INTRODUCTION TO CNS

PHARMACOLOGY

DANIEL CHANS M (MPS)

BPharm, MSc, MPharm Clinical

Pharmacy

Department of Pharmacology and

Therapeutics

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DANIEL CHANS M (MPS) July 2021
NEUROTRANSMISSION IN THE CNS

DANIEL CHANS M (MPS) 2

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 Neurotransmitters…
• Review what is a neurotransmitter?
• Examples of neurotransmitters?
• Functions of the neurotransmitters?
• Inhibitory and excitatory neurotransmitters?
• EPSPs and IPSPs
• Brief: Functions and Pathways of the different
NTs

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DANIEL CHANS M (MPS)
July 2021
 Definitions
• Neurotransmitter

• Neuromodulator

• Neurohormone

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 Neurotransmitters
• Neurotransmitters are endogenous chemicals that
transmit signals from a neuron to a
target cell across a synapse.

• Neurotransmitters are packaged into synaptic

vesicles clustered beneath the membrane on the
presynaptic side of a synapse, and are released into
the synaptic cleft, where they bind to receptors in the
membrane on the postsynaptic side of the synapse.

• Release of neurotransmitters usually follows arrival of

an action potential at the synapse, but may also
follow graded electrical potentials.
 Types of neurotransmitters
Major neurotransmitters:

– Amino acids: glutamate, aspartate, D-serine, γ-amino

butyric acid (GABA), glycine

– Monoamines and other biogenic amines: dopamine (DA),

norepinephrine, epinephrine, histamine, serotonin (5-HT)

– NeuroPeptides: opioid peptides [enkephalins] and

tachykinins [neurokinins and
substance P]

– Others: acetylcholine (ACh), adenosine, anandamide, nitric

oxide, etc.
CNS neurotransmitters may be excitatory, inhibitory, or both.

EXCITATORY: Aspartate, glutamate, histamine, and tachykinins.

INHIBITORY: Dopamine, GABA, glycine, and opioid peptides.

BOTH: Acetylcholine, norepinephrine, serotonin.

– Their actions are exerted via different receptors.

CNS drugs act primarily by affecting the synthesis, storage, release,

reuptake, or degradation of neurotransmitters or by activating or
blocking receptors.

Receptors for CNS neurotransmitters can be classified as ionotropic

(directly coupled with ion channels) or metabotropic (coupled with G
proteins and second messengers).

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 Fast Vs Slow Neurotransmitters

• Neurotransmitters may be divided into:

 Fast neurotransmitters, operating through

ligand gated ion channels (e. g glutamate,
GABA)

 Slow neurotransmitters and

neuromodulators operate mainly through G-
protein-coupled receptors (e. g dopamine,
neuropeptides, prostanoids)

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• A neuromodulator has no intrinsic activity but is active
only in the face of ongoing synaptic activity, where it can
modulate transmission either pre- or postsynaptically.

• A modulating agent, however, does produce changes in

conductance or membrane potential in many instances.

• Modulatory effects typically involve a second-messenger

system.

• A NEUROHORMONE has intrinsic activity and can be

released from both neuronal and non-neuronal cells.

• Most importantly, a neurohormone travels in the

circulation to act at a site distant from its release site. 11
• Neuromodulators are released by neurons and by
astrocytes and produce rapid slower pre-or postsynaptic
responses. e.gs nitric oxide (NO), arachidonic acid
metabolites, neurosteroids, adenosine, and purines.

• Neurotrophic factors: These are substances produced

within the CNS by neurons, astrocytes, microglia, or
transiently invading peripheral inflammatory or immune
cells that assist neurons in their attempts to repair
damage.

• They act on tyrosine-kinase linked receptors, which

regulate gene expression, and control neuronal growth
and phenotypic characteristics.

