Neurotransmitters and Synapses

NEUROTRANSMITTERS
DEFINITION: Are chemical transducers which are released by electrical impulse into the synaptic cleft from presynaptic membrane from synaptic vesicles. It then diffuse to the postsynaptic membrane and react and activate the receptors present leading to initiation of new electrical signals.
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Discovery of neurotransmitters
Loewi, 1921 frog hearts in saline solution Stimulation of vagus nerve results in lower heart rate gave long vagal nerve stimulation Heart #2: Exposed to saline solution from heart #1 Slowed heart rate Conclusion: Neurotransmission is

chemical
nerve releases chemical that can influence other cells
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Fig 8.1, Zigmond Fundamental Neuroscience

Neurotransmitters
substances that mediate chemical signaling between neurons. criteria for a substance to be considered a neurotransmitter.
they must be demonstrated to be present in the presynaptic terminal they must be synthesize by the presynaptic cell. they should be released on depolarization of the terminal there should be specific receptors for them on the postsynaptic membrane or other sites outside the synapse

Synapses
A junction that mediates information transfer from one neuron:
To another neuron
Called neuro-synapses or just synapse

To an effector cell
Neuromuscular synapse if muscle involved Neuroglandular synapse if gland involve

Presynaptic neuron conducts impulses toward the synapse Postsynaptic neuron transmits impulses away from the synapse Two major types:
Electrical synapses Chemical synapses

Synapses

1. Axodendritic synapse 2. Axosomatic synapse 3. Axoaxonic synapse

Figure 11.17

Electrical Synapses
Pre- and postsynaptic neurons joined by gap junctions
allow local current to flow between adjacent cells. Connexons: protein tubes in cell membrane.

Rare in CNS or PNS Found in cardiac muscle and many types of smooth muscle. Action potential of one cell causes action potential in next cell, almost as if the tissue were one cell. Important where contractile activity among a group of cells important.

Chemical Synapses
Most common type Cells not directly coupled as in electrical synapses Components
Presynaptic terminal Synaptic cleft Postsynaptic membrane (PSM)

Chemical neurotransmitters (NTs) released by presynaptic neuron NT binds to receptor on PSM

Chemical Synapse
Events at a chemical synapse
1. Arrival of action potential on presynaptic neuron opens volage-gated Ca++ channels. 2. Ca++ influx into presynaptic term. 3. Ca++ acts as intracellular messenger stimulating synaptic vesicles to fuse with membrane and release NT via exocytosis. 4. Ca++ removed from synaptic knob by mitochondria or calcium-pumps. 5. NT diffuses across synaptic cleft and binds to receptor on postsynaptic membran 6. Receptor changes shape of ion channel opening it and changing membrane potential 7. NT is quickly destroyed by enzymes or taken back up by astrocytes or presynaptic membrane. Note: For each nerve impulse reaching the presynaptic terminal, about 300 vesicles are emptied into the cleft. Each vesicle contains about 3000 molecules.

Types of Synaptic Transmission

Electrical
occurs in gap junction by simple electrical coupling usually bidirectional fast transmission (-) synaptic delay

Chemical
occurs in synaptic cleft utilized a chemical intermediaries (neurotransmitter) unidirectional slow transmission (+) synaptic delay

Synaptic Delay
0.2-0.5 msec delay between arrival of AP at synaptic knob and effect on PSM Reflects time involved in Ca++ influx and NT release While not a long time, its cumulative synaptic delay along a chain of neurons may become important. Thus, reflexes important for survival have only a few synapses

Synaptic Fatigue
Under intensive stimulation, resysnthesis and transport of recycled NT may be unable to keep pace with demand for NT Synapse remains inactive until NT has been replenished

Neurotransmitters
more than 100 have been identified as potential neurotransmitters or potential qualifiers. three major categories
small molecule transmitters
acetylcholine amino acids biogenic amines purines

peptides gaseous transmitters

Neurotransmitters
contained in synaptic vesicles. three kinds of synaptic vesicles
small clear synaptic vesicle
acethylcholine, glycine, GABA and glutamate

small vesicle with dense core

catecholamines

large vesicle with dense core

neuropeptides

Fate of neurotransmitters
1. It is consumed ( broken down or used up) at postsynaptic membrane leading to action potential generation. 2. Degraded by enzymes present in synaptic cleft. 3. Reuptake mechanism( reutilization) this is the most common fate.
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Removal of Neurotransmitter from Synaptic Cleft

