1. Neurotransmitters

2. Review of Neurotransmitters

3. Neurotransmitters
Neurotransmitter – a chemical that transmits information from one neuron to another.
Examples:
Acetylcholine
Transmits information from somatic motor neurons to muscle
Transmits information within the CNS
Transmits information in autonomic nervous system (ANS).
Many others

4. Acetylcholine (ACh)
ACh is a neurotransmitter that can have different effects on different tissues.
In some cases, ACh is excitatory, and in other cases it is inhibitory, depending on the organ involved
How does this happen?

5. Two Types of Acetylcholine (Cholinergic) Receptors
Nicotinic ACh receptors
Can be stimulated by nicotine Found on the motor end plate of skeletal muscle cells, in autonomic ganglia, and in some parts of the CNS
Muscarinic ACh receptors
Can be stimulated by muscarine (from poisonous mushrooms)
Found in CNS and plasma membrane of smooth and cardiac muscles and glands innervated by autonomic motor neurons

6. How Does Acetylcholine Work?
Nicotinic
e.g. Skeletal muscle
ACETYLCHOLINE CAN BIND TO ITS RECEPTOR, WHICH IS ALSO AN ION CHANNEL
Notice that 2 acetylcholines must bind

7. Discovery and analysis of G proteins
MUSCARINIC Ach Receptors Require G-Proteins
Discovery and analysis of G proteins
1994 – Nobel Prize in Physiology or Medicine: Gilman and Rodbell
2012 – Nobel Prize in Chemistry

8. MUSCARINIC Ach Receptor Action
In the heart, K+ channels are opened by the beta-gamma complex, creating IPSPs (hyperpolarization) that slow the heart rate.
In the smooth muscles of the stomach, K+ channels are closed by the alpha subunit, producing EPSPs (depolarization) and the contraction of these muscles.
Binding of acetylcholine opens K+ channels in some tissues (IPSP) or closes K+ channels in others (EPSP).
Heart: K+ channels open, creating IPSPs  heart rate slowed
Smooth muscle: K+ channels close, creating EPSPs  smooth muscles contract (not shown)

9. Agonists and Antagonists
Agonists: drugs that can stimulate a receptor
Nicotine for nicotinic ACh receptors
Muscarine for muscarinic ACh receptors
Antagonists: drugs that inhibit a receptor
Atropine from plants, is an antagonist for muscarinic receptors. Decreases saliva production during surgery.
Curare (from plants) is an antagonist for nicotinic receptors. Clinically, curare is used as a muscle relaxant. Lethal in high doses; poison dart use, surgery.
Atropa belladonna
Curare Vine

10. Acetylcholinesterase (AChE)
AChE is an enzyme that inactivates ACh activity shortly after it binds to the receptor.
Hydrolyzes ACh into acetate and choline, which are taken back into the presynaptic cell for reuse.

11. Action of Acetylcholinesterase (AChE)

12. Monoamines as Neurotransmitters

13. Monoamine Neurotransmitters
Monoamines are regulatory molecules derived from amino acids.
CATECHOLAMINES: these are tyrosine derivatives: dopamine, norepinephrine, epinephrine. Bind to adrenergic receptors.
Norepinephrine is a neurotransmitter and hormone but epinephrine is primarily a hormone
tyrosine
tyrosine
Other monoamines: 2) SEROTONIN (derived from tryptophan)
3) Histamine (derived from histidine)

14. Norepinephrine as a neurotransmitter
Used in both the CNS and PNS
Sympathetic neurons use norepinephrine on smooth muscles, cardiac muscles, and glands.
Used by neurons of the CNS in brain regions associated with arousal
Amphetamines work by stimulating norepinephrine pathways in the brain.

15. Monoamine Action and Inactivation
KNOW THIS PATHWAY

16. Monoamines use G-protein Coupled Channels
THIS IS A SECOND MESSENGER SYSTEM
This is a BETA ADRENERGIC receptor.
Sympathetic neurons of the PNS use norepinephrine as their neurotransmitter.

