1. Neuropharmacology (PHRM 512)
East West University
Department of Pharmacy
Spring 2014
Saquiba Yesmine, PhD

2. Cranial nerves and their distributions
Somatic Parts
Cranial nerves and their distributions

3. Visceral Motor Neurons
Visceral motor neurons arise from cells in lateral regions of spinal cord and send processes out anteriorly. These processes synapse with other cells, usually other visceral motor neurons
The visceral motor neurons located in the spinal cord are referred to as preganglionic motor neurons and their axons are called preganglionic fibers; the visceral motor neurons located outside the CNS are referred to as postganglionic motor neurons and their axons are called postganglionic fibers.

4. Classification of Visceral Motor Nerves
Visceral motor components associated with spinal levels T1 to L2 are termed sympathetic.
the sympathetic system innervates structures in peripheral regions of the body and viscera;
Visceral motor components in cranial and sacral regions, on either side of the sympathetic region, are termed parasympathetic:
the parasympathetic system is more restricted to innervation of the viscera only.

5. Divisions of the Peripheral Autonomic System
On the efferent side, the autonomic nervous system consists of two large divisions: (1) the sympathetic or thoracolumbar outflow and (2) the parasympathetic or craniosacral outflow.
The neurotransmitter of all preganglionic autonomic fibers, most postganglionic parasympathetic fibers, and a few postganglionic sympathetic fibers is acetylcholine (ACh). Some postganglionic parasympathetic nerves use nitric oxide (NO) as a neurotransmitter; nerves that release NO are referred to as nitrergic.

6. Divisions of the Peripheral Autonomic System
The adrenergic fibers comprise the majority of the postganglionic sympathetic fibers; here the primary transmitter is norepinephrine (NE, noradrenaline, levarterenol).
Not all the transmitter(s) of the primary afferent fibers, such as those from the mechano- and chemoreceptors of the carotid body and aortic arch, have been identified conclusively. Substance P and glutamate are thought to mediate many afferent impulses; both are present in high concentrations in the dorsal spinal cord

7. Sympathetic Nerves

8. Parasympathetic Nerves

9. Chemical Mediators

10. Parasympathetic Nervous system
The tenth (vagus) cranial nerve arises in the medulla and contains preganglionic fibers, most of which do not synapse until they reach the many small ganglia lying directly on or in the viscera of the thorax and abdomen.
In the intestinal wall, the vagal fibers terminate around ganglion cells in the myenteric and submucosal plexuses. Thus, in the parasympathetic branch of the autonomic nervous system, preganglionic fibers are very long, whereas postganglionic fibers are very short.
The vagus nerve also carries a far greater number of afferent fibers (but apparently no pain fibers) from the viscera into the medulla; the cell bodies of these fibers lie mainly in the nodose ganglion

11. Enteric Nervous System
Mixing, propulsion, and absorption of nutrients in the GI tract are controlled locally through a restricted part of the peripheral nervous system called the enteric nervous system (ENS).
The ENS is involved in sensorimotor control. Thus contains both afferent sensory neurons and motor nerves and interneurons organized principally into two nerve plexuses: the myenteric (Auerbach's) plexus and the submucosal (Meissner's) plexus.
The myenteric plexus, located between the longitudinal and circular muscle layers, plays an important role in the contraction and relaxation of GI smooth muscle.
The submucosal plexus is involved with secretory and absorptive functions of the GI epithelium, local blood flow, and neuroimmune activities

12. Differences between Autonomic and Somatic Nerves
The efferent nerves of the involuntary system supply all innervated structures of the body.
Voluntary system such as, skeletal muscle is served by somatic nerves.
Synaptic junctions in the autonomic nerves occur in ganglia that are entirely outside the cerebrospinal axis. These ganglia are small but complex structures that contain axodendritic synapses between preganglionic and postganglionic neurons.
Somatic nerves contain no peripheral ganglia, and the synapses are located entirely within the cerebrospinal axis.