Method depends on neurotransmitter

ACh: acetylcholinesterase splits ACh into acetic acid and choline. Choline recycled within presynaptic neuron. Norepinephrine: recycled within presynaptic neuron or diffuses away from synapse. Enzyme is monoamine oxidase (MAO). Absorbed into circulation, broken down in liver.

Receptor Molecules and Neurotransmitters

Neurotransmitter only "fits" in one receptor. Not all cells have receptors. Neurotransmitters are commonly classified as excitatory or inhibitory. Classification is useful but not precise. For example:
ACh is stimulatory at neuromuscular junctions (skeletal) ACh is inhibitory at neuromuscular junction of the heart

Therefore, effect of NT on PSM depends on the type of receptor, and not nature of the neurotransmitter Some neurotransmitters (norepinephrine) attach to the presynaptic terminal as well as postsynaptic and then inhibit the release of more neurotransmitter.

Postsynaptic Potentials
NT affects the postsynaptic membrane potential Effect depends on:
The amount of neurotransmitter released The amount of time the neurotransmitter is bound to receptors

The two types of postsynaptic potentials are:

EPSP excitatory postsynaptic potentials IPSP inhibitory postsynaptic potentials

Types of responses on postsynaptic membrane

Excitatory postsynaptic potential (EPSPs) It is caused by depolarization. Inhibitory Postsynaptic potential (IPSPs) It is caused by hyperpolarization.

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Fast & Slow Postsynaptic potentials

Fast EPSPs & IPSPs work through ligand gated ion channels.eg. Nicotinic receptors(at the level of neuromuscular junction) Slow EPSPs & IPSPs are produced by multi step process involving G protein eg. Muscarinic receptors ( at the level of autonomic gangila)
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Excitatory Postsynaptic Potentials

EPSPs are graded potentials that can initiate an action potential in an axon
Use only chemically gated channels

Postsynaptic membranes do not generate action potentials But, EPSPs bring the RMP closer to threshold and therefore closer to an action potential

Inhibitory Synapses and IPSPs

Neurotransmitter binding to a receptor at inhibitory synapses:
Causes the membrane to become more permeable to potassium and chloride ions Leaves the charge on the inner surface more negative (flow of K+ out of the cytosol makes the interior more negative relative to the exterior of the membrane Reduces the postsynaptic neurons ability to produce an action potential

Summation
A single EPSP cannot induce an action potential EPSPs must summate temporally or spatially to induce an action potential Temporal summation one presynaptic neuron transmits impulses in rapid-fire order Spatial summation postsynaptic neuron is stimulated by a large number of presynaptic neurons at the same time IPSPs can also summate with EPSPs, canceling each other out

Summation

Figure 11.21

Neurotransmitters
Chemicals used for neuronal communication with the body and the brain 100 different neurotransmitters have been identified Classified chemically and functionally
Chemically: ACh, Biogenic amines, Peptides Functionally: Excitatory or inhibitory Direct/Ionotropic (open ion channels) Indirect/metabotropic (activate G-proteins) that create a metabolic change in cell

Neurotransmitter Receptor Mechanisms

Direct: neurotransmitters that open ion channels
Promote rapid responses Examples: ACh and amino acids

Indirect: neurotransmitters that act through second messengers

Promote long-lasting effects Examples: biogenic amines, peptides, and dissolved gases

Channel-Linked Receptors
Composed of integral membrane protein Mediate direct neurotransmitter action Action is immediate, brief, simple, and highly localized Ligand binds the receptor, and ions enter the cells Excitatory receptors depolarize membranes Inhibitory receptors hyperpolarize membranes

Channel-Linked Receptors

Figure 11.23a

G Protein-Linked Receptors
Responses are indirect, slow, complex, prolonged, and often diffuse These receptors are transmembrane protein complexes Examples: muscarinic ACh receptors, neuropeptides, and those that bind biogenic amines

