8. Ionotropic Receptors
8
1. Work very fast; important role in fast neurotransmission
2. Each is made of several subunits (together form the complete receptor)
3. At center of receptors is channel or pore to allow flow of neurotransmitter
4. At rest - receptor channels is closed
5. When neurotransmitter bind -- channel immediately opens
6. When ligand leaves binding site -- channel quickly closes
9.
10. Theory of Drug Action
Emil Fischer’s ‘Lock and Key’ Hypothesis (1890)
Every ‘lock’ has its own ‘key’
If the ‘key’ is not precise, the ‘lock’
does not open
The ‘drug’ is the key that has to fit the
target specifically and productively
11. Theory of Drug Action
Corollary of ‘Lock & Key’ Hypothesis
Does not explain why some ‘keys’ open doors partially? …… e.g., partial agonists or
antagonists
O
O
O
H O
OH
12. Theory of Drug Action
Daniel Koshland’s ‘Induced-Fit’ Hypothesis (1958)
At least two steps …… step 1 is initial binding and step 2 is a
change in structure of the receptor (and/or drug)
Receptor is flexible! …… can wrap around the drug
14. Drugs Associated with Neurotransmitters
Why do people have “drugs of choice”?
• Dopamine - amphetamines, cocaine, ETOH
• Serotonin - LSD, ETOH
• Endorphins - opioids, ETOH
• GABA - benzodiazepines, ETOH
• Glutamate –ETOH
• Acetylcholine - nicotine, ETOH
▹ Anandamide – Marijuana
15. Amino Acid NTs
▹ High concentration in brain (micromolar)
▹ Circuits
▸ Cortico-cortical
▸ Sensory-motor
▹ Point-to-point communication
▹ Consistently excitatory or inhibitory
▸ Mainly ionotropic receptors but do have metabotropic
receptors
▹ Fast acting, short duration (1-5 ms)
▹ Examples: Glutamate, Aspartate, GABA, Glycine
16. GABA and Glutamate
.
▹ Because they are
structurally very
similar, various drugs
affect the presence of
GLU and GABA in the
synaptic gap and
increase or decrease
action potentials.
17. Glutamate
▹ Principal excitatory NT
▹ Biosynthesized as byproduct of cell metabolism
▹ Removed by reuptake
▹ Elevated levels neurotoxic
▹ 4 receptor types
▸ NMDA
▸ AMPA
▸ Kainate
▸ mGluR - Metabotropic
Ionotropic
18. NMDA Binding Sites
▹ 4 outside cell
▸ Glutamate
▸ Glycine
⬩ Obligatory co-agonist
⬩ Inhibitory NT at its “own” receptor
▸ Zinc (inverse agonist)
▸ Polyamine (indirect agonist)
▹ 2 inside cell
▸ Magnesium (inverse agonist)
▸ PCP (inverse agonist)
“The specific subunit composition of each receptor
determines its overall pharmacological properties”
19. GABA (Gamma
Aminobutyric Acid)
• Principal Inhibitory NT
• Biosynthesis:
• Removed by reuptake
• 2 receptor types
• GABAA GABAC (ionotropic; Cl- channel)
• GABAB (metabotropic; K+ channel)
Glu GABA
Glutamic Acid
Decarboxylase (GAD)
and B6
20. GABAa Binding Sites
▹ GABA
▹ Benzodiazepine (indirect agonist)
▸ Probably also site for alcohol
▸ Endogenous inverse agonist binds here
▹ Barbiturate (indirect agonist)
▹ Steroid (indirect agonist)
▹ Picrotoxin (inverse agonist)
Phosphate groups attach to the receptor inside
the cell and regulate receptor sensitivity (via
phosphorylation) to agents such as alcohol
21. GABAergic Drugs
Ro15-4513, a GABAa antagonist
(indirect for GABA, direct for alcohol)
reverses alcohol intoxication
