Transcript Document

CNS Neurotransmitters
Dr. Joan Heller Brown
BIOM 255
2012
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Gross anatomy of the human
brain
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Anatomy of a neuron
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Figure 1.
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• Peripheral Nervous System (PNS)
– Autonomic division : neuron to smooth
muscle, cardiac muscle and gland
– Somatic division : neuron to skeletal muscle
• Central Nervous System ( CNS)
– neuron to neuron
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Sites of CNS drug action
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Multiple sites of CNS drug action
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Conduction
Synthesis and storage
Release and reuptake
Degradation
Receptors, pre-and post-synaptic
Ion channels
Second messengers
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CNS neurotransmitters
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Table 1. Classes of CNS Transmitters
Neurotransmitter
% of
Synapses
Brain
Concentration
Monoamines
Catecholamines: DA, NE,
EPI
Indoleamines: serotonin
(5-HT)
2-5
nmol/mg
protein
(low)
Slow change in
excitability (secs)
GPCRs
Acetylcholine (ACh)
5-10
nmol/mg
protein
(low)
Slow change in
excitability (secs)
GPCRs
μmol/mg
protein
(high)
Rapid inhibition
(msecs)
Ion channels
μmol/mg
protein
(high)
Rapid excitation
(msecs)
Ion channels
Amino acids
Inhibitory: GABA,
glycine
Excitatory: Glutamate,
aspartate
15-20
75-80
Function
Primary
Receptor Class
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Table 1. Classes of CNS Transmitters
Neurotransmitter
% of
Synapses
Brain
Concentration
Monoamines
Catecholamines: DA, NE,
EPI
Indoleamines: serotonin
(5-HT)
2-5
nmol/mg
protein
(low)
Slow change in
excitability (secs)
GPCRs
Acetylcholine (ACh)
5-10
nmol/mg
protein
(low)
Slow change in
excitability (secs)
GPCRs
μmol/mg
protein
(high)
Rapid inhibition
(msecs)
Ion channels
μmol/mg
protein
(high)
Rapid excitation
(msecs)
Ion channels
Amino acids
Inhibitory: GABA,
glycine
Excitatory: Glutamate,
aspartate
15-20
75-80
Function
Primary
Receptor Class
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Classes of Receptors
• GPCR=7 transmembrane spanning =
metabotropic
• Ligand gated ion channel=ionotropic
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Most neurotransmitters can
activate multiple receptor
subtypes and receptor classes
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Table 2. Major Neurotransmitter Receptors in the CNS
Neurotransmitter
Receptor Subtypes
G Protein-Coupled (G) vs.
Ligand-Gated Ion Channel (LG)
DA
D1
D2
D3
D4
D5
G
G
G
G
G
NE/EPI
α1
α2
β1
β2
β3
G
G
G
G
G
5-HT
5-HT1A
5-HT1B
5-HT1D
5-HT2A
5-HT2B
5-HT2C
5-HT3
5-HT4
G
G
G
G
G
G
LG
G
ACh
Muscarinic M1
Muscarinic M2
Muscarinic M3
Muscarinic M4
Nicotinic
G
G
G
G
LG
Glutamate
NMDA
AMPA
Kainate
Metabotropic
LG
LG
LG
G
GABA
A
B
LG
G
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Neurotransmitter regulation of ion
channels affects membrane
potential and action potential
generation (firing)
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Principles of CNS Drug action
• Selectivity for the targeted pathway
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Receptor subtypes
Allosteric sites on receptors
Presynaptic and postsynaptic actions
Partial/inverse agonist (activity dependent)
• Plasticity reveals adaptive changes in drug
response
– Pharmacokinetic: drug metabolism
– Pharmacodynamic: cellular
Monoamine Neurotransmitters
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Table 3. Localization of Monoamines in the Brain
Neurotransmitter
Cell Bodies
Terminals
Norepinephrine (NE)
Locus coeruleus
Lateral tegmental area
Very widespread: cerebral cortex, thalamus,
cerebellum, brainstem nuclei, spinal cord
Basal forebrain, thalamus, hypothalamus,
brainstem, spinal cord
Epinephrine (EPI)
Small, discrete nuclei in
medulla
Thalamus, brainstem, spinal cord
Dopamine (DA)
Substantia nigra (pars
