Neurotransmitters in the Central

Nervous System
Simone Engelender
Neuronal communication
.

 
 Fast synaptic transmission

Interval between action potential at the nerve terminal and postsypatic response: 500 µs
Opening of Ca2+ channels (calcium microdomains ≥100 µM)
Neurotransmitter secretion and start of postsynapse response
 Neurotransmitter criteria
classical definition

a) Synthesis of neurotransmitters (enzymes, prohormones)

b) Vesicular storage (vesicle types, transporters)
c) Release of neurotransmitters (exocytosis)
d) Receptor activation (ionotropic and metabotropic)
e) Inactivation (degradation, uptake)
Synaptic vesicles and
SNARE
Drugs that can alter synaptic transmission

vesamicol bafilomycin

ω-conotoxin hemicholinium-3
Co2+, Mn2+
Known neurotransmitters
⇒ Biogenic amines (classical 
neurotransmitters)
catecholamines (dopamine,
norepinephrine and epinephrine)
serotonin (5-HT)
histamine
⇒ Acetylcholine
⇒ Purinergic transmitters
(ATP, UTP, adenosine)
⇒ Amino acid transmitters
Glutamate (aspartate)
GABA, glycine
⇒ Peptide neurotransmitters
Opioid peptides (endorphins,
dynorphins, enkephalins),
Neuropeptide Y, Neurotensin
Cholecystokinin, Somatostatin,
Tachykinins (substance P,
neurokinin), Oxytocin, Vasopressin,
etc
⇒ Unconventional transmitters
(nitric oxide, carbon monoxide)
 Types of receptors

Ionotropic receptors
The receptor itself incorporates an
ionophore (ion channel), the gating
of which is allosterically regulated
by agonist binding to the receptor.
Metabotropic receptors
The receptor signals via intracellular
intermediates to cause a change in ion
channel gating, cell excitability,
metabolic state or gene expression.
 Structure of ionotropic receptors

-Ionotropic receptors are composed of subunits with four transmembrane domains and
are assembled as tetramers or pentamers.

-TM2 form the main lining of the pore

-Neurotransmitter binding induces rapid conformational changes that promote the

increase in the diameter of the pore.

-Cation or anion selectivity is obtained through the coordination of specific negatively or

positively charged amino acids at strategic locations in the receptor pore.
 Structure of metabotropic receptors

-Metabotropic receptors are G-protein coupled receptors, which are composed of a single subunit with
seven transmembrane domains. Binding site for neurotransmitter lies within the core of the circular
structure formed by the transmembrane segments.

-Third internal loop can have different sizes, depending on the type of metabotropic receptor.

-Third internal loop seems to be important for G-protein coupling and activation. Conformational changes
upon transmitter binding exposes third internal loop.

-Can have different types of coupled G-proteins. A single receptor can activate multiple G-proteins
molecules “collision coupling”. Most common effector enzymes: Adenylate cyclase (cAMP), Phospholipase
C (diacyl-glycerol (DAG) + inositol trisphosphate (IP3 → Ca2+).

-cAMP, cGMP, DAG, Ca 2+ can activate protein kinases but can also modulate ion channels. G proteins
can also couple directly to ion channels.

-Receptor desensitization occur by covalent modifications, such as phosphorylation (fast), or by physical

removal (sequestration/downregulation; slow).
Neurotransmitter receptors
Ionotropic receptors

Metabotropic receptors
 CNS acting drugs
• Opioid analgesics
• Psychotomimetics, stimulants, alcohol and other drugs of
abuse
• Drugs used in psychiatry:
– Antidepressants
– Antipsychotics (neuroleptics)
– Anxiolytics, hypnotic-sedatives
• General anesthetics
• Anticonvulsants (antiepileptics)
• Drugs for Parkinson’s and Alzheimer’s diseases
 Amino acid neurotransmitters
Derived from intermediary glucose metabolism and also glutamine
Excitatory – glutamate, aspartate
Inhibitory – GABA, glycine
 Cartoon of glutamatergic neuron
Two precursors for 
glutamate synthesis

