Download Substance must be found in neurons

Neuropharmacology
Neurotransmitter
Criteria
1. Identity
Substance must be found in neurons
Neurotransmitter
Criteria
1. Identity
2. Synthesis
Cell has precursors and enzymes
necessary for synthesis of n.t.
Neurotransmitter
Criteria
1. Identity
2. Synthesis
3. Release
Must be released from terminals;
(collect substance from cleft
after nerve stimulation)
Neurotransmitter
Criteria
1.
2.
3.
4.
Identity
Synthesis
Release
Receptors
Cross desensitization between
substance and suspected n.t.
Blockade of n.t. action by receptor
antagonists
Applicaton of suspected n.t.
mimics action of nerve stimulation
Neurotransmitter
Criteria
1.
2.
3.
4.
5.
Identity
Synthesis
Release
Receptors
Inactivation
Inactivation mechanism
enzymatic degradation
reuptake
Neurotransmitter
Criteria
1.
2.
3.
4.
5.
6.
Identity
Synthesis
Release
Receptors
Inactivation
Pharmacology
Same effect on ion channels;
p.s.p.’s have same reversal potentials
Same effect on membrane resistance
and potential
Applied substances must be effective
in physiological concentrations
Inhibition of degrading enzyme
prolongs action of both
Neurotransmitter
Criteria
1.
2.
3.
4.
5.
6.
Identity
Synthesis
Release
Receptors
Inactivation
Pharmacology
Acetylcholine Synthesis
Choline Acetyltransferase (ChAT)
Choline + Acetyl CoA
Acetylcholine + CoA
Degradation
Acetylcholine Esterase (AchE)
Acetylcholine
Choline + Acetate
Chemicals that Act
on ACh Systems
black widow spider venom
stimulates release of ACh
botulinum toxin
blocks release of ACh
curare
blocks ACh nicotinic receptors
insecticides
AChE inhibitors
atropine as antidote
blocks muscarinic receptors
Clinical Aspects
of ACh Systems
Alzheimer’s disease
loss of ACh neurons in
the basal nucleus of Meynert
Aricept—ACh agonist
Monoamines
single amine (NH2) group
Catecholamines (CAs)
dopamine (DA)
norepinephrine (NE, noradrenaline)
epinephrine (EPI, adrenaline)
Indoleamines
serotonin (5-hydroxy tryptamine, 5-HT)
Catecholamine synthesis
Serotonin synthesis
Dopamine Systems
Norepinephrine Systems
Serotonin Systems
Characteristics of
Monoaminergic Systems
Diffuse distribution of targets
Fine, unmyelinated axons
Metabotropic synapses
Functions of
Monaminergic Systems
“State” phenomena
sleep and arousal
hunger
mood
Amino Acid Transmitters
Excitatory Amino Acid
Glutamic Acid, or Glutamate
Inhibitory Amino Acids
Gamma Aminobutyric Acid (GABA)
Glutamic Acid
Decarboxylase (GAD)
Glutamic Acid
Glycine
GABA
Glutamate Receptor Subtypes
NMDA receptor binding sites
http://www.sumanasinc.com/webcontent/anisamples/neurobiology/receptors.htm
Glutamate
non-NMDA receptors
Na+ channels
open
removes
blockade
depolarization
NMDA receptors
Ca2+ channels
open
(Mg2+ blockade)
Ca2+ enters
when Mg2+
is removed
postsynaptic
effects
(learning)
Ca2+dependent
K+ channels
open
reinstates blockade
repolarization
NO
a. Non-NMDA Na+ channels open, Na+
enters and depolarizes membrane
b. Mg2+ blockade of NMDA Ca2+ channels
removed by membrane depolarization;
Ca2+ enters
c. Ca2+ dependent K+ channels open;
membrane repolarized
d. Mg2+ blockade reinstated
a
b c
d
GABA receptor binding sites
Diffusible Gases
Nitric Oxide (NO)
Nitric Oxide
Synthase (NOS)
Arginine
NO + Citrulline
Carbon Monoxide (CO)
Heme Oxygenase
Heme
CO + biliverdin
Functions of
Diffusible Gas
Neurotransmitters
regulate blood flow
cerebral
peripheral (e.g. penis)
retrograde messenger
Hebb’s postulate of learning
NO
Peptide
Neurotransmitters
(Often serve hormonal function
as well)
Substance P (P for “Peptide”)
Principal somatosensory transmitter
First peptide transmitter discovered
Gut hormones
e.g. angiotensin
neuropeptide Y
cholecystokinin
Releasing factors for hormones
e.g. tryrotropin releasing hormone
somatotrophin, somatostatin
corticotropin
Opiates
Endogenous morphine-like
neurotransmitters
μ, κ, δ opiate receptors
also… ophanin fq, or
nociception receptors
Mechanisms
of Tolerance
1. Metabolic adaptation
2. Receptor regulation
3. Neural compensation
Drugs that Act on
Ion Channels
tetrodotoxin
blocks voltage-sensitive Na+ channels
cocaine, local anesthetics
block voltage-sensitive Na+ channels
batrachotoxin
prevents inactivation of Na+ channels
tetraethyl ammonium
blocks voltage-sensitive K+ channels