Synapses and Neurotransmitters Loai.physiology@yahoo€¦ · Synapses and Neurotransmitters...

Synapses and Neurotransmitters

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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


Neurons

• Electrical synapse Chemical synapse


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

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

Drugs acting at cholinergic terminal

Acetylcholine Pathway

Nucleus

basalis


Nucleus

basalis

• arousal and reward

• enhancement of sensory

perceptions

• sustaining attention


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


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



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



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



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



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)



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)


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


mood, sleep, sexuality, impulsivity, aggression,

stress, drug abuse

Serotonin Pathway


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

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