13. Differences between Autonomic and Somatic Nerves
Many autonomic nerves form extensive peripheral plexuses.
Such networks are absent from the somatic system.
motor nerves to skeletal muscles are myelinated.
Postganglionic autonomic nerves generally are nonmyelinated.
When the spinal efferent nerves are interrupted, the denervated skeletal muscles lack myogenic tone, are paralyzed, and atrophy,
Smooth muscles and glands generally retain some level of spontaneous activity independent of intact innervation.

14. Differences between Autonomic and Somatic Nerves
The parasympathetic distribution is much more limited. Furthermore, the sympathetic fibers ramify to a much greater extent.
A preganglionic sympathetic fiber may traverse a considerable distance of the sympathetic chain and pass through several ganglia before it finally synapses with a postganglionic neuron.
Terminals make contact with a large number of postganglionic neurons. In some ganglia, the ratio of preganglionic axons to ganglion cells may be 1:20 or more.

15. Differences between Autonomic and Somatic Nerves
The parasympathetic system, in contrast, has terminal ganglia very near or within the organs innervated.
In some organs, a 1:1 relationship between the number of preganglionic and postganglionic fibers has been suggested, but the ratio of preganglionic vagal fibers to ganglion cells in the myenteric plexus has been estimated as 1:8000.
Exception: The cell bodies of somatic motor neurons reside in the ventral horn of the spinal cord; the axon divides into many branches, each of which innervates a single muscle fiber, so more than 100 muscle fibers may be supplied by one motor neuron to form a motor unit.

16. Definitions Neurotransmitter -
the compound which is synthesized and released presynaptically and mimic the action of the endogenous compound that is released on nerve stimulation.
Neuromodulator
The compound which has no intrinsic activity but is active only in the face of ongoing synaptic activity, where it can modulate transmission either pre- or postsynaptically (e.g. changes in conductance or membrane potential). Substances such as CO and ammonia, arising from active neurons or glia, are potential modulators acting through non-synaptic actions.
Neurohormone
The compound which has intrinsic activity and can be released from both neuronal and nonneuronal cells and travels in the circulation to act at a site distant from its release site.

17. Neurotransmitter, Neuromodulator & Neurohormone?
dopamine
Neurotransmitter?
Neurohormone?
Dopamine is released in the synapses at striatum of brain and stimulate post synaptic neuron
Dopamine is released from the hypothalamus and travels through the hypophyseal circulation to the pituitary, where it inhibits the release of prolactin.
Serotonin is a neurotransmitter in the raphe nuclei, but at the facial motor nucleus it acts primarily as a neuromodulator and secondarily as a transmitter.
Most peptides, with their multiple activities in the brain and gut, are generally considered to be neuromodulators, but substance P fulfills the criteria of a neurotransmitter at sensory afferents to the dorsal horn of the spinal cord.

18. Neurotransmitter, Neuromodulator & Neurohormone?
It is difficult to classify neuroactive compounds as neuro-transmitter, neuromodulator or neurohormone until the site of action and the activity of the agent were specified.
It is better to describe the activity of a neuroactive agent at a specified site rather than attempt to give a profitless definition.

19. Differences between Autonomic and Somatic Nerves

20. Ganglion and Nucleus
Neurons exhibit the cytological characteristics of highly active secretory cells.
Large nuclei, large amounts of smooth and rough endoplasmic reticulum; and frequent clusters of specialized smooth endoplasmic reticulum and Golgi complex, in which secretory products of the cell are packaged into membrane-bound organelles for transport from the perikaryon to the axon or dendrites.
Neurons and their cellular extensions are rich in microtubules, which support the complex cellular structure and assist in the reciprocal transport of essential macromolecules and organelles between the cell body and distant axon or dendrites.

21. Synapse

22. Ganglion and Nucleus A ganglion is simply a swelling.
In a nerve, ganglion means a swelling on the nerve.
It is used to mean the swelling caused by a collection of nerve cell bodies on a peripheral nerve: cell bodies take up more space than fibres, so a collection of cell bodies will cause a swelling.
A nucleus is an aggregation of cell bodies in the CNS
(exception: basal ganglia of the brain)
Ganglia are peripheral;
Nuclei are central.

