Synapses and Neurotransmitters
Communication Between
Neurons
• Synapse: A specialized site of contact, and
transmission of information between a neuron
and an effector cell
Figure 45-5
Anterior
Motor
Neuron
Communication Between
Neurons
• Electrical synapse Chemical synapse
Communication Between
Neurons
• Chemical synapse
Neurotransmitter:
is a messenger of
neurologic
information from
one cell to another.
Action of Neurotransmitter on
Postsynaptic Neuron
• postsynaptic membrane contains receptor
proteins for the transmitter released from the
presynaptic terminal.
• The effect of neurotransmitter on the post
synaptic neuron depend on the type of the
receptor
Action of Neurotransmitter on
Postsynaptic Neuron
• Two types of receptors
– Ion channels receptors
– Second messenger receptors
Ion Channels receptors
• transmitters that open sodium
channels excite the postsynaptic
neuron.
• transmitters that open chloride
channels inhibit the postsynaptic
neuron.
• transmitters that open potassium
channels inhibit the postsynaptic
neuron.
Seconded messenger receptors
(as example G-protein)
Ion
Channel
1. Opening specific ion
channels
2. Activation of cAMP or
cGMP
3. Activation of one or
more intracellular
enzymes
4. Activation of gene
transcription.
Agonists and Antagonists
Agonists and Antagonists
Neurotransmitters
• Synthesis : esp. rate-limiting enzyme and/or
substrate
• Clearance and inactivation
• Location and pathway
• Dysfunction and CNS pathology
Neurotransmitters• More than 50 chemical substances does
function as synaptic transmitters.
– small molecules which act as rapidly acting
transmitters.
• acetylcholine, norepinephrine, dopamine,
serotonin, GABA, glycine, glutamate, NO.
– neuropeptides.
• endorphins, enkephalins, VIP, ect.
• hypothalamic releasing hormones.
– TRH, LHRH, ect.
• pituitary peptides.
– ACTH, prolactin, vasopressin, ect.
Fast Neurotransmitteres
Glutamate (L-glutamic acid)
• Main excitatory neurotransmitter in the
mammalian CNS
• 95% of excitatory synapses in the brain are
glutamatergic
• Precursor for the GABA (major inhibitory
neurotransmitter)
Enzymatic Pathways Involved in the Metabolism of Glutamate
Glutamate
Gluck et al, Am J Psychiatry 2002; 159;1165-1173
Slow synaptic transmissionFast synaptic transmission
NMDA
AMPA
KainateKainate
Na+
Ca++
presynaptic
postsynaptic
95% of excitatory synapses in the brain are glutamatergic
Kainate
mGluR I
mG
luR
II
mG
luR
III
glu
glutamate
(glu)glutamine
(gln)
gln
glu
Glutamine synthetase
glutaminase
glu
glu
mGluR I
EAAT1/2
EAAT3
gluAMPA R
NMDA R
(-)
KA R
Glia
Postsynaptic
neuron
Presynaptic
neuron
gln
–ketoglutarate
TCA
Zarate et al. Psychopharmacol Bull 2002;36:35-83
Glutamate
synapses
KA R
Glutamate and CNS disorders
1) Stroke
Ischemia no ATP increase Glutamate
Over activation NMDA R & AMPA R
increase Ca+ cell death
2) dysfunction of glutamatergic transmission may
also involve in schizophrenia-like symptoms,
cognitive dysfunction, Depression and memory
impairment
GABA
• Main inhibitory neurotransmitter in the
mammalian CNS
GABA
• Main inhibitory neurotransmitter in the
mammalian CNS
IonotropicGABAA
Heterooligomeric protein
complex that consists of
several binding sites
coupled to an integral Cl-
channel
MetabotropicGABAB
G - protein coupled
receptor, seven
transmembrane domain
protein
GABA-A- ionotropic receptor
• An integral chloride channel activated by competitive agonists: GABA and muscimol
• Blocked by convulsant bicuculine (competitive antagonist) and picrotoxin (noncompetitive antagonist)
• Allosterically modulated by benzodiazepines and barbiturates, which potentiate the effect of GABA
GABA A and ethanol
Ethanol facilitates GABA ability to activate the
receptor and prolongs the time that the Cl-
channel remains open
GABA
Glutamate GABAGAD
GABA is formed by the α-decarboxylation of glutamate
in the reaction catalyzed by GAD (glutamic acid
decarboxylase)
Synthesis
GABA
GABAGABA-T
succinic
semialdehyde
GABA is catabolized into the succinic semialdehade
in the reaction catalyzed by GABA-T (GABA-Transaminase)
Degradation
Acetylcholine
Choline + Acetyl CoA Acetyl choline + CoAChAT
Acetylcholine synapse
Acetylcholine receptors
Acetylcholine receptors
Drugs acting at cholinergic terminal
Acetylcholine Pathway
Nucleus
basalis
Acetylcholine Pathway
Nucleus
basalis
• arousal and reward
• enhancement of sensory
perceptions
• sustaining attention
Acetylcholine Pathway
Nucleus
basalis
• arousal and reward
• enhancement of sensory
perceptions
• sustaining attention
Alzheimer’s disease – loss of
cholinergic cells in nucleus basalis
Neuromodulators
Biogenic Amines
08/20/2008 Lerant: Catecholamines 2008 37
The biosynthetic pathway for the catecholamine
neurotransmitters
Biogenic Amines Synapses
MAO : Monoamine Oxidase
Dopamine
Dopamine receptors
• G protein-coupled receptors
• D1 excite
• D2 inhibit Mainly presynabtic (Autoreceptor)
• D3 inhibit
• D4 inhibit
• D5 excite
08/20/2008 Lerant: Catecholamines 2008 41
3. Dopaminergic
(DA)
synapse
Dopamine Pathways
Lerant: Catecholamines 2008
DOPAMINERGIC PATHWAYS
Substrantia nigra
of midbrain
Ventral
tegmental area
of midbrain
Striatum
Nigrostriatal
pathway
Nucl.