G Protein-Linked Receptors: Mechanism

Neurotransmitter binds to G protein-linked receptor G protein is activated and GTP is hydrolyzed to GDP The activated G protein complex activates adenylate cyclase Adenylate cyclase catalyzes the formation of cAMP from ATP cAMP, a second messenger, brings about various cellular responses

G Protein-Linked Receptors: Mechanism

Figure 11.23b

G Protein-Linked Receptors: Effects

G protein-linked receptors activate intracellular second messengers including Ca2+, cGMP, and cAMP Second messengers:
Open or close ion channels Activate kinase enzymes (phosphorylation rxns) Phosphorylate channel proteins Activate genes and induce protein synthesis!!

Chemical Neurotransmitters
Acetylcholine (ACh) Biogenic amines Amino acids Peptides Novel messengers: ATP and dissolved gases NO and CO

Neurotransmitters: Acetylcholine
First neurotransmitter identified (by Otto Loewi) and best understood Synthesized and enclosed in synaptic vesicles Degraded by the enzyme acetylcholinesterase (AChE) Released by cholinergic neurons: All skeletal muscle motor neurons
Anterior horn motor neuron (= Lower motor neuron)

Some neurons in the autonomic nervous system

All ANS preganglionic neurons (parasym. and sympathetic) All parasympathetic postganglionic neurons stimulating smooth muscle, cardiac muscle, and glands Symp. postganglionic neurons stimulating sweat glands

Ach binds to cholinergic receptors known as nicotinic or muscarinic receptors

Acetyl Choline Receptors

Nicotinic
1 Found at:
i. Neuromuscular junction of skeletal muscle ii. Postganglionic neurons of parasympathetic nervous system. iii. Ventral tegmental area.

Muscarinic
i. Glands ii. Neuromuscular junctions of cardiac and smooth muscle. iii. Postganglionic neurons of sympathetic nervous system.

Agonist

Nicotine

Muscarine ( a toxin produced by certain mushroom) Atropine

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Antagonist

Curare ( paralyses skeletal muscle)

Comparison of Somatic and Autonomic Systems

Figure 14.2

Cholinergic Receptors: Bind ACh

Nicotinic receptors - Are ion channels (rapid acting) - On sarcolemma of skeletal muscle fibers - On dendrites and cell bodies of ALL postganglionic neurons of the ANS - Excitatory (open Na+ channels fast EPSP) Muscarinic receptor - Are G-protein couple receptors (complex intracellular functions) - On all parasympathetic target organs (cardiac and smooth muscle) - Are excitatory in most cases; inhibitory in others

Acetylcholine
Effects prolonged (leading to tetanic muscle spasms and neural frying) by nerve gas and organophosphate insecticides (Malathion). ACH receptors destroyed by patients own antibodies in myasthenia gravis Binding to receptors inhibited by curare (a muscle paralytic agent
blowdarts in south American tribes and some snake venoms.

Neurotransmitters: Monoamines/Biogenic Amines

Include:
Catecholamines dopamine, norepinephrine (NE), and epinephrine (EP) Indolamines serotonin and histamine

Broadly distributed in the brain Cathecholamine are important sympathetic NTs Play roles in emotional behaviors and our biological clock

Synthesis of Catecholamines
AA tyrosine is parent cpd Enzymes present in the cell determine length of biosynthetic pathway Norepinephrine and dopamine are synthesized in axonal terminals Epinephrine is released by the adrenal medulla as a hormone

Figure 11.22

MAO=monoamine oxidase ,COMT=catecholeo-methyle-transferase

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BIOGENIC AMINES: Norepinephrine

Norepinephrine (aka Noradrenaline)
Main NT of the sympathetic branch of autonomic nervous system Binds to adrenergic receptors ( or -many subtypes, 1, 2, etc) Excitatory or inhibitory depending on receptor type bound Very important role in attention and arousal - an organisms vigilance Also released by adrenal medulla as a hormone Feeling good NT

Clinical Importance
Thought to be involved in etiology of some bipolar affective disorders
Removal from synapse blocked by antidepressants and cocaine Levels lowers in depressed pts. and higher in manic phase of bipolar dis.