α ketoglutarate glutamine

transaminase glutaminase
(phosphate-
(GABA-T)
activated)
glutamate

-Major excitatory transmitter in the brain

-Almost ubiquitously present in the CNS
-Mostly projection neurons (e.g. pyramidal cells of cerebral cortex)
 Glutamate receptors
non-NMDA (AMPA/KA) receptors       
        -Mediate most fast synaptic excitation
-Not very Ca2+ permeable
NMDA receptors
-Ca2+ permeable
-Critical for long term-potentiation (LTP)
Metabotropic (mGluR) receptors
-G-protein coupled receptor
-IP3 formation and intracellular Ca2+
signaling, and inhibition of adenylate cyclase
-Pre- and postsynaptic
-mGluR1, mGluR5 (Gq  ↑ PLC)
-mGluR2, mGluR3, mGluR4, mGluR6,GluR7,
mGluR8 (Gi  ↓ AC)
-mGluR1: long-term synaptic plasticity (LTP,
LTD)
 Ionotropic Glutamate Receptors

I o n o t r o p ic G lu t a m a t e R e c e p t o r s

N M D A re c e p to r K A re c e p to rs A M P A re c e p to rs

NMDA (N-methyl-D-aspartate*) receptors .1

KA (kainate*) receptors .2

AMPA ( .3α-amino-3-hydroxy-5-methylisoxazoleproprionic acid*) receptors

preferred agonist *
 Ionotropic glutamate receptors
Ion (Ca2+) channel

-Non-NMDA receptors: Pentameric (GluR1-GluR4), GluR2 alone produce little current (relatively
impermeable to Ca2+)
-NMDA receptors: obligatory NR1 subunit with multiple NR2(A-D) subunits
-NMDA receptors: well modulated channel. Important for development, learning and also neuronal damage
glycine and d-serine are co-agonists. L-aspartate can also activate NMDA channel
Mg2+ provides a voltage-dependent block
PCP and MK-801 block its ion channel
AP-5 is an antagonist of glutamate-binding site
Long term potentiation (LTP)
Properties of Glutamate Receptors
NMDA and Schizophrenia: PCP (Phencyclidine)

-Developed in the 1950s as an intravenous anesthetic. Postoperative symptoms included

dysphoria, confusion, delirium, and psychosis.

-Popular names: Angel dust, Ozone, Wack and Rocket fuel

-It is a "dissociative drug”: it distorts perceptions of sight, sound and produces feelings
of detachment (dissociation) from the environment and self.

-PCP is addictive

-High doses can cause symptoms that mimic schizophrenia, such as delusions
(‫ )מחשבות שווא‬hallucinations ,((‫הזיות‬paranoia, disordered thinking, a sensation of ,
distance from one's environment, and catatonia.

-Abuse of PCP for long periods can cause memory loss, difficulties with speech and
thinking, depression, and weight loss. PCP has sedative effects, and interactions with
other central nervous system depressants, such as alcohol and benzodiazepines, can lead
to coma.
 NMDA and Schizophrenia: glycine and d-Serine

- NMDARs require the binding of co-agonists (glycine or d-serine) for efficient

opening of the ion channel.

- d-Serine was found to co-agonize the NMDA receptor with even greater
potency than glycine.

- Removal of d-serine can block NMDA-mediated excitatory neurotransmission

and toxicity.

- d-serine is produced by serine racemase in glial cells and neurons, and is

enriched in the same areas as NMDA receptors.

- The use of d-serine and glycine as adjuvant therapy (together with clozapine)
or monotherapy for schizophrenic patients is under investigation.
 NMDA and general anesthetics: ketamine
• Binds to the same PCP site. Also bind to opioid receptors.

• Patients reach rapid hypnotic state, analgesia, unresponsiveness and

amnesia but can open their eyes, have involuntary movements and
spontaneous respiration (Cataleptic state: Dissociative anesthesia).

• May have nystagmus with pupillary dilation, salivation and/or

lacrimation, spontaneous limb movement with increased muscle tone

• Increase of cerebral blood flow and intracranial pressure

(contraindicated in patients with increased intracranial pressure and
cerebral ischemia).

• Can cause increase in blood pressure

• Potent bronchodilator (indicated for patients with bronchospasm)

• Important side effect: hallucinations, vivid dreams, delusions…

 NMDA and Alzheimer’s disease: Memantine
Memantine is a low-affinity non-competitive
antagonist of NMDA receptors. The low affinity and
rapid off-rate kinetics of memantine at the level of
the NMDA receptor preserves the physiological
function of the receptor that can still be activated by
high concentrations of glutamate following
depolarization.