• Examples: chemokines, cytokines and growth factors

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• NEUROPEPTIDES???
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 …
• The functional unit of the central nervous system (CNS)
is the neuron.
• CNS neurons are capable of transmitting information to
and receiving information from other neurons and
peripheral end organs, such as muscle cells
• The depolarization associated with an action potential
results in the calcium-facilitated release of a specific
chemical substance at the synapse between two
neurons
• This chemical substance or neurotransmitter is
released, diffuses across the synaptic cleft, and
interacts with the membrane of the second neuron to
initiate a local change in the ionic composition and a
local altered potential difference in the second
neuron 14
 Intro…
• This potential difference change is known as a
postsynaptic potential, and may be either depolarizing or
hyperpolarizing.
• A depolarizing postsynaptic potential is called an
excitatory postsynaptic potential (EPSP).
• If the magnitude of depolarization produced by EPSPs in the
second neuron is great enough, an action potential
produced in the second neuron will be transmitted in an all-
or-none fashion through the neuron and its processes.
• If, on the other hand, a hyperpolarizing potential (known
as an inhibitory postsynaptic potential,or IPSP) is
produced, it will inhibit the formation of depolarizing action
potentials.
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DANIEL CHANS M (MPS)
• Neurotransmitters are chemical mediators which are
released from nerve endings into the synaptic cleft once
an action potential has been reached eliciting an influx of
Ca2+ ions (a voltage dependent action).

• The neurotransmitter then reaches its target

postsynaptic receptor site with the result being either
direct excitation or inhibition or enhancing excitation or
inhibition.

• Excitatory postsynaptic potential (EPSP) is elicited

following the excitatory transmitter acting on ionotropic
receptor, causing an increase in sodium ion
permeability.

• Inhibitory postsynaptic potential (IPSP) is elicited

following an inhibitory transmitter acting on its receptor,
causing in postsynaptic membrane hyperpolarization 16
owing to selective opening of Cl- channels.
Amino acid transmitters

Excitatory Amino acids – Glutamate & Aspartate

GLUTAMATE

• Glutamate is widely distributed in the CNS

• Prominent glutamatergic pathways are
• The connections between thalamus and cortex, the
projections from cortex to striatum (extrapyramidal
pathway) and to brainstem.

• Synthesis: Glutamate comes from glucose via the TCA

or glutamine.

• Transminase enzyme catalysez the interconversion of

glutamate and alpha-oxoglutarate
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 Glutamate..

• In the neuron, glutamine is converted to glutamate by

the glutaminase enzyme.

• The glutamate is then concentrated in vesicles by the

vesicular glutamate transporter (VGLUT).

• Glutamate is released into the synaptic cleft by Ca2+-

dependent exocytosis.

• The released glutamate acts on postsynaptic glutamate

receptors and is cleared by glutamate transporters
present on surrounding glia.

• In glia, glutamate is converted to glutamine by

glutamine synthetase, released from the glia, taken up
by the nerve terminal, and converted back to glutamate
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by the enzyme glutaminase. DANIEL CHANS M (MPS)
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Glutamate

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• Receptors:

• Four main types are known

 N-methyl-D-aspartate (NMDA) – ionotropic receptor,

activation promote entry of Ca2+, with a distinct site for
glycine. Selectively blocked by Ketamine and
phencyclidine.
 α-amino-3-hydroxy-5-hydroxy-5-methyl-4-
isoxazoleproprionate (AMPA) – ionotropic receptor, with
higher permeability to Ca2+, serve to mediate fast
excitatory synaptic transmission in the CNS

 Kainate receptors –ionotropic receptor with a

presynaptic role

 Metabotropic receptors – linked to IP3 and release of

[Ca2+]i
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• Functions:

• NMDA receptors in the hippocampus are important in the creation of

long-term potentiation (LTP), a crucial component in the formation of
memory.

• Excess stimulation of glutamate receptors, as seen in seizures or

stroke, can lead to unregulated Ca2+ influx and neuronal damage
(Excitotoxicity)

• Glutamate is a predominant excitatory neurotransmitter in the

mammalian CNS.
• When intensely activated, it can be toxic to neurons in a range of acute
CNS injury conditions, including stroke, hypoglycemia, trauma and
status epilepticus.

• Excess glutamate is also implicated in neurodegenerative

conditions with involvement of the NMDA subtype.

• Decreased glutamate function is thought to be involved in the creation of

psychotic symptoms.

• Phencyclidine (PCP) and Ketamine can induce psychotic sympotms. 24

Gamma-aminobutyric acid
(GABA)

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Inhibitory amino acids – GABA and glycine

• GAMMA-AMINOBUTYRIC ACID

• GABA is the main inhibitory transmitter in the brain. GABAergic

neurons distributed in the cortex, thalamus, striatum, basal
ganglia, substantia nigra

• GABA is synthesized from glutamate by the action of glutamic

acid decarboxylase (GAD), degraded by GABA transaminase,
which is inhibited by vigabatrin, an antiepileptic agent.