23. Ganglion and Nucleus
Ganglia (singular ganglion), or neural ganglia, are structures located outside the central nervous system made of concentration of neuron bodies.
Examples of neural ganglia are the ganglia that concentrate cell bodies of sensory neurons in the dorsal roots of the spinal cord and the ganglia of the myenteric plexus responsible for the peristaltic movements of the digestive tube.
In the central nervous system (CNS) the concentrations of neuron bodies are called nuclei and not ganglia.
(for example, beside the spinal column or near viscera)
Ganglia are peripheral;
Nuclei are central.

24. 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 24

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

26. Synapses Axodendritic synapse Axosomatic synapse Axoaxonic synapse
Figure 11.17 26

27. 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 27

28. Electrical Synapses
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. 28

29. Chemical Synapses Most common type
Cells not directly coupled as in electrical synapses
Components
Presynaptic terminal
Synaptic cleft
Postsynaptic membrane (PSM)
Chemical neurotransmitters (NT’s) released by presynaptic neuron
NT binds to receptor on PSM 29

30. Chemical Synapse
At rest, the interior of the typical mammalian axon is 70 mV negative to the exterior.
The resting potential is essentially a diffusion potential based chiefly on the 40 times higher concentration of K+ in the axoplasm as compared with the extracellular fluid and the relatively high permeability of the resting axonal membrane to K+.
Na+ and Cl– are present in higher concentrations in the extracellular fluid than in the axoplasm, but the axonal membrane at rest is considerably less permeable to these ions.
These ionic gradients are maintained by an energy-dependent active transport mechanism, the Na+, K+-ATPase 30

31. Chemical Synapse 31

32. Chemical Synapse
In response to depolarization to a threshold level, an action potential or nerve impulse is initiated.
The action potential consists of two phases. Following a small gating current resulting from depolarization inducing an open conformation of the channel, the initial phase is caused by a rapid increase in the permeability of Na+ through voltage- sensitive Na+ channels.
The result is inward movement of Na+ and a rapid depolarization from the resting potential, which continues to a positive overshoot.
The second phase results from the rapid inactivation of the Na+ channel and the delayed opening of a K+ channel, which permits outward movement of K+ to terminate the depolarization. 32

33. Chemical Synapse Events at a chemical synapse
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. 33

34. Chemical Synapse Events at a chemical synapse
5. NT diffuses across synaptic cleft and binds to receptor on postsynaptic membrane
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. 34

35. Chemical Synapse
Events at a chemical synapse
Note:
For each nerve impulse reaching the presynaptic terminal, about 300 vesicles are emptied into the cleft. Each vesicle contains about 3000 molecules. 35

36. 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. 36

37. Synaptic Delay
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, resynthesis and transport of recycled NT my be unable to keep pace with demand for NT
Synapse remains inactive until NT has been replenished 37

38. 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. 38

39. 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 39

40. 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 40

41. 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 neuron’s ability to produce an action potential 41

42. 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 42

43. Summation
Figure 11.21 43

44. Major Neurotransmitters in the Body
Role in the Body
Acetylcholine
A neurotransmitter used by the spinal cord neurons to control muscles and by many neurons in the brain to regulate memory. In most instances, acetylcholine is excitatory.
Dopamine
The neurotransmitter that produces feelings of pleasure when released by the brain reward system. Dopamine has multiple functions depending on where in the brain it acts. It is usually inhibitory.
GABA
(gamma-aminobutyric acid)
The major inhibitory neurotransmitter in the brain.
Glutamate
The most common excitatory neurotransmitter in the brain.
Glycine
A neurotransmitter used mainly by neurons in the spinal cord. It probably always acts as an inhibitory neurotransmitter.
Norepinephrine
Norepinephrine acts as a neurotransmitter and a hormone. In the peripheral nervous system, it is part of the flight-or-flight response. In the brain, it acts as a neurotransmitter regulating normal brain processes. Norepinephrine is usually excitatory, but is inhibitory in a few brain areas.
Serotonin
A neurotransmitter involved in many functions including mood, appetite, and sensory perception. In the spinal cord, serotonin is inhibitory in pain pathways.
NIH Publication No