• Agonists (anti-anxiety)
Benzodiazepines
Barbiturates
Ethyl alcohol (ETOH)
• Antagonists
• Picrotoxin
• Inverse agonist
Ro 15-4513
22. Biogenic Amines
▹ Medium concentration in brain (nanomolar)
▹ Circuits
▸ Single-source divergent projections
▸ Mainly midbrain to cortex
▹ Modulatory functions
▸ Excitatory or inhibitory as a function of receptor
▹ More metabotropic receptors than ionotropic, but
plenty of both
▹ Slow acting, long duration (10-1000 ms)
▹ Examples: Acetylcholine, Epinephrine, Norepinephrine,
Dopamine, Serotonin
23. Acetylcholine
▹ Mostly excitatory effects
Removal
Acetyl CoA
+
Choline
CoA
+
ACh
Choline
Acetyltransferase
(ChAT)
Ach
Acetate
+
Choline
Acetylcholine
Esterase (AChE)
• 2 receptor types
• Nicotinic (ionotropic)
• Muscarinic (metabotropic)
Synthesis
26. Monoamines
▹ Catecholamines
Dopamine - DA
▸ Dopaminergic
Norepinephrine - NE
▸ Noradrenergic
Epinephrine - E
▸ Adrenergic ~
▹ Indolamines
Serotonin - 5-HT
▸ Serotonergic
27. Monoamines (DA, NE, 5-
HT)
▹ Modulatory (can have both
excitatory and inhibitory
effects- varies by receptor)
▹ Recycled by reuptake
transporter
▹ Excess NT in terminal broken
down by
▸ monoamine oxidase
(MAOA/B)
▸ catechol-O-methyltranferase
- COMT
▹ Axonal varicosities (bead-like
swellings) with both targeted
29. Major DA Pathways
▹ Nigrostriatral (Substantia Nigra Striatum) [Motor movement]
▹ Mesolimbic (VTA limbic system) [Reinforcement and Addiction]
▹ Mesocortical (VTA prefrontal cortex) [Working memory and
planning]
▹ Tuberoinfundibular tract (hypothalamus pituitary) [neuroendocrine
regulation]
30. Norepinephrine
▹ Generally excitatory behavioral effects
▹ Biosynthesis:
DA NE
Dopamine
Beta-hydroxylase
• Many receptor types
(metabotropic)
• 1, 1-2 (postsynaptic, excitatory)
• 2 (autoreceptor, inhibitory)
31. Major NE Pathway
▹ Locus Coeruleus throughout brain [vigilance and attentiveness]
32. Serotonin
▹ Varying excitatory and inhibitory
behavioral effects
▹ Biosynthesis:
Tryptophan 5-HTP 5-HT
Tryptophan
Hydroxylase
5-HT
Decarboxylase
• At least 14 receptor types, all metabotropic and
postsynaptic except:
• 5-HT1A,B,D (autoreceptors) – found in CNS
• 5-HT3 (inhibitory, ionotropic) – found in the
intestines
36. Neuropeptides
▹ Low concentration in brain (picomolar)
▹ Large vesicles
▹ Co-localized with other transmitters
▹ Circuits
▸ Interneuronal
▹ Modulatory functions
▹ Mostly inhibitory
▹ Virtually all metabotropic
▹ Slow acting, long duration (10-1000 ms)
▹ Examples: Enkephalins, Endorphins, Oxytocin,
Vasopressin, Opioids
37. Opioids
▹ -endorphin
▸ made from proopiomelanocortin (POMC)
▸ produced in pituitary gland, hypothalamus, brain stem
▹ Enkephalin
▸ made from proenkephalin (PENK)
▸ produced throughout brain and spinal cord
▹ Dynorphin
▸ made from prodynorphin (PDYN)
▸ produced throughout brain and spinal cord
38. Opioids Receptors
ReceptorHigh affinity ligands
mu -endorphin, enkephalins
delta enkephalins
kappa dynorphins
• Opioids act at all opioid receptors, but with
different affinities
• Distributed throughout brain and spinal
cord, especially in limbic areas
• Some overlap but quite distinct
localizations
39. Opioid Receptors
(cont.)