• GAD is present in many nerve endings of the brain as well as in

the β-cells of the pancreas.

• The activity of GAD requires pyridoxal phosphate (PLP) as a

cofactor.
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 GABA

Daniel Chan M MPS 27

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GABA RECEPTOR

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Daniel Chans. M Dept of Pharm & Therapeutics-MUST

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 GABA-B Receptors

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DANIEL CHANS M (MPS) July 2021
 GABA receptors:
 GABAA- receptors- coupled to a Cl- channel, mediate fast
postsynaptic inhibition.
 Increasing Cl- permeability hyperpolarises the cell,
thereby reducing its excitability.

 GABAB receptors- a G-protein coupled receptor, located

both pre- and postsynaptically, inhibit voltage Ca-channels
and opening K+-channels.

• Examples of Drugs acting on GABAA receptors

• Muscimol –hallucinogenic compound derived from mushroom- a

powerful GABAA –receptor agonist

• Bicuculline – a naturally occurring convulsant compound, an

antagonist that blocks the fast inhibitory synaptic potential.
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• Benzodiazepines – potentiate the effect of GABA on
GABAA receptors. A powerful sedative and anxiolytic

• Picrotoxin – a convulsant that acts by blocking the Cl-

channel associated with the GABAA receptor.

• GABAB- receptor: Baclofen – selective agonist, used to

treat spasticity and related motor disorders.

• NB: Look out more drug examples

• E.g Barbiturates which have GABA potentiating and

GABA mimetic effects

• Etc…..
DANIEL CHANS M (MPS) July 2021 33
• NORADRENALINE

• NA produced in the noradrenergic neurons. Precursor is

tyrosine.

• NA containing cells are located in the locus ceruleus.

• Types of adrenergic receptors (α and β) and their

subtypes have been described in the CNS; all are
GPCRs.

• Arousal and mood.

• Amphetamine-like drugs, which release catecholamines

in the brain, increase wakefulness, alertness and
exploratory activity.

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 Noradrenaline…

• There is a close relationship between mood and

state of arousal; depressed individuals are
usually lethargic and unresponsive to external
stimuli.

• The catecholamine hypothesis of affective

disorders suggested that depression results
from a functional deficiency of noradrenaline in
certain parts of the brain, while mania results
from an excess.

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• Blood pressure regulation

• NA has also a role in in blood pressure regulation by

decreasing the discharge of sympathetic nerves
emerging from the CNS.

• Noradrenergic synapses in the medulla probably form

part of the baroreceptor reflex pathway, because
stimulation or antagonism of α2-adrenoceptors in this
part of the brain has a powerful effect on the activity of
baroreceptor reflexes.

• Clonidine and methyldopa are hypotensive agent that

acts centrally.

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Biosynthesis of Catecholamines
• DOPAMINE

• Dopamine is particularly important in neuropharmacology, since

it is involved in several common disorder of brain function,
notably Parkinson’s disease, schizophrenia, Tourrete’s
syndrome and attention deficit disorder, as well as in drug
dependence and certain endocrine disorders.

• The synthesis of dopamine follows the same route as that of

noradrenaline (, namely conversion of tyrosine to dopa (the rate-
limiting step), followed by decarboxylation to form dopamine.
Dopaminergic neurons lack dopamine β-hydroxylase, and thus
do not produce noradrenaline.

• Dopamine is largely recaptured, following its release from nerve

terminals, by a specific dopamine transporter, one of the large
family of monoamine transporters.

• It is metabolized by monoamine oxidase and catechol-O-methyl

transferase, the main products being dihydroxyphenylacetic acid
(DOPAC) and homovanillic acid (HVA, the methoxy derivative of
DOPAC). 38
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 Dopamine Pathways

• The Mesolimbic Dopamine Pathway: midbrain ventral

tegmental area to the nucleus accumbens, a part of the limbic
system of the brain.

• Thought to be involved in many behaviours such as pleasurable

sensations, the powerful euphoria of drugs of abuse, as well as
delusions and hallucinations of psychosis.

