Neurotransmitters

in CNS
 Discovery of neurotransmitters

Early 20th century

Histological examinations
of Ramón y Cajal
German pharmacologist
Otto Loewi 1921
Criteria for neurotransmitters
Categories of Neurotransmitters
Excitatatory Amino Acids
◦ Glutamate
Inhibitory Amino Acids
◦ GABA & Glycine
Monoamine Mediators & Pathways
◦ Noradrenaline
◦ Dopamine
◦ 5 HT
◦ Acetylcholine
◦ Histamine
Speed & receptors…
Fastneurotransmitters (e.g. glutamate,
GABA) operate through ligand-gated ion
channels

Slow neurotransmitters and

neuromodulators (e.g. dopamine,
neuropeptides, prostanoids) operate
mainly through G-protein-coupled
receptors.
GLUTAMATE
Glutamate & GABA interlinked
 Glutamate Roles

Synaptic plasticity
Excitotoxicity
Pain Perception
Long term
Potentiation
Glutamate receptors
Ionotropic (fast): Na+ in
◦ AMPA: fast excitatory signals
◦ Kainate: fast excitatory, autoreceptor (↑ GLT
release)
Ionotropic (slow): Na+, Ca2+ in
◦ NMDA: sustained, high-frequency excitatory
signals
◦ Activated by repeated excitatory stimulation:
escalation
Metabotropic (slow): K+ out; Ca2+ in
Main sites of drug action on NMDA and
GABAA receptor
NMDA receptors
Highly permeable to Ca2+, as well as to
other cations Na+
Activation of NMDA receptors
Ca2+ entry.
Blocked by Mg2+
Activation requires glycine & glutamate
Selective NMDA blocking agents
◦ Ketamine & Phencyclidine (PCP-angel dust)
both dissociative anaesthetic
NMDA receptor antagonist.
Competitive antagonists
Selfotel: anxiolytic
Uncompetitive channel blockers
Amantadine: Parkinson's disease
Alzheimer's
Memantine: Alzheimer's disease
Xenon: an anaesthetic.
Eliprodil: an anticonvulsant with
neuroprotective drug.
Non-competitive antagonists
Ketamine
GABA
GABA
GABA functions as an inhibitory
transmitter in many different CNS
pathways.
About 20% of CNS neurons are
GABAergic; most are short interneurons,
but long GABAergic tracts run to the
cerebellum and striatum.
GABA serves as a transmitter at about
30% of all the synapses in the CNS.
 GABA Receptors

Two types of GABA Receptors:

◦ GABA-A
 Cl- channel  binding Cl- conductance in
presynaptic neurons
 “fast” response (1msec)
 Benzodiazepines, barbiturates
◦ GABA-B
 G-protein coupled receptor
 K+ conductance
 “slow” response (1sec)
Main sites of drug action on NMDA and
GABAA receptor
GABAergic Drugs
a)GABAA receptor Agonists
barbiturates, benzodiazepines, carisoprodol,
chloral hydrate, etomidate, glutethimide,
muscimol, neuroactive steroids,, propofol,, .

b)GABAA receptor Antagonists

bicuculline, cicutoxin, flumazenil,
furosemide, gabazine, picrotoxin,
GABAB receptor
GABAB Receptor Agonists
baclofen, propofol,
GABAB Receptor Antagonists:
phaclofen, saclofen.
GABA reuptake inhibitors: tiagabine.
GABA-transaminase inhibitors: gabaculine,
phenelzine, valproate, vigabatrin,
GABA analogues: pregabalin, gabapentin.
Monoamine Transmitters