45. Cholinergic Transmission

46. Cell Signaling and Synaptic Transmission
Most cell-to-cell communication in the CNS involves chemical transmission. Chemical transmission requires several discreet specializations:
Transmitter synthesis. Small molecules like ACh and NE are synthesized in nerve terminals; peptides are synthesized in cell bodies and transported to nerve terminals.
Transmitter storage. Synaptic vesicles store transmitters, often in association with various proteins and frequently with ATP.
Transmitter release. Release of transmitter occurs by exocytosis. Depolarization results in an influx of Ca2+, which in turn appears to bind to proteins called synaptotagmins. An active zone is established to which vesicles dock and then fuse with scaffolding proteins on the presynaptic membrane. After fusing with the membrane and exocytotic release of their contents, synaptic vesicle proteins are recycled through endocytosis.

47. Cell Signaling and Synaptic Transmission
Transmitter recognition. Receptors exist on postsynaptic cells, which recognize the transmitter. Binding of a neurotransmitter to its receptor initiates a signal transduction event, as previously described.
Termination of action. A variety of mechanisms terminate the action of synaptically released transmitter, including hydrolysis (for acetylcholine and peptides) and reuptake into neurons by specific transporters such as NET, SERT, and DAT (for NE, 5-HT, DA). Inhibitors of NET, SERT, and DAT increase the dwell time and thus the effect of those transmitters in the synaptic cleft. Inhibitors of the uptake of NE and/or 5-HT are used to treat depression and other behavioral disorders

48. Cholinergic Transmission
Choline is transported into the presynaptic nerve terminal by a sodium-dependent carrier (A).
This transport can be inhibited by hemicholinium drugs.
ACh is transported into the storage vesicle by a second carrier (B) that can be inhibited by vesamicol.
Release of transmitter occurs when voltage-sensitive calcium channels in the terminal membrane are opened, allowing an influx of calcium.
The resulting increase in intracellular calcium causes fusion of vesicles with the surface membrane and exocytotic expulsion of ACh into the junctional cleft. This step is blocked by botulinum toxin.
Acetylcholine's action is terminated by metabolism by the enzyme acetylcholinesterase.
Receptors on the presynaptic nerve ending regulate transmitter release.

49. Cholinergic Transmission
The terminals of cholinergic neurons contain large numbers of small membrane-bound vesicles concentrated near the synaptic portion of the cell membrane as well as a smaller number of large dense-cored vesicles located farther from the synaptic membrane.
The large vesicles contain a high concentration of peptide cotransmitters, while the smaller clear vesicles contain most of the acetylcholine. Vesicles are initially synthesized in the neuron soma and transported to the terminal. They may also be recycled several times within the terminal.
Acetylcholine is synthesized in the cytoplasm from acetyl-CoA and choline through the catalytic action of the enzyme choline acetyltransferase (ChAT). Acetyl-CoA is synthesized in mitochondria, which are present in large numbers in the nerve ending.
Choline is transported from the extracellular fluid into the neuron terminal by a sodium-dependent membrane carrier (carrier A). This carrier can be blocked by a group of drugs called hemicholiniums. Once synthesized, acetylcholine is transported from the cytoplasm into the vesicles by an antiporter that removes protons (carrier B). This transporter can be blocked by vesamicol.
Acetylcholine synthesis is a rapid process capable of supporting a very high rate of transmitter release. Storage of acetylcholine is accomplished by the packaging of "quanta" of acetylcholine molecules (usually 1000–50,000 molecules in each vesicle).