• The Mesocortical Dopamine Pathway: also projects from

the midbrain ventral tegmental area but sends its axons to
areas of the prefrontal cortex,
• May have a role in mediating cognitive symptoms
(dorsolateral prefrontal cortex) and affective symptoms
(ventromedial prefrontal cortex) of schizophrenia.
 Dopamine pathways….

• The Nigrostriatal Dopamine Pathway: projects from the

substantia nigra to the basal ganglia or striatum, is part of
the extrapyramidal nervous system and controls motor
function and movement, typical in Parkinson’s Disease.
• Tuberoinfundibular Dopamine Pathway: projects from
the hypothalamus to the anterior pituitary gland and
controls prolactin secretion.
• The fifth dopamine pathway arises from multiple sites,
including the periaqueductal grey, ventral mesencephalon,
hypothalamic nuclei, and lateral parabrachial nucleus, and
it projects to the thalamus. Its function is not currently well
known.
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 Storage, release, and reuptake

• Inside the brain dopamine functions as a

neurotransmitter, and is controlled by a set of
mechanisms that are common to all
neurotransmitters.
• After synthesis, dopamine is transported from
the cytosol into synaptic vesicles by the
vesicular monoamine transporter 2 (VMAT2).
• Dopamine is stored in and remains in these
vesicles until an action potential occurs and
causes the contents of the vesicles to be ejected
into the synaptic cleft.
 Storage, release, and reuptake
• Once in the synapse, dopamine binds to and activates
dopamine receptors, which can be located either on
postsynaptic target cells or on the membrane of the
dopamine-releasing cell itself (i.e., autoreceptors).

• After an action potential, the dopamine molecules quickly

become unbound from their receptors. They are then
absorbed back into the presynaptic cell, via reuptake
mediated either by the high-affinity dopamine transporter
(DAT) or by the low-affinity plasma membrane mono
amine transporter (PMAT).

• Once back in the cytosol, dopamine is subsequently

repackaged into vesicles by VMAT2, making it available
for future release.
 Storage
• Dopamine synthesized within neurons from common amino acid
precursors and taken up into synaptic vesicles via a vesicular
monoamine transporter.
• Upon stimulation, vesicles within nerve terminals fuse with the
presynaptic terminal and release the neurotransmitter into the
synaptic cleft.
• Once released, the monoamines interact with postsynaptic
receptors to alter the function of postsynaptic cells, and they may
also act on presynaptic autoreceptors on the nerve terminal to
suppress further release.
• In addition, released dopamine may be taken back up from the
synaptic cleft into the nerve terminal by DAT Dopamine
Transporters, a process known as reuptake.
• Once monoamines are taken up, they may be subject to
enzymatic degradation, or they may be protected from
degradation by uptake into vesicles.
 Degradation
• Two enzymes that play major roles in the degradation of dopamine
are monoamine oxidase (MAO) and catechol O-
methyltransferase (COMT).
MAO is located on the outer membrane of mitochondria.
• Two MAO isozymes exist:
– MAO-A: preferentially deaminates serotonin and norepinephrine.
– MAO-B: deaminates dopamine, histamine, and a broad spectrum
of phenylethylamines.
• COMT is located in the cytoplasm and is widely distributed
throughout the brain and peripheral tissues.
• It has a wide substrate specificity, catalyzing the transfer of methyl
groups from S-adenosylmethionine to the m-hydroxyl group of
most catechol compounds.
• The predominant metabolite of dopamine is homovanillic acid
(HVA).
Degradation….
 Dopamine receptors: 5 subtypes

• D1 (and D5) activate adenylyl

cylclase,

• D2 (and D3 & D4) inhibit

adenylyl cyclase.

• Some D2 receptors may also

suppress Ca++ currents and
activate K+ currents.

 D1 receptors- most abundant

in the striatum, limbic system,
thalamus and hypothalamus.

 D2 receptors- occur in the

pituitary.

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 Dopaminergic functions:
• Motor control (nigrostriatal system): PD is a disorder of motor
control associated with a deficiency of dopamine in the
nigrostriatal pathway.

• Behavioural effects ( mesolimbic and mesocortical systems):

evidence has shown that schizophrenia in humans is
associated with dopaminergic hyperaactivity.