◦ Noradrenaline (Norepineprine)
◦ Dopamine
◦ 5 HT (Serotonin)
◦ Acetylcholine
◦ Histamine
NORADRENALINE
Noradrenaline Synthesis
The basic processes responsible for the
synthesis, storage, release and reuptake of
noradrenaline are the same in the brain as in
the periphery and the same types of
adrenoceptor are also found in pre- and
postsynaptic locations in the brain.
Noradrenaline Function
The actions of noradrenaline are mainly
inhibitory (β-receptors), but some are
excitatory (α- or β-receptors).
Noradrenergic transmission functions in
◦ the 'arousal' system, controlling wakefulness
and alertness
◦ blood pressure regulation
◦ control of mood (functional deficiency
contributing to depression).
Noradrenaline excess
NA Sympathetic nervous system of brain
ADD, ADHD
ADD with comorbid anxiety
Anxiety – PTSD
Panic attacks
Depression
Sleep disturbances
Mediating survival mechanisms
 What cofactors
that drive
Dopamine to
Copper & Noradrenaline?
Ascorbic Acid
Noradrenaline Pathway
The cell bodies of noradrenergic neurons
occur in small clusters in the pons and
medulla, and they send extensively
branching axons to many other parts of the
brain and spinal cord
 The most prominent cluster is the locus
coeruleus (LC), located in the pons. 
◦ descending control of pain pathways
Noradrenergic Drugs
Psychotropic drugs that act partly or
mainly on noradrenergic transmission in the
CNS include
◦ Antidepressants
◦ Cocaine
◦ Amphetamine.
◦ Antihypertensive drugs – clonidine &
methyldopa
DOPAMINE
Dopamine & Brain Function
The brain is designed to orientate itself to
experience of high emotional valence
Emotional significance
Pain and pleasure
Motivation
Cerebral microcirculation
Dopamine Significance
Dopamine is particularly important in
relation to neuropharmacology;
◦ Parkinson's disease
◦ Schizophrenia – hyperdopaminergic state
◦ Attention deficit disorder
◦ Substance abuse
◦ Endocrine disorders
◦ Fatigue, concentration difficulty, low
motivation (anhedonia)
Dopamine Synthesis
Dopaminergic
neurons lack
dopamine β-
hydroxylase, and
thus do not
produce
noradrenaline.
Tyrosine
hydroxylase
needs iron as
cofactor
Dopamine Metabolism
Dopamine Distribution
Distribution of dopamine in the brain is
more restricted than that of noradrenaline

Dopamine is most abundant in the corpus

striatum, a part of the extrapyramidal
motor system concerned with the
coordination of movement
Dopamine Pathways & Function
Nigrostriatal
pathway - 75% of the
dopamine in brain
◦ Cell bodies in the substantia nigra whose
axons terminate in the corpus striatum.
◦ Motor Control
 Parkinsons Disease – dopamine deficiency
here.
Dopamine Pathways & Function
Mesolimbic/mesocortical pathways
◦ Cell bodies in midbrain and whose fibres project
to parts of the limbic system, especially
the nucleus accumbens and the amygdaloid
nucleus and to the frontal cortex.
◦ Focus and orient frontal lobes to pay attention
◦ Emotion and drug-induced reward systems
◦ Mesocorticol dopamine deficiency - ADHD
◦ Mesolimbic dopamine deficiency -
Schizophrenia
Dopamine Pathways & Function
Tuberohypophyseal system 
◦ Group of short neurons running from the
ventral hypothalamus to the median eminence
and pituitary gland

◦ Regulate secretions of pituitary gland

 Prolactin release (inhibited)
 Growth hormone release (stimulated)
Dopamine Pathway
Dopamine Receptors
There are five dopamine receptor subtypes.
Dopamine receptors.pdf
◦ D1 and D5 receptors are linked to stimulation of
adenylyl cyclase – excitatory frontal lobe
◦ D2, D3 and D4 receptors are linked to inhibition
of adenylyl cyclase - inhibitory subcortical
areas
◦ Most known functions of dopamine mediated
mainly by receptors of the D2 family -
schizophrenia
Dopamine Drugs
 Pharmacological Treatment of
Parkinson’s Disease
Goals:
= restore dopamine receptor function.

