General Properties of Chemical Synaptic Transmission 1- One – Way Conduction 2- Synaptic Delay 3- Synaptic Fatigue 4- Post-Tetanic Facilitation 5- Long - Term Potentiation 6- Effect of Hypoxia on Synaptic Transmission 7- Effects of pH on Synaptic Transmission 8- Effect of Drugs on Synaptic Transmission

1- One – Way Conduction: * At synapses, conduction of impulses occurs in one direction only; from the presynaptic to the postsynaptic neurons & not in the opposite direction. * This is known as “Bell- Magendie law”. - Action potential generated at the initial segment of the axon will travel in 2 directions: Mechanism:

a) along the axon toward its terminal endings ; orthodromic (forward conduction): The forward impulse -----> transmitter release from the synaptic knobs ----> action on the postsynaptic neuron (excitation or inhibition). b) Spread back over the soma & dendrites, antidromic (backward conduction): The backward impulse produces no effect because there are no transmitter vesicles in the presynaptic neuron. Also, impulses travelling backword on the postsynaptic neurons can’t excite the presynaptic neuron.

2- Synaptic Delay: Definition: It is time passed between arrival of an action potential to the synaptic knob and the occurrence of response in the postsynaptic neuron. - This represents the time required for:

a) Release and diffusion of the neurotransmitter b) Binding of the transmitter to the postsynaptic receptors. c) Generation of PSPs & its summation to generate action potential. - The minimum time for synaptic delay is about 0.5 millisecond. - Significance: can be used to determine the number of synapses present in a polysynaptic reflex.

3- Synaptic Fatigue: Definition: - It is progressive decline in rate of discharge of the postsynaptic neuron, following intense prolonged stimulation of the presynaptic neuron. - In sever conditions, synaptic transmission completely stops. This is called "synaptic block".

Mechanism: Depletion of the stores of the neurotransmitter in the synaptic knobs, because there is no enough time resynthesis and reuptake mechanisms that refill the stores under intensive stimulation. Synaptic fatigue disappears when the transmitter has been replenished. - Hypoxia accelerate synaptic fatigue while strychnine delays it. Significance: * Under normal conditions, rates of resynthesis and reuptake of the neurotransmitter are sufficient for synaptic transmission for long periods of time without the development of fatigue. * Synaptic fatigue when occurs protects CNS from overexcitability (a protective mechanism).

4- Post-Tetanic Facilitation: Rapid repeated stimulation of the presynaptic terminal (at a rate not producing fatigue) for a period of time ---------------> then restimulation shows ↑ postsynaptic discharge above normal for a period of seconds or even minutes. stoppage stoppage stoppage - This is called post-tetanic facilitation or potentiation.

Mechanism: - It is caused mainly by excess rise of the concentration of Ca2+ ions in the synaptic knob which causes more and more vesicles to release their transmitter, producing a greater response of the postsynaptic neuron. Significance: - It is still unclear, but it may have a role in the short-term memory processes in the central nervous system .

5- Long - Term Potentiation: Brief rapid repeated stimulation of presynaptic terminal -----> prolonged ↑in rate of postsynaptic discharge. - It resembles post-tetanic potentiation, but is much more prolonged and can last for several days .

Mechanism: It is initiated mainly by an increase of the intracellular Ca2+ concentration in the postsynaptic neuron through opening of certain Ca2+ channels in the postsynaptic membrane . After binding of glutamate to its specific NMDA receptros. Significance: It occurs in many parts of the nervous system , but it has a special significance in the hippocampus; which plays an important role in learning and memory.

6- Effect of Hypoxia on Synaptic Transmission: - Hypoxia ↓neuronal excitability & synaptic transmission. - This is due to the need of the neurons for adequate oxygen supply. - interruption of cerebral circulation for about 7 seconds causes loss of consciousness (coma) & for about 2-3 minutes causes irreversible damage of the brain.

7- Effects of pH on Synaptic Transmission: - In brain synapses, alkalosis ↑ excitability and synaptic transmission while acidosis ↓it. - So, ↑pH to 7.8 to 8.0, produces severe convulsions whereas, ↓pH around 7.0 produces coma. This latter condition is always seen in severe uremic or diabetic acidosis .

8- Effect of Drugs on Synaptic Transmission: Drugs ↓ ing neuronal excitability & synaptic transmission Drugs ↑ing neuronal excitability 1- Volatile anesthetics: ↑ threshold needed for excitation of the postsynaptic neuron. 2- Tranquilizers: ↑Cl- influx ----> inhibition of postsynaptic neurons at specific regions in the nervous system. 1- Caffeine (found in coffee) and theophylline (found in tea ): ↓threshold needed for excitation of the postsynaptic neuron. 2- Strychnine: inhibits the action of glycine (inhibitory neurotransmitter) on the neurons.

General Properties of Chemical Synaptic Transmission 1- One – Way Conduction 2- Synaptic Delay 3- Synaptic Fatigue 4- Post-Tetanic Facilitation 5- Long - Term Potentiation 6- Effect of Hypoxia on Synaptic Transmission 7- Effects of pH on Synaptic Transmission 8- Effect of Drugs on Synaptic Transmission

THE CENTRAL NERVOUS SYSTEM NEUROTRANSMITTERS IN THE CENTRAL NERVOUS SYSTEM Neurotransmitters of the central nervous system can be broadly classified into two groups: (i) Small- molecule neurotransmitters. ) ii) Neuropeptides.