• Amphetamine, cocaine activate mesolimbic dopaminergic

reward pathways which play a key role in in drug dependence.

• Endocrine control (tuberohypophyseal system): involved in

the control of prolactin secretion.
• Kidneys
• Important in sexual arousal and gratification

DANIEL CHANS M (MPS) July 2021 51

• Many antipsychotic drugs by blocking D2 receptors, increase
prolactin secretion and can cause breast development and lactation,
even in males.

• Bromocriptine, a dopamine receptor agonist derived from ergot, is

used clinically to suppress prolactin secretion by tumors of the
pituitary gland.

• Vomiting: Pharmacological evidence strongly suggests that

dopaminergic neurons have a role in the production of nausea and
vomiting.

• Thus 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

DANIEL CHANS 52M (MPS

July 2021
• Many 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.

• 5-HYDROXYTRYPTAMINE (Serotonin)

• Tryptophan is converted to 5-hydroxytryptophan by tryptophan

hydroxylase (inhibited by chlorophenylalanine). Then to 5-
hydroxytryptamine by L-aromatic amino acid decarboxylase.

• 5-HT is degraded by MAO.

DANIEL CHANS M53(MPS)

July 2021
• Serotonergic projections:

• Serotonin occur in the pons and upper medulla called

raphei nuclei – involved in the regulation of pain
perception.
• 90% is in enterochromaphin cells
• In the limbic system, 5-HT is co-localised with NA, the 2
transmitters seem to work in conjunction in the regulation
of arousal.
• Serotonin pathways are associated with
 Hallucination and behavioural changes
 Sleep, wakefulness and mood
 Control of sensory transmission including nociception
 Control of body temperature
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• Serotonin receptors & functions

• They are characterized as 5-HT1,5-HT2, . . . 5-HT7 subsets.

• The main receptor subtypes in the CNS are 5-HT1A, 5-HT1B, 5-HT1D, 5-
HT2, 5-HT3.

• 5HT1A receptors are found in the raphei nuclei, the main target of some
drugs used to treat anxiety and depression e.g Buspirone).

• 5-HT2 receptors exert an excitatory post-synaptic effect, they are

targets of hallucinogenic drugs. LSD inhibits the firing of 5-HT neurons
in the raphei nuclei.

• 5-HT3 receptors are found chiefly in the area postrema (a region of the
medulla involved in vomiting.

• They are excitatory ionotropic receptors, and specific antagonists (e.g.

ondansetron) are used to treat nausea and vomiting

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• 5-HT4 receptors are important in the gastrointestinal tract
and are also expressed in the brain, particularly in the
striatum.

• They exert a presynaptic facilitatory effect, particularly on

ACh release, thus enhancing cognitive performance.

• 5-HT6 receptors occur in the CNS, particularly in the

hippocampus, cortex and limbic system.

• They are considered potential targets for drugs to

improve cognition or relieve symptoms of schizophrenia.

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• 5-HT7 receptors occur in the hippocampus, cortex,
thalamus and hypothalamus, and also in blood vessels
and the gastrointestinal tract.

• Likely CNS functions include thermoregulation and

endocrine regulation, as well as suspected involvement
in mood, cognitive function, and sleep.

• Selective antagonists are being developed for clinical

use in a variety of potential indications.

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• Drugs acting selectively on 5-HT receptors or transporters
include:
– buspirone, a 5-HT1A receptor agonist used in treating anxiety

– antipsychotic drugs (e.g. clozapine), which partly owe their

efficacy partly to an action on 5-HT receptors

– 'triptans' (e.g. sumatriptan), 5-HT1D agonists used to treat

migraine

– 5-HT2 antagonists (e.g. ketanserin) was used for Hypertension

– selective serotonin uptake inhibitors (e.g. fluoxetine) used to

treat depression and other types eg SNRIs-Serotonin
Norepinephrine Reuptake Inhibitors, etc

– ondansetron, 5-HT3 antagonist, used to treat chemotherapy-

induced emesis 59
 ACETYLCHOLINE

• There are numerous cholinergic neurons in the CNS

• ACh occurs in all parts of the forebrain, midbrain and brainstem.

• ACh has mainly excitatory effects, which are mediated by various

subtypes of nicotinic (ionotropic) or muscarinic (GPCR) receptors.

