The Cerebral Cortex and Higher Intellectual...
Transcript of The Cerebral Cortex and Higher Intellectual...
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Neuromodulators
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Dopamine
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Norepinephrine
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Norepinephrine receptors
• α family
• Β family
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Norepinephrine receptors
• α family
• Β family
Current Nomenclature of
Adrenergic Receptor Subtypes
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Subtype Differentiation
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β1- The dominant receptor in heart and adipose tissue equally sensitive to epinephrine and
norepinephrine.
β2- Responsible for relaxation of vascular, uterine, and airway smooth muscle. Less sensitive
to NE as compared to E.
β3- Insensitive to commonly used β–adrenergic receptor antagonists. Previously referred to as
the “atypical” β–adrenergic receptor.
Subtype Differentiation
α1- Postsynaptic. 1A and 1B subtypes defined by their differential affinity for agents such as
WB4101 & phentolamine. No 1C subtype.
α2- Postsynaptic & presynaptic. First thought to be exclusively presynaptic. 2A & 2B
subtypes differentiated by their affinity for agents such as prazosin & oxymetazoline.
(The Biochemical Basis of
Neuropharmacology, 2003)
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08/20/2008 Lerant: Catecholamines 2008 8
Noradrenergic
(NE)
synapse
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Norepinephrine Pathway
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Norepinephrine Pathway
• LC noradrenergic system is highly responsive
external stimuli attention
• Learning/memory and seep/wake cycle
• Anxiety and stress response
• In FRONTAL CORTEX:
– Mood regulation Hypofunction of
pathwayDepression
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NE: Locus Ceruleus FRONTAL CTX
α2 postsynaptic receptor
In FRONTAL CORTEX:
• Attention, working
memory, information
processing.
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NE: Locus Ceruleus FRONTAL CTX
β1 postsynaptic receptor
In FRONTAL CORTEX:
• Mood regulation.
• Hypofunction of pathway:
• Depression
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NE: Locus Ceruleus LIMBIC CTX
• Emotions
• Energy level
• Psychomotor
agitation
• Psychomotor
retardation
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Serotonin
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Serotonin synthesis
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Serotonin Pathway
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Serotonin Receptors
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Serotonin Receptors
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Serotonin Pathway
Wide spreadAlmost 17 type of receptor
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Serotonin Pathway
Wide spreadAlmost 17 type of receptor
mood, sleep, sexuality, impulsivity, aggression,
stress, drug abuse
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Serotonin Pathway
Wide spreadAlmost 17 type of receptor
Serotonin system dysfunction involve in :
Depression, Schizophrenia,
OCD, Eating Disorders, Autism
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Antipsychotics
Clozapine
Risperidone
Olanzapine
Anxiolytics
Buspirone
Gepirone
Antiemetics
Ondansetron
Granisetron
Anti-migraine
Sumatriptan
Potent antagonist actions at
5-HT2A receptors, in addition
to D2 antagonism
Partial 5-HT1A agonists
Effective for treating GAD, OCD
5-HT3 antagonist used for
Minimizing chemotherapy-
induce nausea
5-HT1 agonist, exerts some
Selectivity on 5-HT1D receptors
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Selective Serotonin Reuptake
Inhibitors
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Divergence and Convergence
in Neurotransmitter Systems
• Divergence
– One transmitter activates more
than one receptor subtype
greater postsynaptic response
• Convergence
– Different transmitters converge
to affect same effector system
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serotonin neuron
dopamine neuron
Substantia
nigra
Raphe
dopamine
5HT2A
receptor serotonin
5HT2A
receptor
11-18
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Monoamines & Behavior
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Newer Antidepressants and Mood Stabilizers
I. Serotonin-Norepinephrine reuptake inhibitor
Venlafaxine, Milnacipran, Duloxetine
SRI
NRI
DRI
SNRI
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II. Serotonin Receptor
Antagonist/Reuptake Inhibitor
(SARIs)
Nefazodone, Trazodone
5HT2
NRI
SRI
Nefazodone
SARI (nefazodone) actions at 5HT
synapses
5HT2A
5HT1A
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Receptor Action
5-HT1A Antagonist
5-HT1B Antagonist
5-HT1D Antagonist
5-HT2A Inverse agonist
5-HT2B Inverse agonist
5-HT2C Inverse agonist
5-HT5A Antagonist
5-HT6 Antagonist
5-HT7 Irreversible antagonist[2]
D1 Antagonist
D2 Antagonist
D2S Antagonist
D2L Antagonist
D3 Inverse agonist
D4 Antagonist
D5 Antagonist
α1A Antagonist
α1B Antagonist
α2A Antagonist
α2B Antagonist
α2C Antagonist
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Neuropeptides
• Neuropeptides are peptides released by
neurons as intercellular messengers.