Common adverse drug reactions (≥1% of

patients) include: confusion, dizziness,
drowsiness, headache, insomnia, agitation,
and/or hallucinations. Less common adverse
effects include: vomiting, anxiety, hypertonia,
cystitis, and increased libido.
 Cartoon of GABAergic neuron
Two pathways for 
GABA synthesis
α ketoglutarate glutamine

transaminase glutaminase
(GABA-T) (phosphate-
activated)
glutamate
glutamic acid
decarboxylase
(GAD65/67)
GABA

- Major inhibitory transmitter in the brain

- Glutamic acid decarboxylase (GAD 65/67) is the critical biosynthetic enzyme for GABA.
- GAD is not present in glutamatergic neurons. GABA and glutamate NT pools never colocalize.
- Major postsynaptic GABA receptor is GABAA.
- Release is regulated by GABAB metabotropic autoreceptors at the terminals
- Inactivation by GABA transporters (same family as NET, DAT, SERT, GLYT): neuron and glia
- Metabolized by GABA-T (back to Krebs Cycle – so called GABA shunt)
- GABA neurons are prominent in the cortex where they are local circuit interneurons. Can also be
long-axoned GABA projection neurons (e.g. striatum to substantia nigra).
Benzodiazepine
GABA
GABA receptors

Channel pore
GABAA receptors
Chloride - Major inhibitory receptor in the brain
Barbiturates - Ionotropic
- Multiple subunits providing numerous
Steroids combinatorial possibilities
- Well modulated channel -many drugs can
interact with this channel:
Picrotoxin -Barbiturates
- Benzodiapines (regulates and potentiate
GABA binding) Used in Status Epilepticus
Cl-
-Ethanol
-Neuroactive steroids (metabolites of
GABAB receptors progesterone, coticosterone and testosterone
-Metabotropic, dimeric receptor potentiate GABA currents), anesthetics
Can be pre- and postsynaptic
Coupled to adenylate cyclase, inhibitory -Picrotoxin (convulsant-prevent ion flow)
Agonist: Baclofen (muscle relaxant): spinal cord -Bicucullin (convulsant-decrease binding of
injury, cerebral palsy, etc. GABA)
 GABA receptors
• GABA-A: inhibitory
ionotropic ↑ chloride conductance

• GABA-B inhibitory (presynaptic)

metabotropic ↓ Ca++ conductance

inhibitory (post-synaptic)
↑ K+ conductance
 GABAA Receptor

-
Cl
channel

β2

α1
GABA
binding site α1

β2

γ2
 GABA receptors
agonists and antagonists
Agonists           Antagonists

• GABA-A Muscimol Bicuculline,

(binds to GABA site) Picrotoxin
BDZ: Flumazenil

• GABA-B Baclofen Saclofen

Amanita muscaria contains

muscimol (alkaloid)- cause
hallucinations
 BDZ X Barbiturates
• Barbiturates produce their effects by increasing the length of time the
chloride GABAA ion channel remains open.

• The benzodiazepines increase the opening frequency of the GABAA

chloride ion channel.

• The more extensive opening of the chloride ion channel seems to be one of
the reasons for the increased toxicity of barbiturates compared to
benzodiazepines in overdose.
 GABAA and benzodiazepines
• Unlike barbiturates, BDZ increase GABA binding

• Sedation rather general anesthesia, decreased anxiety, muscle relaxation, coronary

vasodilation, anterograde amnesia /hypnosis

• Effective anticonvulsivants and used in status epilepticus (Diazepam)

• Used for anxiolysis, sedation and amnesia prior to anesthesia or small procedure that
does not require anesthesia.

• Midazolam (Hypnotic) used for small procedures since it has a short half-life and it can
be administered iv and by infusions

• Decrease blood pressure and respiratory drive (can result in apnea in children, patients
with decreased hepatic function, alchool abuse…)

• Competitive antagonist: Flumazenil

• Also used in alcohol withdrawal syndrome: Prevent seizures and delirium

 GABAA and benzodiazepines
Side effects
• Drowsiness
• Dizziness
• Upset stomach
• Blurred Vision
• Headache
• Confusion
• Depression
• Impaired coordination
• Changes in heart rate
• Trembling
• Weakness
• Dreaming or nightmares
• Chest pain
• Vision changes
• Jaundice
• Amnesia, cognitive decline
• Paradoxical reactions: mania, anger, impulsivity, violent outbursts
 GABAA and barbiturates
• Binds to site different from GABA and also BDZ. Enhance the effects of GABA and
can produce profound CNS depression (pentobarbital, thiopental)

• Also block the AMPA receptor, which can explain the strong CNS-depressant effects
of these agents

• Sedation and anesthesia. They are also effective as anxiolytics, hypnotic and as
anticonvulsants.

