PHARM DISC 2

1. Compare and contrast classic, retrograde and volume neurotransmission. Note any specific neurotransmitters that are produced each way.

2. Provide a brief overview of signal transduction cascades.

3. Based on any required lecture material in Module 1, write two possible quiz/exam questions. You may write multiple choice questions or short essay questions. Please include the answer, a rationale, and the source. The questions should be appropriately challenging and must be original (you may not use questions that are on NEI’s website or located online).

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Second level
Third level
Fourth level
Fifth level
*
Stahl’s Essential Psychopharmacology, 3rd edition, 2008, copyright NEI. All rights reserved.

Contributor: Stephen M. Stahl, M.D.

Basic Neuroscience

To review principles of chemical neurotransmission
To explain G-protein systems as targets of psychotropic drugs
Objectives*

*
*

The Nervous System

Nervous System
Anatomically
CNS: central nervous system
Brain
Spinal Cord

PNS – peripheral nervous system
Connects CNS to rest of the body (organ function: gut, heart, urinary bladder, muscle etc)
Includes cranial and spinal nerves

Functionally

Somatic nervous system –
processing of sensory information (conscious and unconscious)
control of striated muscles (movement)
Autonomic nervous system –
control of visceral activities including cardiovascular, digestion, temp, weight and reproduction.
Composed of sympathetic and parasympathetic

Lobes of the cerebral cortex*
*

*
Folds allow for greater surface area which fits more cortex into a smaller space. Used as anatomical landmarks.
Gyri- ridges
Sulci- depressions or groves
Frontal lobe- prefrontal cortex: executive function (personality,planning, judgement, decision making, etc). Dorsolateral prefrontal: attention, concentration, working memory, management of retrograde memory recall and mood Orbital cortex: emotional reaction to environmental situations. Primary motor cortex (precentral gyrus): all voluntary movement. Premotor and supplementary motor areas: planning and control of movement. Broca’s area – expressive speech.
Parietal lobe- primary somatosensory cortex (postcentral gyrus): receives most direct and least processed information then sends it to secondary areas. Somatosensory association area: integration of information. Angular gyrus: visual and auditory information converge
Temporal lobe- primary auditory cortex and auditory association cortex. Visual association area. Wernicke’s area: language understanding. Emotion and memory circuitry (limbic system)
Insula- viseral/sensory area
Occipital lobe- primary visual cortex and secondary visual cortex
Neuroscience, 9-15-2009

Cellular Level
Neurons
Electrically and chemically excitable
Dendrite, cell body, axon
Glia
Astrocytes: structure, scaffolding, BBB, phagocytosis, removal of excess NT and toxin
Oligodendrocytes: myelin
Microglia: phagocytosis, release cytokines (immune response), response to damage

Neurotransmission
*

dendrites
dendritic spines
cell body (soma)
axon
en passant
presynaptic
axon terminals
presynaptic
axon terminals
General Structure of the Neuron*
1-1A

*
• Anatomically, neurons are set up in a wiring network to deliver information to each other through synapses in mostly a one direction network (anterograde- axon of first neuron to dendrite, soma, or axon of second neuron)
• Synapses can occur on many places of the neuron (i.e., dendrites, soma)
• All neurons have a cell body (Soma) and it receives information from other neurons through dendrites
• While the anatomical system fosters neurotransmission, it’s the chemical messengers who play a critical role in the process
• Electrical impulses convert to chemical signals (i.e., excitation-secretion coupling) at the synapses in this process; however, the chemical messengers can convert back to an electrical impulse or trigger a cascade of more chemical messengers as the transmission process unfolds
• Technically communication can travel in more than one direction and/or outside of the synapses (i.e., retrograde neurotransmission, volume neurotransmission, diffusion)
• Signal transduction cascades have two primary targets: phosphoproteins and genes.
• Phosphoproteins are a latter part of the messaging cascade and assist with gene expression through enzyme systems
• It is these gene expressions that can modify behavior but behavior can also modify genes through socio-environmental regulation of proteins which affect gene expression

Another General Structure of the Neuron
dendritic spines
dendrites
cell body (soma)
axon
dendritic
tree
1-1B