• The nicotinic receptors mediate the central effects of nicotine.

• Nicotinic receptors are mainly located pre-synaptically; there are few

examples of transmission mediated by postsynaptic nicotinic
receptors.

• Muscarinic receptors appear to mediate the main behavioral

effects associated with ACh, namely effects on arousal and on
learning and short-term memory.

• Muscarinic antagonists (e.g. scopolamine) cause amnesia.

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• Devil’s breath-zombie drugs
• The main functions of cholinergic pathways are related to
arousal, learning, memory and motor control.

• Nicotine increases alertness and also enhances learning

and memory, as can various synthetic agonists at
neuronal nAChRs.

• Conversely, CNS-active nAChR antagonists such as

mecamylamine cause detectable, although slight,
impairment of learning and memory.

• Degeneration of cholinergic neuron in the nucleus basalis of

Meynert, which projects mainly to the cortex, is associated
with Alzheimer’s disease.

• Cholinergic interneurons in the corpus striatum is important in61

relation to Parkinson’s disease and Huntington’s chorea.
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 Read…
• Purines
• Histamine
• NO

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• Other transmitters and modulators
• Purines
• ATP functions as a neurotransmitter, being stored in vesicles and released
by exocytosis.
• It acts, via ionotropic receptors, as a fast excitatory transmitter in certain
pathways and, via metabotropic receptors, as a neuromodulator.
• Cytosolic ATP is present at relatively high concentration and can be
released directly if neuronal viability is compromised (e.g. in stroke).
Excessive release may be neurotoxic.
• Released ATP is rapidly converted to ADP, AMP and adenosine.
• Adenosine is not stored in vesicles but is released by carrier mechanisms
or generated from released ATP, mainly under pathological conditions.
• Adenosine exerts mainly inhibitory effects, through A1 and A2 receptors,
resulting in sedative, anticonvulsant and neuroprotective effects, and acting
as a safety mechanism.
• Methylxanthines (e.g. caffeine) are antagonists at A2 receptors and
increase wakefulness.

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 Histamine

• Histamine fulfils the criteria for a neurotransmitter.

Histaminergic neurons originate in a small area of the
hypothalamus and have a widespread distribution.

• H1, H2, H3 and H4 receptors are widespread in the brain.

• H1 and H3 receptors are mainly excitatory; H2 receptors are

inhibitory.

• The functions of histamine are not well understood, the main

clues being that histaminergic neurons are active during
waking hours, and H1 receptor antagonists are strongly
sedative.

• SOME H1 receptor antagonists are antiemetic.

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• Neuronal nitric oxide synthase (nNOS) is present in many central
nervous system neurons, and nitric oxide (NO) production is
increased by mechanisms (e.g. transmitter action) that raise
intracellular Ca2+.

• NO affects neuronal function by increasing cGMP formation,

producing both inhibitory and excitatory effects on neurons.

• In larger amounts, NO forms peroxynitrite, which contributes to

neurotoxicity.

• Inhibition of nNOS reduces long-term potentiation and long-term

depression, probably because NO functions as a retrograde
messenger.

• Inhibition of nNOS also protects against ischaemic brain damage in

animal models.

• Carbon monoxide shares many properties with NO and may also be

a neural mediator.
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The brain, behavior, and the environment have interpenetrating effects

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The blood-brain barrier

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REFERENCES AND FURTHER READINGS
• Katzung Bertram G: Basic & Clinical
Pharmacology, 10th International Edition 2007.

• Rang H.P., Dale M.M., Ritter J.M., Moore P.K:

Pharmacology. Fifth Edition, International Edition
2003.

• Goodman G: The Pharmacological basis of

therapeutics. Tenth Edition.

• Craig Stitzel. Modern Pharmacology with Clinical

applications. Fifth Edition.
• Other Pharmacology text books 73
DANIEL CHANS M (MPS)
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• Next time…

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 CNS DRUGS
• Sedatives, Hypnotics
• Anxiolytics
• Antidepressants
• Antipsychotics
• Antiepileptics
• Analgesics
• CNS Stimulants & Psychotomimetics
• Anaesthetics
• Neurodegenerative Diseases
• Drugs Of Abuse And Dependence
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 END

• THANK YOU

DANIEL CHANS M (MPS) 76

July 2021