Download Receptors

Chemical
Messengers
•Autocrine
•self signal
•Paracrine
•neighbor signal
•Endocrine
•distant signal
•Pheromone
•airborne signal
•same species
•Allomone
•airborne signal
•different species
Endocrine Glands
Homeostasis
Mechanism
Receptors
input signals
skin responds to cold
temperature
sends signal to brain
Control Center
integrating center
brain interprets temp signal
makes you shiver
Effectors
output mechanism
muscles shiver creating heat
Neurotransmitters
•Neuropeptides
•Amines
•Quaternary amines
•Acetylcholine (ACh)
•Monoamines
•Catecholamines
•Epinephrine (EPI)
•Norepinephrine (NE)
•Dopamine (DA)
•Indoleamines
•Serotonin (5-HT)
•Melatonin
•Amino acids
•Gamma-aminobutyric acid (GABA)
•Glutamate (GLU)
•Glycine
•Histamine (HIST)
•Opioid peptides
•Enkephalins (ENK)
•Endorphins (END)
•Peptide Hormones
•Oxytocin (Oxy)
•Substance P
•Cholecystokinin (CCK)
•Vasopressin (ADH)
•Neuropeptide Y (NPY)
•Brain-derived Neurotrophic factor
•Hypothalamic Releasing Hormones
•GnRH
•TRH
•CRH
•Lipids
•Anandamide
•Gases
•Nitric Oxide (NO)
Acetylcholine
Synthesis
Breakdown
Cholinergic
Synapse
•
Choline
•
Acetyl CoA
•
Cholinesterase (ChAT)
•
Acetylcholinesterase
(AChE)
•
Choline transporter
•
Vesicular ACh transporter
(VAChT)
Cholinergic (Ach) System
Cholinergic
Receptors
•
Nicotinic receptors
•
Muscle Type
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•
•
•
CNS Type
Muscarinic receptors
•
M1
•
•
Iontotropic
•
•
Blood vessels
Lungs
Exocrine Glands
M4
•
•
Heart
M3
•
•
•
metabotropic
CNS
Autonomic ganglia
M2
•
•
CNS
M5
•
Nicotinic ACh Receptor
Neuromuscular junction
Autonomic ganglia
CNS
Catecholamine Synthesis
Noradrenergic (NE) System
Noradrenergic
Receptors
•
Alpha 1 receptors
•
•
•
•
•
•
Alpha 2 receptors
•
•
•
Heart
kidneys
Beta 2 receptors
•
•
•
•
•
•
•
brain
Beta 1 receptors
•
•
All metabotropic
Smooth muscle
Skin
GI tract
Kidney
brain
Lungs
GI tract
Liver
uterus
Vascular smooth muscle
Skeletal muscle
Beta 3 receptors
•
Fat cells
Dopaminergic
Synapse
•
Tyrosine
•
Tyrosine Hydroxylase
•
DOPA
•
Aromatic Amino Acid Decarboxylase
•
Dopamine Transporter
•
Vesicular Monoamine Transporter
•
D2 Autoreceptor
Dopaminergic (DA) System 1
Mesolimbic
* Ventral Tegmental Area (VTA)
Dopaminergic (DA) System 2
Mesostriatal
*
Basal Ganglia
Dopaminergic Receptors
• D1 receptors
• D2 receptors
• D3 receptors
• D4 receptors
• D5 receptors
Serotonin
(5-Hydroxytryptamine)
(5-HT)
Serotonergic
Synapse
•
Tryptophan
•
Tryptophan hydroxylase
•
5-HTP
•
Aromatic l-amino acid
decarboxylase (AADC)
•
5-HT
•
5-HT transporter
•
5-HT autoreceptor
Serotoninergic (5-HT) System
Serotonergic
Receptors
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CNS
5-HT7 receptors
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•
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5-HT1B receptor
CNS
5-HT6 receptors
•
•
CNS
PNS
GI Tract
5-HT5A-B receptors
•
•
CNS
PNS
GI Tract
5-HT4 receptors
•
•
•
• Metabotropic
CNS
PNS
Blood Vessels
GI Tract
5-HT3 receptors
•
•
•
•
CNS
Blood Vessels
5-HT2A-C receptors
•
•
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•
•
• Iontotropic
5-HT1A-F receptors
CNS
Blood Vessels
GI Tract
Glutamate
Synthesis
• Glutamine
• Glutaminase
• Glutamic Acid
• Glutamate
• Aspartic Acid
• Aspartate
Glutamate Synapse
Glutamate
Receptors
•
AMPA receptors
•
•
Kainate receptors
•
•
GluK1-5
NMDA receptors
•
•
•
•
GluA1-4
GluN1
GluN2A-C
GluN3A-B
Metabotropic receptors
•
mGluR1-8
Iontotropic
Metabotropic
AMPA Receptor
Long-Term Potentiation (LTP)
each triangle represents a single
action potential
Slope of
the EPSP
(one
characteristic
measure of an
action potential)
baseline response
potentiated response
Hippocampus has a three synaptic pathway
Stimulate one area (mossy fibers) and record the action potentials in another (CA1)
Stimulate multiple times to get a baseline response
Once a stable baseline is established give a brief high frequency stimulating pulse
Use the same stimulating pulse as in baseline but now see a potentiated response
This potentiated response can last hours, days, or even weeks (LTP)
Normal
Synaptic
Transmission
Glutamate Channels:
NMDA
Mg2+ block
no ion flow
AMPA
Na+ flows in
depolarizes cell
LTP
Induction
With repeated activation
the depolarization drives the
Mg2+ plug out of the NMDA
channels