compacta)
Ventral tegmental area
Arcuate nucleus
Striatum
Limbic forebrain, cerebral cortex
Median eminence
Serotonin (5-HT)
Raphe nuclei (median and
dorsal), pons, medulla
Very widespread: cerebral cortex, thalamus,
cerebellum, brainstem nuclei, spinal cord
Monoamine Biosynthesis
Catecholamines
Indoleamines
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Important monoamine metabolites
formed in the CNS
• NE MAO, COMT MHPG (MOPEG)
• DA  MAO, COMT HVA
• 5HT  MAO  5HIAA
Noradrenergic Pathways in the Brain
Locus ceruleus to cortical and subcortical sites
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Serotonergic Pathways in the Brain
Midline raphe nuclei to cortical and subcortical areas
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CNS functions regulated by NE
• Arousal
• Mood
• Blood pressure control
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CNS functions regulated by
5HT
• Sleep
• Mood
• Sexual function
• Appetite
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Figure 15-1, G&G
Monoamine Biosynthesis
Catecholamines
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Major Dopaminergic (DA) pathways
• Nigrostriatal
(substantia nigra to striatum)
• Mesolimbic/mesocortical
(ventral tegmental midbrain to
n.accumbens, hippocampus, and cortex)
• Tuberoinfundibular
(arcuate nucleus of hypothalamus to
median eminence then anterior pituitary)
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CNS functions regulated by DA
• Nigrostriatal
(substantia nigra to striatum)
– extrapyramidal motor control
• Mesolimbic/mesocortical
hippocampus, and cortex)
(ventral tegmental to n.accumbens,
– emotion
– cognition
• Tuberoinfundibular
(arcuate nucleus of hypothalamus to median
eminence then anterior pituitary)
– prolactin release
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Brain Amines and Disease
States
• Biogenic amine theory of depression
• Dopaminergic theory of schizophrenia
• Dopaminergic involvement in
Parkinson’s disease
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Brain Amines and Disease
States
• Biogenic amine theory of depression
• Dopaminergic theory of schizophrenia
• Dopaminergic involvement in
Parkinson’s disease
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Brain Amines and Disease
States
• Biogenic amine theory of depression
• Dopaminergic theory of schizophrenia
• Dopaminergic involvement in
Parkinson’s disease
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DA involvement in Parkinson’s disease (PD)
• Pathology of disease: DA neurons in nigrostriatal pathway
degenerate
• Replacing DA is a therapeutic approach to treat PD
• Parkinson like symptoms are side effects of DA receptor
blockade with antipsychotic drugs
• MPTP, a neurotoxin, destroys DA neurons and induces PD
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ACh as a CNS neurotransmitter
• Memory (ChEI in Alzheimers disease)
– Basal forebrain to cortex/hippocampus (A)
• Extrapyramidal motor responses (benztropine
for Parkinsonian symptoms)
– Striatum (B)
• Vestibular control (scopolamine patch for motion
sickness)
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Cholinergic pathways in the CNS
B
A
Nucleus basalis to cortex (A) and interneurons in striatum ( B)
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Amino Acid Neurotransmitters
• Inhibitory
– GABA and Glycine
– Hyperpolarize = don’t fire
• Excitatory
– Glutamate ( and Aspartate)
– Depolarize = fire
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GABA Synthesis
COOH
Glutamic acid decarboxylase
(GAD)
NH2 – CH – CH2 – CH2 - COOH
Glutamate
NH2 – CH2 – CH2 – CH2 - COOH
GABA
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Location and CNS functions of GABA
• Nigrostriatal pathway
– extrapyramidal motor responses
• Interneurons throughout the brain
– inhibit excitability, stabilize membrane
potential, prevent repetitive firing
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Synaptic effects of GABAA receptor activation
Inhibitory transmitters (I) hyperpolarize the membrane.