▹ Metabotropic, with either
▸ moderately fast indirect action on ion
channels
▸ long-term action via changes in gene
expression
▹ Most analgesic effects from mu receptor action
▹ Some analgesic effects from delta
▹ Many negative side effects from kappa
40. Endorphins
▹ Morphine and heroin are
agonists that bind to receptor
sites, thereby increasing
endorphin activity
41. An Evolutionary
Perspective
Nesse and Berridge, 1997
▹ An electrochemical brain
▸ Neurotransmitters have retained
function for millions of years and are
found in many species - from
invertebrates to humans
▹ Maximization of Darwinian
fitness
▸ Evolution created many chemically-
“The problem is rooted in the fundamental design of the human nervous system”
42. Darwinian Fitness
▸ DA and opioids are part of chemically-
mediated incentive mechanisms that
act as signals (motivation/reward) for a
fitness benefit
⬩ you “like” something (opioids) or
⬩ you “want” something (dopamine)
▸ Furthermore, DA plays a role in drawing
attention/highlighting significant or
surprising stimuli
⬩ Mechanisms for greater control? As
43. Mismatch
▸ Technological inventions such as the
hypodermic needle, synthetic psychoactive
drugs, video games, snacks etc are
evolutionarily novel features that create
specific ecological pressures
⬩ They can be inherently pathogenic
because they bypass the adaptive
mechanisms and act directly on
neurotransmitter systems
⬞ positive emotions are signals to approach
○ drugs that artificially induce positive
emotions give a false signal of a fitness
44. Drug Effects
▹ External drugs hijack these
evolved incentive mechanisms
and most likely impair
adaptation
▸ When exposed to drugs the wanting
system motivates persistent pursuit
of drugs that no longer give pleasure
– a core feature of addiction.
▸ Drugs produce sensitization of
45. Metabotropic Receptors
45
1. Work more slowly than ionotropic receptors
2. Though it takes longer for postsynapic cell to respond, response is somewhat longer-lasting
3. Comprise a single protein subunit, winding back-and-forth through cell membrane seven times
(transmembrane domains)
4. They do not possess a channel or pore
46. BIG CONCEPT
Bring the attention of your
audience over a key concept
using icons or illustrations
46
47. White
Is the color of milk and
fresh snow, the color
produced by the
combination of all the
colors of the visible
spectrum.
YOU CAN ALSO SPLIT YOUR
CONTENT
Black
Is the color of ebony and
of outer space. It has
been the symbolic color
of elegance, solemnity
and authority.
47
48. IN TWO OR THREE COLUMNS
Yellow
Is the color of
gold, butter and
ripe lemons. In
the spectrum of
visible light,
yellow is found
between green
and orange.
Blue
Is the colour of
the clear sky and
the deep sea. It is
located between
violet and green
on the optical
spectrum.
Red
Is the color of
blood, and
because of this it
has historically
been associated
with sacrifice,
danger and
courage.
48
56. LET’S REVIEW SOME
CONCEPTS
Yellow
Is the color of gold, butter and ripe
lemons. In the spectrum of visible
light, yellow is found between
green and orange.
Blue
Is the colour of the clear sky and
the deep sea. It is located between
violet and green on the optical
spectrum.
Red
Is the color of blood, and because
of this it has historically been
associated with sacrifice, danger
and courage.
Yellow
Is the color of gold, butter and ripe
lemons. In the spectrum of visible
light, yellow is found between
green and orange.
Blue
Is the colour of the clear sky and
the deep sea. It is located between
violet and green on the optical
spectrum.
Red
Is the color of blood, and because
of this it has historically been
associated with sacrifice, danger
and courage.
56
63. CREDITS
Special thanks to all the people who made and
released these awesome resources for free:
▹ Presentation template by SlidesCarnival
▹ Photographs by Unsplash
63
64. PRESENTATION DESIGN
This presentation uses the following typographies and colors:
▹ Titles: Dosis
▹ Body copy: Source Sans Pro
You can download the fonts on these pages:
https://www.fontsquirrel.com/fonts/source-sans-pro
https://www.fontsquirrel.com/fonts/dosis
Aqua #0db7c4 / Red #f24745 / Green #a9d039
You don’t need to keep this slide in your presentation. It’s only here to serve you as a design guide if you need to create
new slides or download the fonts to edit the presentation in PowerPoint®
64
67. SlidesCarnival icons are editable shapes.
This means that you can:
● Resize them without losing quality.
● Change line color, width and style.
Isn’t that nice? :)
Examples:
67
69. 69 Now you can use any emoji as an icon!
And of course it resizes without losing quality and you can change the color.
How? Follow Google instructions
https://twitter.com/googledocs/status/730087240156643328
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70. Free templates for all your presentation needs
Ready to use,
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Blow your audience
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