Release enhanced by amphetamines

BIOGENIC AMINES: Dopamine

Dopamine
Binds to dopaminergic receptors of substantia nigra of midbrain and hypothalamus Involved in important physiology functions including: Motor control Coordinating autonomic functions Regulating hormone release Motivational behavior and reward; i.e., a feeling good NT Hypothesized to be at the heart of the mechanisms of ALL addictivedrugs and behaviors. For example, Release enhanced by amphetamines Reuptake blocked by cocaine Deficient in Parkinsons disease Receptor abnormalities have been linked to development of schizophrenia

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Small Molecule Transmitters

Biogenic Amines they have roles outside the nervous system as hormones. include catecholamines - epinephrine (adrenaline), norepinephrine (noradrenaline) and dopamine from amino acid tyrosine serotonin (5 HT) from amino acid tryptophan histamine from histidine

Biogenic Amines: Serotonin (5-HT)

Synthesized from the amino acid tryptophan Since tryptophan not synthesized in humans, its levels available for synthesis of serotonin are dependent on diet. Diets high in tryptophan can markedly elevate serotonin levels May play a role in sleep, appetite, and regulation of moods (aggression) Low 5-HT levels associated with increased aggressiveness and risk taking Acts in a pathway that monitors carbohydrate intake, acting as a negative regulator of motivation to ingest carbohydrate
Has led to the use of SSRIs (see below) as obesity pills (fenfluramine)

Drugs that block its uptake relieve anxiety and depression and aggression
SSRIs = selective serotonin reuptake inhibitors Include drugs such as Prozac, Celexa, Lexapro, Zoloft

Ecstasy targets serotonin receptors

=5-HT Hydroxy tryptamine HIAA=hydroxyindoleacetic acid

Formation of serotonin

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Histamine
Histamine forming cells are in posterior hypothalamus also found in gastric mucosa and in mast cells. Formed by decarboxylation of amino acid histidine with the help of enzyme histaminase. Three known types of histamine receptors in found e.g. H1, H2, H3. H3 receptors are presynaptic. Its function in brain is not very certain. Its main function is that it is excitatory.
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BIOSYNTHESIS

OF

CATECHOLAMINES

Small Molecule Transmitters

Biogenic Amines
involved in setting the level of arousal (sleep and waking),
attention and mood. important in homoestatic functions (ANS) and motor system.
Catecholamines (NE and E)
from the brainstem nuclei (locus ceruleus and nucleus subceruleus) and postganglionic sympathetic cells.

Serotonin (from midline of the brainstem (raphe nuclei) Histamine (from the hypothalamus) Dopamine (from substancia nigra and tegmental area)

Small Molecule Transmitters

Purines --- ATP has potential to act as a transmitter or cotransmitter in the CNS and PNS. has receptors coupled to an ion channel. can modify the action of other transmitters with which it is co-released (NE, 5-HT etc)

Neurotransmitters: Amino Acids

Include:
GABA Gamma ()-aminobutyric acid Glycine Aspartate Glutamate

Found only in the CNS

Small Molecule Transmitters

Amino acids --- Glutamate major excitatory CNS neurotransmitter present in all cells and has a key role in multiple metabolic pathways. a precursor to GABA a potent neurotoxin at high concentrations

Glutamic acid
It is the most commonly found neurotransmitter in the brain. It is always excitatory. Glutamate is formed during Krebs cycle for ketoglutarate. Glutamate is carried into astrocytes where it is converted to glutamine and passed on to glutaminergic neurones. Glutamate is neurotoxic while glutamine is not. There are two types of receptors e.g. metabotropic and iontropic receptors.
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Amino Acid Neurotransmitters

Excitatory Amino Acids
1. Glutamate
Indirect action via G proteins and 2nd messengers Direct action -- opens Ca++ channels (ionotropic)
NMDA receptors (have a high permeability to Ca++)

Widespread in brain where it represents the major excitatory neurotransmitter Important in learning and memory! Highly toxic to neurons when present for extended periods - Stroke NT -excessive release produces excitotoxicity: neurons literally stimulated to death; most commonly caused by ischemia due to stroke (Ouch!) Aids tumor advance when released by gliomas (ouch!)