The IPSP stabilizes against excitatory (E) depolarization and action
potential generation
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The ionotropic GABAA receptor
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Subunit composition of GABAA
receptors
• Five subunits, each with four transmembrane
domains (like nAChR)
• Most have two alpha (α),two beta (β), one
gamma (γ) subunit
• α1 β2 γ2 is predominant in mammalian brain but
there are different combinations in specific
brain regions
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Modified from nAChR, G and G 2011
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Pharmacology of the GABAA
receptor
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GABAA receptor pharmacology
• There are two GABA binding sites per receptor.
• Benzodiazepines and the newer hypnotic drugs bind
to allosteric sites on the receptor to potentiate
GABA mediated channel opening.
• Babiturates act at a distinct allosteric site to also
potentiate GABA inhibition.
• These drugs act as CNS depressants
• Picrotoxin blocks the GABA-gated chloride channel
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GABAA receptor involvement in seizure
disorders
• Loss of GABA-ergic transmission contributes to
excessive excitability and impulse spread in epilepsy.
• Picrotoxin and bicuculline ( GABA receptor blocker)
inhibit GABAA receptor function and are convulsants.
• BDZs and barbiturates increase GABAA receptor
function and are anticonvulsants.
• Drugs that block GABA reuptake (GAT) and
metabolism ( GABA-T) to increase available GABA are
anticonvulsants
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Glycine as an inhibitory CNS
neurotransmitter
• Major role is in the spinal cord
• Glycine receptor is an ionotropic chloride
channel analagous to the GABAA receptor.
• Strychnine, a competitive antagonist of
glycine, removes spinal inhibition to
skeletal muscle and induces a violent motor
response.
The metabotropic GABAB receptor
• These receptors are GPCRS
• Largely presynaptic, inhibit transmitter release
• Most important role is in the spinal cord
• Baclofen, an agonist at this receptor, is a muscle
relaxant
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Glutamate as a CNS
neurotransmitter
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Glutamate
• Neurotransmitter at 75-80% of CNS
synapses
• Synthesized within the brain from
– Glucose (via KREBS cycle/α-ketoglutarate)
– Glutamine (from glial cells)
• Actions terminated by uptake through
excitatory amino acid transporters (EAATs) in
neurons and astrocytes
Glutamate Synthesis
Glutamine (from glia)
COOH
NH2 – CH – CH2 – CH2 - COOH
Glutamate
transaminases
α-ketoglutarate
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Figure 24.
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Glutamate Receptor Subtypes
Subunits
GluR
1-4
GluA1-4
GluR
5-7,
GluK1-3
KA1,2
GluK4-5
GluN1
NR1,
GluN2A-D
NR2A-2D
GluN3A-B
mGlu1
mGlu5
mGlu2
mGlu3
mGlu4
mGlu6-8
Ionotropic glutamate
receptors: ligand gated
sodium channels
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Glutamate
Figure 20A.
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Pharmacology of NMDA
receptors
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NMDA receptor
as a coincidence
detector :
requirement for
membrane
depolarization
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NMDA receptor
uses glycine as a
co-agonist
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NMDA receptor
channel is blocked
by phencyclidine
(PCP)
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NMDA receptor is Ca++ permeable
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Calcium (Ca++) permeability of
AMPA vs NMDA receptors
• It is the GluR2 subunit that makes most
AMPA receptors Ca++ impermeant
• The GluR2 subunit contains one amino
acid substitution : arginine (R) versus
glutamine (Q) in all other GluRs
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RNA editing of GluR subunits
Properties of NMDA Receptor
• Blocked at resting membrane potential
(coincidence detector)
• Requires glycine binding
• Permeable to Ca++ as well as Na
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NMDA receptors involvement
in disease
- seizure disorders
- learning and memory
- neuronal cell death
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NMDA receptors in seizure
disorders
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NMDA receptors in long term
potentiation
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Figure 32.
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NMDA receptors in excitotoxic
cell death
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Necrosis
Apoptosis
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End of CNS NT lecture slides
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Extra stuff
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Drugs acting on serotonergic neurons
Drugs acting on noradrenergic neurons
Drugs acting on serotonergic neurons