1. The Physiology of Neurotransmitters
AP 151
The Physiology of Neurotransmitters
An excellent resource for this unit can be found at the following link:

2. 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

3. Synapses Axodendritic synapse Axosomatic synapse Axoaxonic synapse
Figure 11.17

4. 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.

5. 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

6. 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.

7. 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.

8. Synaptic Delay Synaptic Fatigue
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

9. 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.

10. 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

11. 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

12. 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

13. 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

14. Summation
Figure 11.21

16. Neurotransmitters
Chemicals used for neuronal communication with the body and the brain
50 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

17. 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

18. 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

19. Channel-Linked Receptors
Figure 11.23a

20. 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

21. 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

22. G Protein-Linked Receptors: Mechanism
Figure 11.23b

23. 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 rxn’s)
Phosphorylate channel proteins
Activate genes and induce protein synthesis!!

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

25. 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

26. Comparison of Somatic and Autonomic Systems
Figure 14.2

27. 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

28. 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.

29. Neurotransmitters: Monoamines/Biogenic Amines
Include:
Catecholamines – dopamine, norepinephrine (NE), and epinephrine (EP)
Indolamines – serotonin and histamine
Broadly distributed in the brain
Cats. are important sympathetic NTs
Play roles in emotional behaviors and our biological clock

30. Synthesis of Catecholamines
AA tyrosine is parent cpd
Enzymes present in the cell determine length of biosynthetic pathway
Norepinephrine and dopamine are synthe-sized in axonal terminals
Epinephrine is released by the adrenal medulla as a hormone
Figure 11.22

31. 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

32. BIOGENIC AMINES: 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 addictive-
drugs and behaviors. For example,
Release enhanced by amphetamines
Reuptake blocked by cocaine
Deficient in Parkinson’s disease
Receptor abnormalities have been linked to development of schizo-
phrenia

33. 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
SSRI’s = selective serotonin reuptake inhibitors
Include drugs such as Prozac, Celexa, Lexapro, Zoloft
Ecstasy targets serotonin receptors

34. Neurotransmitters: Amino Acids
Include:
GABA – Gamma ()-aminobutyric acid
Glycine
Aspartate
Glutamate
Found only in the CNS

35. 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!)

36. Amino Acids Inhibitory Amino Acids 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

37. 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

38. 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 cerebro-vasculature
Some types of male impotence treated by stimulating NO release (Viagra)
Viagra  NO release  smooth muscle relaxation  increased blood flow  erection
Can’t be taken when other pills to dilate coronary b.v. taken

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

40. 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)