Small - Molecule Neurotransmitters - Rapidly acting, causing most of the fast responses of the nervous system, such as transmission of sensory impulses to the brain and motor signals to the muscles. Synthesized in the presynaptic terminals. Stored in vesicles in the presynaptic terminals. Released during the process of synaptic transmission to act on the postsynaptic membrane receptors .

Small - Molecule Neurotransmitters Class I Acetylcholine Class II (Biogenic Amines) Dopamine Norepinephrine Serotonin Histamine Class III (Amino Acids) Glutamate Aspartate γ- Aminobutyric acid (GABA) Glycine Class IV Nitric oxide (NO) Carbon monoxide (CO)

- These are widely distributed in the central nervous system . Acetylcholine : - Synapses that release acetylcholine are known as cholinergic synapses. - These are widely distributed in the central nervous system . - There are two types of receptors that can bind acetylcholine: 1- Nicotinic Acetylcholine Receptors. 2- Muscarinic Acetylcholine Receptors.

1- Nicotinic Acetylcholine Receptors. - These receptors are ligand- gated ionic channels. - Once activated by binding with acetylcholine, the receptor opens its gate to permit influx of Na+ ions, causing depolarization (EPSP) in the postsynaptic membrane.

2- Muscarinic Acetylcholine Receptors - Five types of muscarinic receptors have been identified (M1 to M5 receptors). - All are G – proteinscoupled receptors. - Activation of M1 receptors closes K+ channels causing depolarization and excitation of the postsynaptic neuron - Activation of M2 receptors causes opening of K+ channels causing hyperpolarization and inhibition of the neuron.

1 Gs protein closes Depolarization

Small - Molecule Neurotransmitters Class I Acetylcholine Class II (Biogenic Amines) Dopamine Norepinephrine Serotonin Histamine Class III (Amino Acids) Glutamate Aspartate γ- Aminobutyric acid (GABA) Glycine Class IV Nitric oxide (NO) Carbon monoxide (CO)

Dopamine - Secreted as a transmitter by dopaminergic neurons, located largely in the substania nirga of the midbrain, which project their axons mainly to the basal ganglia. - Five types of dopamine receptors have been identified (D1 to D5 receptors), and all are acting through the G-proteins second messenger system. - Dopamine can produce either an excitatory or an inhibitory effect depending upon the type of its postsynaptic receptor.

- The action of released dopamine is terminated mainly by its rapid reuptake into the presynaptic terminal, where it is stored once more in synaptic vesicles .

Norepinephrine - Norepinephrine is secreted by noradrenergic neurons whose cell bodies are located mainly in a region called the “locus ceruleus” in the pons, from which the noradregnergic neurons send nerve fibers both downward to the spinal cord , and upward to widespread areas of the brain. - The receptors for norepinephrine include both alpha () and beta () adrenergic receptors. Both groups act through G-proteins, and there are multiple form of receptors in each group .

- In many of these areas, norepinephrine appears to activate excitatory receptors, but in some other areas it activates inhibitory receptors. - After dissociation from its receptor, most of the norepinephrine is taken back into the presynaptic terminal where it is stored in synaptic vesicles in preparation for release again into the synaptic cleft - One important function of epinephrine is to control the activity of certain brain centers that play an important role in regulating the psychological mood.

Serotonin - Serotonin secreting neurons in the nervous system are located in the “raphe nuclei” in the brain stem , which project their axons to many areas in the brain and spinal cord. - After dissociation from its receptor, most serotonin is transported back into the presynaptic terminal by an active reuptake mechanism - Serotonin is involved in the activation of the pain control system in the spinal cord, and its action in the higher regions of the nervous system (the brain and brain stem) is believed to control the mood of the person and plays a role in sleep .

Small - Molecule Neurotransmitters Class I Acetylcholine Class II (Biogenic Amines) Dopamine Norepinephrine Serotonin Histamine Class III (Amino Acids) Glutamate Aspartate γ- Aminobutyric acid (GABA) Glycine Class IV Nitric oxide (NO) Carbon monoxide (CO)

Glutamate - It is the most abundant excitatory transmitter in the nervous system - It is found in most areas of the brain and spinal cord . - It activates ligand-gated cation channels, allowing increased Na+ and Ca++ influx, thus causing excitation of the postsynaptic neuron.

Gamma- Amino Butyric Acid (GABA): - It is the major inhibitory transmitter in the brain - It is a potent postsynaptic & presynaptic inhibitor - GABA activates Cl- channels and K+ channels, allowing increased Cl- influx and increased K+ efflux. Both effects cause hyperpolarization and inhibition of the postsynaptic neuron.

Glycine - It is a neurotransmitter responsible for direct inhibition of synapses (postsynaptic inhibition). - It is secreted by interneurons located in certain regions of the brain stem and spinal cord. - Glycine exerts its inhibitory effect by increasing Cl- conductance (Cl- flow currents) through a ligand - gated Cl- channel in the postsynaptic membrane.

Neuropeptides - Several families of peptides with relatively high molecular weight whose actions are usually slow and prolonged. - Synthesized in the soma of neurons rather than in the synaptic terminal - Stored within secretory vesicles that are then transported to the nerve terminals by the mechanism of “axonal streaming” of the axon cytoplasm. - Examples: Substance P, Neuropeptide Y.

Change in the number of postsynaptic receptors 4 Prolonged effect on calcium channels 2 3 1

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