NMDA =N methyl-D-aspartate receptors, when glutamate & glycine bind to receptor ion channels open, Mg block channels 57

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Small Molecule Transmitters

Amino acids --- Glycine an inhibitory neurotransmitter in a much more restricted territories. predominantly found in spinal cord and also present in lower brainstem, cerebellum and the retina. acts as a co-transmitter at NMDA-type glutamate receptors.

Glycine
It is simplest of all aminoacids, consisting of amino group and a carboxyl group attached to a carbon atom H
+

H3 N+

H
+

Coo60

Glycine..
Its an inhibitory neurotransmitter. It binds to a receptor which makes the post synaptic membrane more permeable to Cl- Ion and cause hyperpolarization (inhibition). The glycine receptor is primarily found in the ventral part of the spinal cord. Strychnine is glycine antagonist.
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Gamma Aminobutyric acid (GABA)

It is one of the inhibitory neurotransmitter of CNS and is also found in retina. It is formed by decarboxylation of glutamate. The enzyme that catalyzes this reaction is glutamate decarboxylase(GAD) There are three types of GABA receptors e.g. GABAA B & C. GABA A & B receptors are widely distributed in CNS. GABAC are found in retina only. GABA B are metabotropic (G-protein) in function.
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Amino Acids
Inhibitory Amino Acids 1. GABA (Gamma aminobutyric acid) Direct or indirect action (depending on type of receptor Main inhibitory neurotransmitter in the brain - Selectively permeable to Cl- (hyperpolarizes memb.) Cerebral cortex, cerebellum, interneurons throughout brain and spinal cord Inhibitory effects augmented by alcohol and benzodiazepines (antianxiety drugs like Valium and Librium) and barbiturates - these drugs increase the number of GABA receptors and thus enhance the inhibitory activity of GABA Decreased GABA inhibition amy lead to epilepsy

Neurotransmitter

Postsynaptic effect

Derived from

Site of synthesis

Postsynaptic receptor

Fate

Functions

1.Acetyl choline (Ach)

Excitatory

Acetyl co-A + Choline

Cholinergic nerve endings Cholinergic pathways of brainstem

Adrenal medulla and some CNS cells Begins inside axoplasm of adrenergic nerve ending is completed inside the secretary vesicles CNS, concentrated in basal ganglia and dopamine pathways e.g. nigrostriatal, mesocorticolim bic and tuberohypophyseal pathway

1.Nicotinic 2.Muscarinic

Broken by acetyl cholinesterase

Cognitive functions e.g. memory Peripheral action e.g. cardiovascular system

For details refer ANS. e.g. fight or flight, on heart, BP, gastrointestinal activity etc. Norepinehrine controls attention & arousal.

2. Catecholamines i. Epinephrine (adrenaline) ii.Norepinephrine

Excitatory in some but inhibitory in other Excitatory

Tyrosine produced in liver from phenylalanine Tyrosine, found in pons. Reticular formation, locus coerules, thalamus, midbrain Tyrosine

Excites both alpha & beta receptors 1 2 1 2

1.Catabolized to inactive product through COMT & MAO in liver 2.Reuptake into adrenergic nerve endings 3.Diffusion away from nerve endings to body fluid

iii. Dopamine

Excitatory

D1 to D5 receptor

Same as above

Decreased dopamine in parkinsons disease. Increased dopamine concentration causes schizophrenia

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Neurotransmitter

Postsynaptic effect

Derived from

Site of synthesis Spinal cord

Postsynaptic receptor Spinal cord

Fate

Functions

6. Aspartate

Excitatory

Acidic amines

Aspartate & Glycine form an excitatory / inhibitory pair in the ventral spinal cord

7. Gama amino butyric acid(GABA)

Major inhibitory mediator

Decarboxylation of glutamate by glutamate decarboxylase (GAD) by GABAergic neuron.

CNS

GABA A increases the Cl - conductance, GABA B is metabotropic works with G protein GABA transaminase catalyzes. GABA C found exclusively in the retina.