Several types of drugs:

◦ Levodopa
◦ Dopamine Receptor Agonists
◦ Monoamine Oxidase Inhibitors (MAOIs).
◦ Catechol-O-Methyltransferase (COMT) inhibitors.
Amantidine.
Vomiting
Dopaminergic neurons have a role in the production of
nausea and vomiting.
Nearly all dopamine receptor agonists (e.g.
bromocriptine) and other drugs that increase
dopamine release in the brain (e.g. levodopa) cause
nausea and vomiting as side effects,
Dopamine antagonists (e.g. phenothiazines,
metoclopramide) have antiemetic activity.
◦ D2 receptors occur in the area of the medulla
(chemoreceptor trigger zone) associated with the initiation
of vomiting and are assumed to mediate this effect.
SEROTONIN
Serotonin (5-HT)
Lysergic acid diethylamide (LSD), a drug known to
be a powerful hallucinogen acted as a 5-HT
antagonist on peripheral tissues, and suggested that its
central effects might also be related to this action.
5HT2A

5-HT is mainly found in 99% in gut, but1% in brain

important.

Selective serotonin reuptake inhibitors constitute

an important group of antidepressant drugs.
5-HT Synthesis
5-HT synthesis
resembles
noradrenaline.

Except precursor is
Tryptophan not Tyrosine

Availability of
tryptophan is the main
factor regulating
synthesis
5-Hydroxytryptamine pathways
Serotonin Pathways
5-HT neurons are concentrated in the
midline raphe nuclei in the pons and
medulla,
◦ Projecting diffusely to the cortex
◦ Limbic system
◦ Hypothalamus
◦ Spinal cord

Similar to the noradrenergic projections.

5-HT Functions
Functionsassociated with 5-HT pathways
mainly vegetative functions
◦ Social engagement
◦ Mood and emotion
◦ Appetite
◦ Sleep/wakefulness
◦ Control of sensory pathways, including
nociception
◦ Body temperature control
◦ Vomiting
Serotonin imbalance
Depression
Anxiety
Obsessions and Compulsions
Pain Sensitivity
Aggression
Sleep Disorders
5-HT receptor selective drugs
Serotonin reuptake inhibitors
(SSRIs)- fluoxetine, used as
antidepressants
5-HT1D receptor agonists, - sumatriptan -
treat migraine
5-HT1A receptor agonist used in treating
anxiety - buspirone & vitamin D
5-HT3 receptor antagonists, -  ondansetron
- antiemetic agents
5-HT receptor antagonists
5-HT3 receptor antagonist :Ondansetron
Chemotherapy induce vomiting
5-HT4 receptor antagonist :Metoclopramide
Gastrokinetic and anti emetic
5-HT reuptake inhibitors ( SSRI )
Fluoxetine :Depression and OCD
ACETYLCHOLINE
Acetylcholine Synthesis

Synthesis, storage and release of

acetylcholine (ACh) in the central
nervous system (CNS) are essentially
the same as in the periphery
Acetylcholine pathways
ACh is widely distributed in the CNS,
important pathways being:
◦ Magnocellular forebrain nuclei  which send a
diffuse projection
 Degeneration – Alzheimer’s Dementia
◦ Septohippocampal projection
◦ Short interneurons in the striatum and nucleus
accumbens.
Acetylcholine pathways
Acetylcholine Receptors
Acetylcholine has mainly excitatory
effects
◦ Nicotinic (ionotropic)
◦ Muscarinic (G-protein-coupled – some
muscarinic ACh receptors (mAChRs) are
inhibitory.
The mAChRs in the brain are
predominantly of the M1 class
Acetylcholine Function
Muscarinic receptors appear to mediate the
main behavioural effects associated with
ACh,
◦ Arousal
◦ Learning
◦ Short-term memory
◦ Reward

Muscarinic antagonists (e.g. scopolamine)

cause amnesia.
 Acetylcholine Drugs
Acetylcholinesterase Inhibitor: Alzheimers
disease
◦ Tacrine
◦ Donepezil
◦ Galantamine
◦ Rivastigmine

. Muscarinic Cholinergic Receptor Antagonists:

Trihexyphenidyl and Benztropine
Histamine
Histaminergic neuron origin
Projections
Roles
1)arousal
2)body temp
3) sleep
Antihistminics :H1 receptor blocker
sedation as side effect
References
Rang et al (2007) Rang & Dale’s
Pharmacology 6th Ed.
Jay Lombard DO – Neurotransmitters &
Behaviour