View
229
Download
5
Category
Preview:
Citation preview
1
Dr. Joan Heller Brown
BIOM 255
2012
CNS Neurotransmitters
2
Gross anatomy of the human brain
3
4
Anatomy of a neuron
5Figure 1.
6
8
• 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
9
Sites of CNS drug action
10
Multiple sites of CNS drug action
• Conduction• Synthesis and storage• Release and reuptake• Degradation• Receptors, pre-and post-synaptic• Ion channels• Second messengers
12
13
CNS neurotransmitters
14
Table 1. Classes of CNS Transmitters
Neurotransmitter % of Synapses
BrainConcentration
Function Primary Receptor Class
MonoaminesCatecholamines: DA, NE, EPIIndoleamines: 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
Amino acidsInhibitory: GABA, glycine
Excitatory: Glutamate, aspartate
15-20
75-80
μmol/mg protein(high)
μmol/mg protein(high)
Rapid inhibition (msecs)
Rapid excitation (msecs)
Ion channels
Ion channels
16
Table 1. Classes of CNS Transmitters
Neurotransmitter % of Synapses
BrainConcentration
Function Primary Receptor Class
MonoaminesCatecholamines: DA, NE, EPIIndoleamines: 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
Amino acidsInhibitory: GABA, glycine
Excitatory: Glutamate, aspartate
15-20
75-80
μmol/mg protein(high)
μmol/mg protein(high)
Rapid inhibition (msecs)
Rapid excitation (msecs)
Ion channels
Ion channels
17
Classes of Receptors
• GPCR=7 transmembrane spanning = metabotropic
• Ligand gated ion channel=ionotropic
18
Most neurotransmitters can activate multiple receptor
subtypes and receptor classes
19
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
GGGGG
NE/EPI α1
α2
β1
β2
β3
GGGGG
5-HT 5-HT1A
5-HT1B
5-HT1D
5-HT2A
5-HT2B
5-HT2C
5-HT3
5-HT4
GGGGGG
LGG
ACh Muscarinic M1
Muscarinic M2
Muscarinic M3
Muscarinic M4
Nicotinic
GGGG
LG
Glutamate NMDAAMPAKainate
Metabotropic
LGLGLGG
GABA AB
LGG
20
21
Neurotransmitter regulation of ion channels affects membrane potential and action potential
generation (firing)
22
Principles of CNS Drug action
• Selectivity for the targeted pathway – 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
24
Monoamine Neurotransmitters
Neurotransmitter Cell Bodies Terminals
Norepinephrine (NE) Locus coeruleusLateral tegmental area
Very widespread: cerebral cortex, thalamus, cerebellum, brainstem nuclei, spinal cordBasal 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 areaArcuate nucleus
StriatumLimbic forebrain, cerebral cortexMedian eminence
Serotonin (5-HT) Raphe nuclei (median and dorsal), pons, medulla
Very widespread: cerebral cortex, thalamus, cerebellum, brainstem nuclei, spinal cord
Table 3. Localization of Monoamines in the Brain
26
Catecholamines Indoleamines
Monoamine Biosynthesis
Important monoamine metabolites formed in the CNS
• NE MAO, COMT MHPG (MOPEG)
• DA MAO, COMT HVA
• 5HT MAO 5HIAA
28
Noradrenergic Pathways in the Brain
Locus ceruleus to cortical and subcortical sites
29
Serotonergic Pathways in the Brain
Midline raphe nuclei to cortical and subcortical areas
30
CNS functions regulated by NE
• Arousal
• Mood
• Blood pressure control
31
CNS functions regulated by 5HT
• Sleep
• Mood
• Sexual function
• Appetite
Figure 15-1, G&G
33
Catecholamines
Monoamine Biosynthesis
34
35
36
• 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)
Major Dopaminergic (DA) pathways
37
CNS functions regulated by DA
• Nigrostriatal (substantia nigra to striatum)
– extrapyramidal motor control
• Mesolimbic/mesocortical (ventral tegmental to n.accumbens, hippocampus, and cortex)
– emotion– cognition
• Tuberoinfundibular (arcuate nucleus of hypothalamus to median eminence then anterior pituitary)
– prolactin release
38
Brain Amines and Disease States
• Biogenic amine theory of depression
• Dopaminergic theory of schizophrenia
• Dopaminergic involvement in Parkinson’s disease
40
Brain Amines and Disease States
• Biogenic amine theory of depression
• Dopaminergic theory of schizophrenia
• Dopaminergic involvement in Parkinson’s disease
42
Brain Amines and Disease States
• Biogenic amine theory of depression
• Dopaminergic theory of schizophrenia
• Dopaminergic involvement in Parkinson’s disease
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
45
46
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)
47
B
A
Cholinergic pathways in the CNS
Nucleus basalis to cortex (A) and interneurons in striatum ( B)
48
49
50
Amino Acid Neurotransmitters
• Inhibitory – GABA and Glycine– Hyperpolarize = don’t fire
• Excitatory– Glutamate ( and Aspartate)– Depolarize = fire
51
NH2 – CH – CH2 – CH2 - COOH
COOH
NH2 – CH2 – CH2 – CH2 - COOH
Glutamic acid decarboxylase (GAD)
Glutamate GABA
GABA Synthesis
52
53
54
Location and CNS functions of GABA
• Nigrostriatal pathway– extrapyramidal motor responses
• Interneurons throughout the brain– inhibit excitability, stabilize membrane
potential, prevent repetitive firing
55
Synaptic effects of GABAA receptor activation
Inhibitory transmitters (I) hyperpolarize the membrane.
The IPSP stabilizes against excitatory (E) depolarization and action potential generation
56
The ionotropic GABAA
receptor
57
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
58Modified from nAChR, G and G 2011
60
Pharmacology of the GABAA
receptor
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
62
64
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
66
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.
68
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
69
Glutamate as a CNS neurotransmitter
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
71
NH2 – CH – CH2 – CH2 - COOH
COOH
Glutamate Synthesis
Glutamate
α-ketoglutarate
Glutamine (from glia)
transaminases
72Figure 24.
GluA1-4 GluK1-3 GluN1GluN2A-DGluN3A-B
mGlu1
mGlu5
SubunitsmGlu2
mGlu3
mGlu4
mGlu6-8GluK4-5
Glutamate Receptor Subtypes
GluR 1-4 GluR 5-7, KA1,2
NR1, NR2A-2D
74
Ionotropic glutamate receptors: ligand gated
sodium channels
Glutamate
76Figure 20A.
77
Pharmacology of NMDA
receptors
78
NMDA receptor as a coincidence detector : requirement for membrane depolarization
79
NMDA receptor uses glycine as a co-agonist
80
NMDA receptor channel is blocked by phencyclidine (PCP)
81
NMDA receptor is Ca++ permeable
82
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
RNA editing of GluR subunits
84
Properties of NMDA Receptor
• Blocked at resting membrane potential (coincidence detector)
• Requires glycine binding
• Permeable to Ca++ as well as Na
85
NMDA receptors involvement in disease
- seizure disorders - learning and memory
- neuronal cell death
86
NMDA receptors in seizure disorders
87
88
NMDA receptors in long term potentiation
89
90
91Figure 32.
92
NMDA receptors in excitotoxic cell death
93
Necrosis Apoptosis
94
End of CNS NT lecture slides
95
Extra stuff
Drugs acting on serotonergic neurons
Drugs acting on noradrenergic neurons
Drugs acting on serotonergic neurons
Recommended