Metabolized by transamination to succinate in the citric acid cycle.

GABA A causes hyperpolarization (inhibition) Anxiolytic drugs like benzodiazepine cause increase in Cl- entry into the cell & cause soothing effects. GABA B cause increase conductance of K+ into the cell.

8. Glycine

Inhibitory

Is simple amino acid having amino group and a carboxyl group attached to a carbon atom

Spinal cord

Glycine receptor makes postsynaptic membrane more permeable to Clion.

Deactivated in the synapse by simple process of reabsorbtion by active transport back into the presynaptic membrane

Glycine is inhibitory transmitted found in the ventral spinal cord. It is inhibitory transmitter to Renshaw cells.

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Peptides
more than 100 neuropeptides have been identified. co-released with classic neurotransmitters but can function as a sole or primary neurotransmitter at a synapse. synthesized in the cell body and transported to the axon examples hypothalamic hormones, neuropeptide Y, opioids, tachykinins, etc.

Neurotransmitters: Peptides
Neuropeptide receptors are all G-protein linked
Alter levels of intracellular second messengers

Include:
Substance P mediator of pain signals Neuropeptide Y - stimulates appetite and food intake Beta endorphin, dynorphin, and enkephalins Opiods: include
Endorphins, Enkephalins, Dynorphin Act as natural opiates, reducing our perception of pain Found in higher concentrations in marathoners and women who have just delivered

Bind to the same receptors as opiates and morphine

Gas Neurotransmitters
neither packed into synaptic vesicles nor released

by exocytosis. synthesis is triggered by depolarization highly permeant and simply diffuse from the nerve terminal to the neighboring cells. destroyed by diffusion or binding to superoxide anions or various scavenger proteins. do not bind to a receptor

examples: NO (inhibitory transmitter) and CO

Neurotransmitters: Novel Messengers

Nitric oxide (NO)
Same substance produced by sublingual nitroglycerin produces to increase vasodilation in relief of angina A short-lived toxic gas; diffuses through post-synaptic membrane to bind with intracellular receptor (guanynyl cyclase)
Is a free radical and therefore highly reactive compound

Do not confuse with laughing gas (nitrous oxide) Is involved in learning and memory Important in control of blood flow through cerebrovasculature Some types of male impotence treated by stimulating NO release (Viagra)
Viagra NO release smooth muscle relaxation increased blood flow erection Cant be taken when other pills to dilate coronary b.v. taken

Destruction of Small molecule Transmitters

Acetylcholine
enzymatic hydrolysis by acetylcholenesterase reuptake of choline at the presynaptic terminal by Na+ symporter.

Amino acid
Reuptake into the neurons and glial cells
Glutamate - Na+ - K+ transporter GABA - Na+ Cl- transporter Glycine - Na+ Cl- transporter

Destruction of Small molecule Transmitters

biogenic amines Reuptake into the neuron and glial cells Na+ Cl- transporter enzymatic hydrolysis by MOA and COMT purines hydrolyzed by ATPase

Neurotransmitter Receptors
small molecule transmitters biogenic amines (metabotropic receptors except 5
HT3) catecholamines (1, 2, 1, 2, and 3)
histamine (H1 and H2 ) dopamine (D1, D2, D3, D4, and D5) serotonin (5HT1, 5HT2, 5HT3 and 5HT4)

purines
ionotropic (P2X) and metabotropic (P2Y)

peptides
neuropeptide receptors

RELESE OF NEUROTRANSMITERS

MEDICAL PHYSIOLOGY 23TH EDITION by Ganong

RELESE OF NEUROTRANSMITERS

MEDICAL PHYSIOLOGY 23TH EDITION by Ganong

Functional Classification of Neurotransmitters

Two classifications: excitatory and inhibitory
Excitatory neurotransmitters cause depolarizations (e.g., glutamate) Inhibitory neurotransmitters cause hyperpolarizations (e.g., GABA)

Functional Classification of Neurotransmitters

Some neurotransmitters have both excitatory and inhibitory effects
Determined by the receptor type of the postsynaptic neuron Example: acetylcholine
Excitatory at neuromuscular junctions with skeletal muscle (nicotinic receptor) Inhibitory in cardiac muscle (muscarinic receptor)

Alzheimers Disease
a form of dementia in which memory function is gradually and progressively lost due to degeneration of cholinergic neurons in the basal forebrain areas, neocortex, hippocampus and amygdala (implicated in memory function).