• May co-localize with other classical
transmitters in same neuron
• All neuropeptide receptors are G-protein
linked receptors
• Function of Neuropeptides:
• -- They can do just about everything
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Neuropeptides
• Neuropeptides are peptides released by
neurons as intercellular messengers.
• May co-localize with other classical
transmitters in same neuron
• All neuropeptide receptors are G-protein
linked receptors
• Function of Neuropeptides:
• -- They can do just about everything
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Neuropeptides synthesis
Golgi apparatus
Roughendoplasmic
reticum
SynapseNucleus
Axonal transport
Precursor breakdown and liberation of neuropeptide
Receptor
Precursor protein
Peptidase
ReleaseMaturemRNA
Translation
Precursor mRNA
TranscriptionUsually are more potent than classical neurotransmitter : lower concentration
and longer effect
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Example of Neuropeptides
Opioids1) Enkephalin delta (δ)
2) Endorphins mu (μ)
3) Dynorphin kappa (κ)
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Example of Neuropeptides
1) enkephalin
Leu-Enkephalin
Opioid receptor : δ receptor
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Enkephalin pathway
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Enkephalin pathway
Function : analgesia by block the pain
before it is relayed
to the brain
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Example of Neuropeptides
2) Endorphins
Carbon
Hydrogen
Nitrogen
Sulfur
Oxygen
Endogenousendorphin Morphine
Opioid receptor
μ receptor
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Endorphin location and function
Cerebral cortex - influence mood, ephoria and emotional
aspect of pain
Thalamus – influence poorly localized deep pain
Midbrain (periaqueductal grey matter) - modulation of pain
Brain stem - respiratory control, cough reflex,
nausea/vomiting etc.
Hypothalamus - temperature and neuro-endocrine function
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Non-traditional Neurotransmitters
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Nitric Oxide
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Nitric Oxide
NOS-1 (nNOS)
Constitutive
Neuronal
Ca++ -dependent
NOS-2 (iNOS)
Inducible
Mostly Glial
Ca++ -independent
Pro-inflammatory
NOS-3 (eNOS)
Constitutive/Inducible
Vascular endothelium
Ca++ -dependent
Arginine NO
Citrulline
Nitric Oxide Synthase
COOH
NH
NH
NH2
C
NH2
(NADPH, THB)
• NO is a diffusible bioactive gas produced
from arginine by nitric oxide synthase
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Nitric Oxide (NO)
• NO is a diffusible bioactive gas produced from arginine by nitric oxide
synthase
• NO is widely distributed in brain and peripheral tissues
• NO is not stored and synthesis is regulated by the enzyme activity
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Nitric Oxide
• Regulation of blood flow - Neuron-derived NO plays a major role in
the regulation of blood flow, vasodilation and increased blood flow
• At the cellular level, NO can changes intracellular metabolic functions
that modify neuronal excitability and influence neurotransmitter
release
• In the brain, NO acts as a neuromodulator to control behavioral
activity, influence memory formation, and intensify responses to
painful stimuli
• May be responsible for glutamate induced neurotoxicity
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Brain-derived neurotrophic factor
“BDNF”
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Tyrosine kinase
Receptor activation:
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Our axons can be >1 m in length---how does the
neurotrophin/receptor complex signal to the neuronal
cell body?
Miller and Kaplan (2001) Neuron 32:767-770
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Transport of NGF
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NGF signal can be
transduced at the tips of
growing neuronal
processes
Sympathetic neurons were
placed in a TC system that
allowed the somas and
neurites to be bathed in
different media.
L: Most neurons die when
grown without NGF for 30
hr.
R: Neurons can be kept
alive by adding NGF only
to the compartments with
growing neurites.
In both cases, anti-NGF
prevented TrkA activation
in the central compartment.
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Memory
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•Long term potentiation LTP , and LTD
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• Spines
![Page 56: The Cerebral Cortex and Higher Intellectual Functionsmsg2018.weebly.com/uploads/1/6/1/0/16101502/slides_10.pdf · (The Biochemical Basis of Neuropharmacology, 2003) 08/20/2008 Lerant:](https://reader033.fdocuments.net/reader033/viewer/2022042913/5f49bd2a748e9e12703af405/html5/thumbnails/56.jpg)
• Spines
• Long term potentiation LTP and LTD
• The glutamate receptor (NMDA)
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• Spines
• Long term potentiation LTP and LTD
• The glutamate receptor (NMDA)
• neuromodulators “NO, 5HT, norepinephrine”