*
1-1B

Classical synaptic
Retrograde
Volume (nonsynaptic) neurotransmission
Three Types of Neurotransmission*

*
*
Synaptic transmission: rapid and point-to-point, transmission from presynaptic terminal to postsynaptic cell
Retrograde signaling: involves activity-dependent release of a substance from the postsynaptic cell which then affects release of transmitter from the presynaptic terminal
Volume transmission is slower, involves release of neurotransmitter at a distance from its target sites which are extrasynaptic
receptors

Classical Synaptic Neurotransmission*
reception
Integration/chemical
encoding
electrical encoding
signal propagation
signal transduction

A
B
3-1
neurotransmitter
light
hormone
drug
nerve impulse
neurotransmitter

*
Synaptic transmission involves release of a neurotransmitter from the presynaptic nerve ending and its binding to a postsynaptic receptor to produce a change in function (excitation or inhibition) in the postsynaptic neuron. Remember, though communication within a neuron can be electrical, communication between neurons is chemical.

3-3
Classical Neurotransmission Versus Retrograde Neurotransmission
classical
A
A
retrograde
CB1 receptor
cGMP
targets
EC
EC
NGF
(nerve growth
factor)
NGF
NGF
NGF
NGF
NO
(nitric oxide)

*
In retrograde transmission: The Neurotransmitter is released from the postsynaptic cell and binds to receptors on the terminal of the presynaptic neuron

3-4
Classical Neurotransmission Versus Volume Neurotransmission*

*
In volume neurotransmission: There is no tight junction between presynaptic terminal and postsynaptic cell—it occurs without a synapse.. Release is at sites distant to the target cell. Receptors are extrasynaptic

3-5
Volume Neurotransmission*
A
B
DA neuron
D1 receptors
synaptic neurotransmission at 1 and diffusion to 2 and 3
3
1
2

G-protein linked neurotransmission
Ion-channel linked neurotransmission
Hormones
Neurotrophins
Four Types of Signalling*

*
*
As we begin discussing signal transduction, make sure to check out the video under Optional resources in the course section to help you understand.

3-11
cell nucleus
First Messenger
membrane
Second Messenger
Third Messenger
Fourth Messenger/
Gene Expression
Four Types
of Signalling*
Ca++
ion channel linked
neurotrans-
mitter
CaMK
G-protein linked
neurotrans-mitter

A
CREB

P04
hormone

hormone
nuclear
receptor
complex

HRE
neurotrophin

Ras/
Raf/
MEK
ERK/RSK/
MAPK/
GSK3

genes

Activating a Third Messenger Kinase through Cyclic AMP*
3-17
first messenger –
neurotransmitter
second messenger
inactive
protein kinase
activation
third messenger-
active
protein kinase

*
This picture can be found on page 14 in your book and shows the activation of a thris messenger protein kinase. Prior to this- remember, there are four elements of the G-protein linked second messenger system. Can you name them? I’ll start you off—one of the elements is the G protein. Also, before this stage, the first messenger has already changed the receptor so it can bind to the G protein; and the G protein has changed it’s shape so it can then bind to an enzyme that will be able to synthesize that second messenger.

3-18
Activating a Third Messenger Phosphatase
through Calcium
1
first messenger –
neurotransmitter
2
second messenger
Ca++
inactive
calcineurin
2
3
third messenger –
active calcineurin
(phosphatase)

regulatory enzymes
3-19
Third Messenger Kinases put Phosphates on Critical Proteins*
third messenger-
kinase
voltage-gated ion channel
Ligand- gated ion channel
4
first messenger
1
second messenger
2
4
4
4
4
4

regulatory enzymes
voltage-gated ion channel
ligand- gated ion channel
third messenger –
active calcineurin
(phosphatase)
3-20
Third Messenger Phosphatases Undo what Kinases Create – Take Phosphates Off Critical Proteins*
4
4
4
1
first messenger –
neurotransmitter
2
second messenger
Ca++
inactive
calcineurin
2

first messenger
second messenger
inactive
protein kinase
activation
third messenger-
active
protein kinase
3-30
inactive TF
activated “early” TF

4
4
FOS –
fifth messenger
5
Signal Transduction
Leading to
Gene Expression*

Epigenetics*

Please read the Stahl article for further explanation
*

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