17. Serotonin as a neurotransmitter
Used by neurons in the raphe nuclei (middle region of brainstem)
Implicated in mood, behavior, appetite, and cerebral circulation
The drug LSD and other hallucinogenic drugs may be agonists.
Serotonin specific reuptake inhibitors (SSRIs) are used to treat depression.
Prozac, Paxil, Zoloft
Over a dozen known receptors allow for diversity of serotonin function.
Different drugs that target specific serotonin receptors could be given for anxiety, appetite control, and migraine headaches.
serotonin

18. Dopamine as a neurotransmitter
Neurons that use dopamine (dopaminergic neurons) are highly concentrated in the midbrain in two main areas:
Nigrostriatal dopamine system: involved in motor control
Mesolimbic dopamine system: involved in emotional reward
Nigrostriatal – axons coming from substantia nigra --> basal ganglia
Mesolimbic – axons coming from vental tegmental area  nucleus accumbens and prefrontal cortex
dopamine

19. Nigrostriatal dopamine system: (motor)
Parkinson disease is caused by degeneration of these neurons.
Patients are treated with L-dopa and monoaminoxidase inhibitors
Activates the substantia nigra brain region.
dopamine

20. Mesolimbic dopamine system
involved in emotional reward.
Schizophrenia is associated with too much dopamine.
Dopamine antagonists are used to treat schizophrenia
Activates the limbic system.
Associated with addictions to nicotine, alcohol, other drugs
dopamine

21. Abused because it elevates energy/mood Crosses the blood-brain barrier
Cocaine
Abused because it elevates energy/mood
Crosses the blood-brain barrier
In mesolimbic reward system, it is a triple-reuptake inhibitor:
Blocks reuptake of dopamine
Blocks reuptake of serotonin
Blocks reuptake of norepinephrine
Danger:
Blocks Na+ ion channels
Raises heart rate/blood pressure
Increase risk of stroke, seizure

22. Other Neurotransmitters

23. Amino acids as NTs Excitatory NT – glutamate and aspartate
Glutamate – major excitatory neurotransmitter
Produces EPSPs in 80% of synapses in cortex
Constitutes major energy use in the brain
Involved in memory
Astrocytes take glutamate from the synaptic cleft to maintain homeostasis
glutamate

24. NMDA and AMPA receptors work together in memory storage.
Glutamate Receptors
All glutamate receptors also serve as ion channels (named according to the molecules they bind)
NMDA receptors
AMPA receptors
Kainate receptors
NMDA and AMPA receptors work together in memory storage.

25. Inhibitory NTs
Glycine
produces IPSPs
Binding of glycine opens Cl− channels, causing an influx of Cl−.
Makes it harder to reach threshold
Important in the spinal cord for regulating skeletal muscle movement.
This allows antagonistic muscle groups to relax while others are contracting
(e.g. biceps relax while triceps contract).

26. Glycine, cont
Also important in the relaxation of the diaphragm, which is necessary for breathing
The poison strychnine blocks glycine receptors, which produces death by asphyxiation.

27. GABA , another inhibitory neurotransmitter
Gamma-aminobutyric acid
most common neurotransmitter in the brain
used by 1/3 of the brain’s neurons.
inhibitory, opens Cl− channels
involved in motor control. Degeneration of GABA-secreting neurons in the cerebellum results in Huntington disease.

28. GABA receptors contain a chloride channel

29. Polypeptides as neurotransmitters
Also Called Neuropeptides
Many chemicals used as hormones or paracrine signals are also found in the brain acting as neurotransmitters.
CCK: involved in a feeling of satiety after a meal
Substance P: mediates sensations of pain in certain neural pathways in the brain

30. Endogenous Opioids
Asian opium poppy plant (Papaver somniferum)
Opioid receptors bind drugs such as opium and morphine, resulting in pain relief.
Endogenous opioids are polypeptides produced by the brain and pituitary gland; includes enkephalin, β-endorphin, and dynorphin
Opioids also produce euphoria so they may mediate reward pathways;
may be related to feeling of well-being after exercise

31. Neuropeptide Y
Most abundant neuropeptide in the brain
Plays a role in stress response, circadian rhythms, and cardiovascular control.
Works by inhibiting the release of glutamate in the hippocampus (excess glutamate (excitatory) release can cause convulsions)
Also stimulates hunger.