50. Continuation of Cholinergic Transmission
Release of transmitter is dependent on extracellular calcium and occurs when an action potential reaches the terminal and triggers sufficient influx of calcium ions.
The increased Ca2+ concentration "destabilizes" the storage vesicles by interacting with special proteins associated with the vesicular membrane. Fusion of the vesicular membranes with the terminal membrane occurs through the interaction of vesicular proteins (vesicle-associated membrane proteins, VAMPs), eg,
synaptotagmin and synaptobrevin, with several proteins of the terminal membrane (synaptosomeassociated proteins, SNAPs), eg, SNAP-25 and syntaxin.
Fusion of the membranes results in exocytotic expulsion of — in the case of somatic motor nerves—several hundred quanta of acetylcholine into the synaptic cleft.
The amount of transmitter released by one depolarization of an autonomic postganglionic nerve terminal is probably smaller. In addition to acetylcholine, several cotransmitters will be released at the same time.
The ACh vesicle release process is blocked by botulinum toxin through the enzymatic removal of two amino acids from one or more of the fusion proteins.

51. Continuation of Cholinergic Transmission
After release from the presynaptic terminal, acetylcholine molecules may bind to and activate an acetylcholine receptor (cholinoceptor). Eventually (and usually very rapidly), all of the acetylcholine released will diffuse within range of an acetylcholinesterase (AChE) molecule.
AChE very efficiently splits acetylcholine into choline and acetate and terminates the action of the transmitter. Most cholinergic synapses are richly supplied with acetylcholinesterase; the half-life of acetylcholine in the synapse is therefore very short.

52. Adrenergic Transmission

53. Adrenergic Transmission
Tyrosine is transported into the noradrenergic ending by a sodium-dependent carrier (A).
Tyrosine is converted to dopamine, which is transported into the vesicle by a
carrier (B) that can be blocked by reserpine.
The same carrier transports norepinephrine (NE) and several other amines into these granules.
Dopamine is converted to NE in the vesicle by dopamine-hydroxylase.
Release of transmitter occurs when an action potential opens voltage-sensitive
calcium channels and increases intracellular calcium. Fusion of vesicles with the surface membrane results in expulsion of norepinephrine, cotransmitters, and dopamine-hydroxylase.
Adrenergic Transmission

54. Adrenergic Transmission
Adrenergic neurons transport a precursor molecule into the nerve ending, then
synthesize the catecholamine transmitter, and finally store it in membrane bound vesicles.
In most sympathetic postganglionic neurons, norepinephrine is the final product.
In the adrenal medulla and certain areas of the brain, norepinephrine is further converted to epinephrine.
Synthesis terminates with dopamine in the dopaminergic neurons of the central nervous system.
Several important processes in these nerve terminals are potential sites of drug action.

55. One of these, the conversion of tyrosine to dopa, is the rate-limiting step in
catecholamine transmitter synthesis. It can be inhibited by the tyrosine analog metyrosine. A high-affinity carrier for catecholamines located in the wall of the storage vesicle can be inhibited by the reserpine alkaloids.
Another carrier transports norepinephrine and similar molecules into the cell cytoplasm (reuptake 1). It can be inhibited by cocaine and tricyclic antidepressant drugs, resulting in an increase of transmitter activity in the synaptic cleft.

56. Continuation of Adrenergic Transmission
Release of the vesicular transmitter store from noradrenergic nerve endings is similar to the calcium-dependent process described above for cholinergic terminals.
In addition to the primary transmitter (norepinephrine), ATP, dopamine- -hydroxylase, and peptide cotransmitters are also released into the synaptic cleft.
Indirectly acting sympathomimetics—eg, tyramine and amphetamines—are capable of releasing stored transmitter from noradrenergic nerve endings.
These drugs are taken up into noradrenergic nerve endings by uptake 1.
In the nerve ending, they may displace norepinephrine from storage vesicles, inhibit monoamine oxidase, and have other effects that result in increased
norepinephrine activity in the synapse.

57. Biosynthesis of catecholamines
The rate-limiting step, conversion of tyrosine to dopa,
It can be inhibited by metyrosine (a-methyltyrosine).
The alternative pathways shown by the dashed arrows have not been found to be of physiologic significance in humans.
However, tyramine and octopamine may accumulate in patients treated with monoamine oxidase inhibitors.

59. Metabolism of catecholamines by catechol-O-methyltransferase (COMT) and monoamine oxidase (MAO).
Norepinephrine and epinephrine
metabolized by -
MAO and COMT