• Certain barbiturates have anticonvulsant activity (Phenobarbital, mephobarbital)

• More sedation than BDZ, may have euphoriant effects (specially among geriatric
patients)

• In patients with pain, restlessness, excitement, delirium and increase of pain may
occur

• Interaction with ethanol can increase CNS depression

• Tolerance, addition, overdose

• Thiopental is an ultra-short acting barbiturate used as a "truth serum". The drug

decrease inhibitions, making people more likely to be caught off guard when
questioned.
 GABAA and barbiturates
- Physical and psychic dependence

- Intoxication include:
Respiratory depression, lowered blood pressure, fatigue, fever, unusual
excitement, irritability, dizziness, poor concentration, sedation, confusion,
impaired coordination (Ataxia), nystagmus, impaired judgment, addiction,
and respiratory arrest, which may lead to death.
 GABAA and ethanol
• Bicuculline and Flumazenil reduce ethanol
consumption in rodents.

• Injection of agonist muscimol in the limbic

system can substitute ethanol in rodents.
 GABAA and ethanol
• Death from ethyl alcohol consumption is possible when
blood alcohol level reaches 0.4%. A blood level of 0.5%
or more is commonly fatal. Levels of even less than
0.1% can cause intoxication, with unconsciousness often
occurring at 0.3–0.4%
 GABAA and ethanol
BAC(mg/ Symptoms
dL)
50 Euphoria, talkativeness, relaxation

100 Central nervous system depression, impaired motor and sensory

function, impaired cognition

> 140 Decreased blood flow to brain

300 Stupefaction, possible unconsciousness

400 Possible death

> 550 Death

 GABAA and general anesthetics
• GABAA is sensitive to inhaled gases, such as halotane.

• Also to intravenous agents: barbiturates, propofol, etc.

• They decrease the closure of ion channel of GABAA

receptor.

• Probably GABAA receptor has a specific site for binding

anesthetics since mutations in the receptor can eliminate
their effects.
 GABAA and Antiepileptic drugs
Valproate GABA-Transaminase gastrointestinal upsets, alopecia,
inhibitor (+/-) peripheral edema, weight gain,
hepatotoxicity, teratogenicity

Vigabatrin GABA-Transaminase fatigue, drowsiness, weight gain,

inhibitor behavioral and mood changes,
depression, agitation, confusion,
psychosis (rare), visual defects (after
long term use)
Tiagabine GABA reuptake inhibitor dizziness, fatigue, confusion,
depression, confusion, ataxia, tremor,
gastrointestinal upsets, psychosis
(rare), skin rash
Gabapentin Alter GABA release and dizziness, fatigue, drowsiness,
(Neuropathic and uptake ? gastrointestinal upsets, ataxia,
herpetic pain) tremor
 GABAA and Antiepileptic drugs
Seizure Type Drug
Simple and complex Lamotrigine (Lamictal), Oxcarbazepine (Trileptal),
partial Gabapentin (Neurontin), Topiramate (Topamax)
Phenytoin (Dilantin), Carbamezapine (Tegretol),
Valproate
Secondarily generalized Same as “Simple and complex Partial”
tonic-clonic

Absence Ethosuximide, Lamotrigine, Valproate

Myoclonic Lamotrigine, Valproate, Clonazepam
Atonic Lamotrigine, Valproate, Felbamate
Tonic-clonic Same as “Simple and complex Partial”
 Glycine neurotransmission
- Major inhibitory neurotransmitter in spinal cord and brainstem

- Actions terminated by uptake (GLYTs) by neurons and glia

-Glycine receptors are ionotropic (similar to GABAA receptors):

permeable to Cl-

- Receptors blocked by strychnine

−α and β subunits. β subunit is widespread and may have

additional functions besides its association with glycine receptors.

- Glycine also binds to NMDA-R (co-agonist)

 Glycine receptors

Action: inhibitory,
↑ chloride conductance

Agonists taurine, β-alanine

Antagonist strychnine