RECEPTORS DYSFUNCTION
1. Presynaptic effect i) Botulinum toxin: Its an exotoxin that binds to the presynaptic membrane and prevents the release of Ach resulting in weakness and reduction of tone. It is used to control dystonia in which body shows overactive muscular activity.
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Clinical Correlation (fusion-exocytosis complex)

Tetanus toxin
act on synaptobrevin (CNS) spastic paralysis

Botulinum toxins B, D, F and G

act on synaptobrevin (neuromuscular junction) flaccid paralysis

Botulinum toxin C
acts on syntaxin causes flaccid paralysis

Botulinum toxins A and B

act on SNAP-25 Causes flaccid paralysis

 Botox (Botulinum toxin)

local injection of small doses is effective in the treatment of conditions characterized by muscle hyperactivity. examples are
achalasia (lower esophageal sphincter) used to remove wrinkles

ii) Lumbert Eaton syndrome Antibodies directed against Ca++ channels located in presynaptic terminals and interfere with transmitter release causing weakness. iii)Neuromyotonia Patient complains of muscle spasm and stiffness resulting in continuous motor activity in the muscle. It is cased by antibody directed against the presynaptic voltage gated K+ channel so that the nerve terminal is always in a state of depolarization 82

2. Effects at Postsynaptic level: i) Curare binds to the acetylcholine receptor (AchR) and prevents Ach from acting on it and so that it induces paralysis. ii) Myasthenia gravis: is caused by an antibody against the Ach receptors and Ach receptors are reduced hence the Ach released has few Ach receptor available to work and patients complain of weakness that increases with exercise.
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Psychosis
can be due to hyperactivity of dopaminergic synapses can be treated by dopamine antagonists (chlorpromazine and other antipsychotic drugs), which inhibit dopamine receptors in the postsynaptic membrane.

Synaptic strength
Can be facilitated like long term potentiation. Can be depressed ( inhibited) by longterm depression.

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Classification of Neurotransmitters
A. B. Amines Acetyl choline (Ach) Monoamines Catecholamines Epinephrine Nor epinephrine Dopamine (Substantia nigra, sympathetic ganglia)
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III. Purine derivatives eg. Adinosine & ATP. IV. Polypeptides ( a very long list of names) eg. Enkephaline, hormones ( VIP etc) ( refer to the list in Ganong 21st edition pg.97) V. Nonsynaptic transmitters eg. Gases, nitric oxide & cabon mono oxide.

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Excitatory neurotransmitters
acetylcholine norepinephrine serotonin glutamate

Inhibitory neurotransmitters
GABA glycine dopamine

Generation of AP in the motorneuron

CNS
Depolarization of the terminal buttons

Calcium influx (opening of voltage-gated channel) Release of neurotransmitters (Ach) in NMJ

Skeletal Muscle

Binding of Ach with Ach receptors

Depolarization of motor end plate ( Na+ influx) Generation of end plate potential (EPP) Production of action potential

Generation of AP in the presynaptic neuron

Depolarization of the terminal buttons

EXCITATORY CHEMICAL TRANSMISSION

Calcium influx (opening of voltage-gated channel)

Release of excitatory neurotransmitters in the synaptic cleft Binding of excitatory NTA with its receptors

Depolarization of the postsynaptic cell ( Na+ influx) Generation of excitatory post potential (EPSP) Production of action potential

INHIBITORY CHEMICAL TRANSMISSION

Generation of AP in the presynaptic neuron

Depolarization of the terminal buttons

Calcium influx (opening of voltage-gated channel)

Release of inhibitory neurotransmitters in the synaptic cleft

Binding of excitatory NTA with its receptors

Depolarization of the postsynaptic cell ( Cl- influx and K efflux)

Generation of inhibitory post potential (iPSP)

Production of action potential