Ca2+ then rushes in through
the NMDA channels
Ca2+ stimulates a retrograde
messenger to maintain LTP
Ca2+ also stimulates CREB to
activate plasticity genes
LTP-induced Neural Changes
Neurobiological Changes via Learning
Dendritic changes:
•Increased dendritic arborization
•Increased dendritic bulbs
Synaptic changes:
•More neurotransmitter release
•More sensitive postsynaptic area
•Larger presynaptic areas
•Larger postsynaptic areas
•Increased interneuron modulation
•More synapses formed
•Increased shifts in synaptic input
Physiological changes:
•Long-Term Potentiation
•Long-Term Depression
GABA
Synthesis
• Glutamate
• Glutamic Acid
Decarboxylase
(GAD)
• GABA
GABA Synapse
GABA
Receptors
•
GABAA receptors
•
GABAB receptors
•
GABAC receptors
Iontotropic
Metabotropic
GABAA Receptor
GABAA
receptor
properties
•
Benzodiazepines (BDZ) and
barbiturates cause sedation and
reduced anxiety by binding to
modulatory sites on the GABA
receptor complex
•
BDZ binding sites are widely
distributed in the brain.
•
They are in high concentration in the
amygdala and frontal lobe.
•
Natural differences in anxiety levels
are correlated with the number of
BDZ binding sites.
•
PET scans of patients with panic
disorder show less benzodiazepine
binding in the CNS, particularly in
the frontal lobe.
GABA and Anxiety
The Science of Drug Action
Pharmacology: study of the actions of drugs and their
effects on living organisms.
Neuropharmacology: study of drug-induced
changes in nervous system cell functioning.
Psychopharmacology: emphasizes drug-induced
changes in mood, thinking, and behavior.
Neuropsychopharmacology: identifies chemical
substances that act on the nervous system to alter behavior.
.
The Science of Drug Action
Drug action: molecular changes produced by a drug when it
binds to a target site or receptor.
Drug effects: The molecular changes that alter physiological
or psychological functions.
Therapeutic effects: the drug–receptor interaction produces
desired physical or behavioral changes.
Side effects: all other non-therapeutic effects.
Specific drug effects: are based on physical and
biochemical interactions of a drug with a target site in living tissue.
Nonspecific drug effects: are based on certain unique
characteristics of the individual, (e.g., mood, expectations,
perceptions, attitudes, placebo effects).
Therapeutic Index
 Effective dose
 dose of a drug that produces a meaningful effect in some percentage of
test subjects
 ED50 = effective dose for half the animals in a drug test
 Lethal dose
 dose of a drug that has a lethal effect in some percentage of test subjects
 LD50 = lethal dose for half the animals in a drug test
 Therapeutic index = LD50/ED50
 Always greater than one
 Most drugs have an LD1 well above the ED95
Pharmacokinetic Factors
1. Drug Route of Administration
2. Absorption and Distribution
• Lipid Solubility
• Ionization
• pH
• Stomach Content
• Gender
• Other
•
•
BBB
Placenta
3. Drug Binding
•
Drugs bind to proteins in blood, or
temporarily stored in bones or fat
cells (inactivating drug)
•
Reduces the concentration of drug
at site of action
•
Competition of binding can alter
the concentration of free active
drug potentially leading to
overdose
•
Drug is not altered by liver
enzymes
•
Can terminate action of drugs
4. Inactivation (Biotransformation)
5. Excretion
• Organs:
–
–
–
–
Intestines
Kidneys
Lungs
Sweat glands
• Products:
–
–
–
–
–
Feces
Urine
Water Vapor
Sweat
Saliva
Mechanism of Drug Action
Effects on specific neurotransmitter
systems:
Drugs may alter the availability of
a neurotransmitter by changing the
rate of:
•
•
•
•
Synthesis
Metabolism
Release
Reuptake
Drugs may activate or prevent the
activation of a receptor
Drugs can acts as Agonists
Normal receptor at rest,
channel is closed
Agonist binds and has same effect
as endogenous neurotransmitter,
channel opens
Neurotransmitter binds
receptor and opens channel
Drugs can act as Antagonists
Typical antagonist binds in place
of endogenous neurotransmitter,
prevents neurotransmitter action
Non-competitive binding antagonist doesn’t
interfere with neurotransmitter binding but
still prevents neurotransmitter action
Presynaptic Drug Actions
8. Blockade of NT
degradation
MAO inhibitors
Prozac
Chemical Weapons
Postsynaptic Drug Actions