32. Endocannabinoids
Neurotransmitters - bind to the same receptors that bind to the active ingredient in marijuana (THC)
They have effects similar to that of THC
Short fatty acids produced in the dendrites and cell bodies and released directly from the plasma membrane (no vesicle)
Retrograde neurotransmitters released from the postsynaptic neuron; inhibit further neurotransmitter release from the presynaptic axon

33. Nitric Oxide
Nitric oxide (not nitrous oxide laughing gas)
A gas produced by some neurons in the CNS and PNS from the amino acid L-arginine
Diffuses across the presynaptic axon plasma membrane (no vesicle)
Diffuses into the target cell and activates the production of cGMP as a second messenger
Causes blood vessel dilation (Viagra works by stimulating the action of nitric oxide) and helps kill bacteria
May also act as a retrograde NT

34. Carbon Monoxide (CO)
Another gas used as a neurotransmitter
Also activates the production of cGMP in target cells
May promote sensory adaptation in olfactory neurons

35. ATP & Adenosine as NTs
Used as cotransmitters released via vesicles with another neurotransmitter
Classsified chemically as purines; bind to purinergic receptors
P1 receptor for ATP
P2 receptor for adenosine
Released with norepinephrine to stimulate blood vessel constriction and with ACh to stimulate intestinal contraction
Released by non-neural cells; act as paracrine regulators in blood clotting, taste, and pain

36. Synaptic Integration

37. Convergence
neuron receives input from several neurons
incoming impulses represent information from different types of sensory receptors
allows nervous system to collect, process, and respond to information
makes it possible for a neuron to sum impulses from different sources

38. Divergence
one neuron sends impulses to several neurons
can amplify an impulse
impulse from a single neuron in CNS may be amplified to activate enough motor units needed for muscle contraction

39. Summation: Spatial
Spatial summation occurs due to convergence of signals onto a single postsynaptic neuron.
All of the EPSPs and IPSPs are added together at the axon hillock.

40. Summation: Temporal
Temporal summation is due to successive waves of neurotransmitter release that add together at the initial segment of the axon.

41. 2 types of synaptic inhibition:
Postsynaptic inhibition is produced by inhibitory neurotransmitters such as glycine (spinal cord) and GABA (brain).
Hyperpolarizes the postsynaptic neuron and makes it less likely to reach threshold voltage at the axon hillock
Presynaptic inhibition is when an axoaxonic synapse sends GABA (or another inhibitory NT) that slows down the impulse before it reaches the terminal bouton. (inactivates Ca2+ channels)
EXAMPLE: Opiates  depolarize axon  inactivates Ca2+ channel  inhibits release of Substance P

42. Synaptic Plasticity
Synaptic plasticity – the ability of synapses to change in response to activity.
Synaptic plasticity involves enlargement or shrinkage of dendritic spines

43. Synaptic Plasticity: LTP
If repeated use increases synaptic transmission:
Promotes long term potentiation – when repeated stimulation enhances (potentiates) excitability
Due to Insertion of AMPA receptors
A mechanism of learning: frequent use of a neural pathway  AMPA receptors  LTP
Happens in hippocampus
Glutamate is neurotransmitter

44. SYNAPTIC CHANGES IN MEMORY
Glutamate binds to NMDA receptor
Causes Ca2+ to diffuse into the cell,
Ca2+ binds to Calmodulin  activates a 2nd messenger system.
LTP: long-term potentiation induced, genes activated by transcription factors.

45. NMDA AND AMPA RECEPTORS
NMDA Receptors –
In rats with enhanced NMDA receptor expression  smarter in studies of navigating a maze
AMPA Receptors –
Increased numbers in LTP

46. Long Term Depression
If repeated use decreases synaptic transmission
Promotes long term depression - when repeated use decreases excitability
Reduces their efficacy
Due to removal of AMPA receptors from postsynaptic membrane
homeostasis
Also important for learning

47. Long Term Depression
Endocannabinoids act as retrograde neurotransmitters  suppress release of neurotransmitters from presynaptic membrane
EXAMPLE: Short term: “depolarization-induced suppression of inhibition” (DSI):
1. depolarization  endocannabinoids
2. endocannabinoids  presynaptic neuron
3. suppress release of GABA (which would otherwise be inhibitory)

48. Both LTP and LTD depend on a rise in calcium ion concentration within the postsynaptic neuron
Rapid rise leads to LTP
Smaller but prolonged rise leads to LTD