The outcomes of the two are similar, but strychnine blocks specific postsynaptic inhibitory receptors whereas tetanus toxin prevents the presynaptic release of a specific inhibitory neurotransmitter. Other drugs and diseases that affect synaptic transmission are too numerous to mention but the examples show that any site along the synaptic pathway can be interfered with pharmacologically or pathologically.
Assignment
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