accumbens
Mesolimbic
pathway
Prefrontal
CTX
Mesocortical
pathway
Lerant: Catecholamines 2008
DOPAMINERGIC PATHWAYS
Substrantia nigra
of midbrain
Ventral
tegmental area
of midbrain
Striatum
Nigrostriatal
pathway
Nucl.
accumbens
Mesolimbic
pathway
Prefrontal
CTX
Mesocortical
pathway
• Degeneration of nigro-striatal DA system
and Decreased DAergic trans-mission in
the basal ganglia will lead to
Parkinson Disease
Lerant: Catecholamines 2008
DOPAMINERGIC PATHWAYS
Substrantia nigra
of midbrain
Ventral
tegmental area
of midbrain
Striatum
Nigrostriatal
pathway
Nucl.
accumbens
Mesolimbic
pathway
Prefrontal
CTX
Mesocortical
pathway
PLEASURE, REWARD AND BEHAVIOR
REINFORCING PATHWAY
PLEASURE,
REWARD AND
BEHAVIOR
REINFORCING
PATHWAY
Lerant: Catecholamines 2008
DOPAMINERGIC PATHWAYS
Substrantia nigra
of midbrain
Ventral
tegmental area
of midbrain
Striatum
Nigrostriatal
pathway
Nucl.
accumbens
Mesolimbic
pathway
Prefrontal
CTX
Mesocortical
pathway
PLEASURE,
REWARD AND
BEHAVIOR
REINFORCING
PATHWAY
natural
drug-induced
cocaine
Lerant: Catecholamines 2008
DOPAMINERGIC PATHWAYS
Substrantia nigra
of midbrain
Ventral
tegmental area
of midbrain
Striatum
Nigrostriatal
pathway
Nucl.
accumbens
Mesolimbic
pathway
Prefrontal
CTX
Mesocortical
pathway
PLEASURE,
REWARD AND
BEHAVIOR
REINFORCING
PATHWAY
natural
drug-induced
cocaine
Hyperactivity of mesolimbic pathway:
- positive symptoms of schizophrenia
(hallucinations, etc)
Lerant: Catecholamines 2008
DOPAMINERGIC PATHWAYS
Substrantia nigra
of midbrain
Ventral
tegmental area
of midbrain
Striatum
Nigrostriatal
pathway
Nucl.
accumbens
Mesolimbic
pathway
Prefrontal
CTX
Mesocortical
pathway
PATHWAY INVOLVED IN MOTIVATION TO
EXPLORE THE ENVIRONMENT: CURIOSITY,
INTEREST, COGNITIVE FLEXIBILITY, DRIVE
FOR SOCIAL ENGAGEMENT.
Relative hypofunction in schizophrenia:
Primary mesocortical dopamine deficiency will
increase the NEGATIVE SYMPTOMS like
Cognitive blunting, social isolation, apathy,
anhedonia
Norepinephrine
Norepinephrine receptors
• α family
• Β family
Current Nomenclature of
Adrenergic Receptor Subtypes
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.
Helpful rule of thumb- A drug needs to be at least ten-fold selective for one subtype over the
other subtypes to be considered a useful subtype selective agent.
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)
08/20/2008 Lerant: Catecholamines 2008 52
Noradrenergic
(NE)
synapse
Norepinephrine Pathway
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
NE: Locus Ceruleus FRONTAL CTX
β1 postsynaptic receptor
In FRONTAL CORTEX:
• Mood regulation.
• Hypofunction of pathway:
• Depression
α2 postsynaptic receptor
In FRONTAL CORTEX:
• Attention, working
memory, information
processing.
Serotonin
Serotonin synthesis
Serotonin Pathway
Serotonin Receptors
Serotonin Pathway
Wide spreadAlmost 17 type of receptor
Serotonin Pathway
Wide spreadAlmost 17 type of receptor
mood, sleep, sexuality, impulsivity, aggression,
stress, drug abuse
Serotonin Pathway
Wide spreadAlmost 17 type of receptor
Serotonin system dysfunction involve in :
Depression, Schizophrenia,
OCD, Eating Disorders, Autism
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
Selective Serotonin Reuptake
Inhibitors
serotonin neuron
dopamine neuron
Substantia nigra
Raphe
dopamine
5HT2A
receptor serotonin
5HT2A
receptor
11-18
Newer Antidepressants and Mood Stabilizers
I. Serotonin-Norepinephrine reuptake inhibitor
Venlafaxine, Milnacipran, Duloxetine
SRI
NRI
DRI
SNRI
II. Serotonin Receptor
Antagonist/Reuptake Inhibitor
(SARIs)
Nefazodone, Trazodone
5HT2
NRI
SRI
Nefazodone
SARI (nefazodone) actions at 5HT synapses
5HT2A
5HT1A
Nitric Oxide
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
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
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