Introduction to Neuropharmacology

2. • At the end of the lecture, students must be able to
– understand the importance of neuropharmacology.
– explain the chemical signaling system in CNS.
– list the targets of drug action in CNS.
– describe the importance of blood brain barrier for
neuropharmacology.
– describe the importance of neurotransmitters in CNS
from pharmacologic aspect.

3. 1. Importance of neuropharmacology
2. Chemical signaling system in CNS.
3. Targets of drug action in CNS.
4. Importance of Blood brain barrier for neuropharmacology
5. Pharmacologic significance of neurotransmitters of CNS
a) Glutamate
b) GABA
c) Glycine
d) Noradrenaline
e) Dopamine
f) 5-HT (serotonin)
g) Acetylcholine
h) Histamine

4. • Brain function is the single most important aspect of physiology
that defines the difference between humans and other species.
• Disorders of brain are a major concern of human society, and it is a
field in which pharmacological interventions plays a key role.
• This lecture will introduce some basic principles of
neuropharmacology that underlie in the pharmacology of most of
the drugs for the upcoming CNS diseases.

5. • Neuropharmacology is significant and important because
– Centrally acting drugs are of significance to humankind.
– Most commonly administer to themselves for non-medical reasons (alcohol,
tea, coffee, nicotine, opiates and amphetamine etc.)
Neurotransmission

6. • Brain is basically – chemical machine.
• Controls – ranging – from milliseconds (eg. returning a tennis
serve) or years (remembering how to ride a bicycle).
• Neurotransmission – same as peripheral nervous system
• Chemical substance released by one neurone – acting on the
membrane of an adjacent neurone (post synaptic neurone) –
excitation or inhibition.

8. Glial cells, the astrocytes, are the main non-neuronal cells in the CNS
surronded by neurones 10 to 1.

11. • Target
– enzymes,
– ion channels,
– receptors and
• (Ionotropic receptors
• G-proteins coupled receptor
• Kinase linked receptors
• Nuclear receptors )
– transport proteins.

12. •is a highly selective permeability barrier
that separates the circulating blood from
the brain extracellular fluid (BECF) in
the central nervous system (CNS).
•is formed by capillary endothelial cells,
which are connected by tight junctions.

13. • allows the passage of water, some gases, and lipid soluble molecules by
passive diffusion, as well as the selective transport of molecules such as
glucose and amino acids that are crucial to neural function.
• Astrocytes are necessary to create the blood–brain barrier.
• A small number of regions in the brain, including the circumventricular
organs (CVOs), do not have a blood–brain barrier..

14. a) Glutamate
b) GABA
c) Glycine
d) Noradrenaline
e) Dopamine
f) 5-HT (serotonin)
g) Acetylcholine
h) Histamine

15. • Principal excitatory neurotransmitter in CNS.
• Source – glucose (via KCAC), or glutamine (synthesised by glial cells)
• Stored in synaptic vesicles and released by exocytosis
• Terminated by reuptake into the nerve terminals, neighboring
astrocytes, (in the astrocytes, glutamate is degraded into glutamine)
recycled, and back to the neurones, convert back to glutamate.
Glutamine is inactive form.

17. • Receptor subtypes – NMDA, AMPA, kinate, metabotropic.
• First three are named according to their specific agonists.
(NMDA,AMPA and kinate)
• NMDA = N-methyl-D-aspartic acid / AMPA – a-amino-3-
hydroxy-5-methylisoxazole-4-propianic acid

19. • AMPA & kinate receptors – responsible for fast
excitatory neurotransmission
• NMDA & metabotropic receptors – long term adaptive
and pathological changes in brain.
• Piracetam, aniracetam – used in dementia

20. • Potential therapeutic targets of glutamate antagonists
– Reduction in brain damage following strokes and head injury
– Treatment of epilepsy
– Alzheimer’s disease
– Schizophrenia
• Drawbacks
– Hallucinations
• Currently using
– Ketamine – (anaesthesia and analgesia)
– Memantine (Alzheimer’s disease)

21. • Main inhibitory neurotransmitter in CNS.
• Present uniformly throughout the brain
• Synthesis
– Formed from glutamate by the action of GAD, enzyme found only in the
GABA-synthesizing neurones in the brain.
• Termination
– By transamination (into glutamate) by GABA transaminase enzyme.
• Receptors
– Two types
– GABAA and GABAB

22. • GABAA- Entry of Cl- permeability into the cells – hyperpolarization –
reducing excitability
• GABAB - Opening K+ channels – inhibiting adenylyl cyclase &
inhibiting the Ca2+ channels thus reducing the transmitter release

23. • GABA receptors (GABAA receptors)
– GABA binding site
– Several modulatory sites
– The ion channel
• Drugs targeting on GABAA
receptors
• Benzodiazepines
• Barbituates
• GA
• Drugs targeting on GABAB receptors
• Baclofen (skeletal muscle relaxant)

24. • Present high concentration in grey matter of the spinal cord.
• Inhibitory neurotransmitter
• Cause hyperpolarisation
• Acts on its own receptor
• e.g. tetanus toxin – prevent glycine release from inhibitory
interneurons in the spinal cord, causing reflex hyperexcitability and
violent muscle spasms.

25. • Synthesis, storage, release and reuptake are same as in
periphery.
• Functional aspects
– Arousal
• Controlling alertness and wakefullness
– Control of mood
• Depressive individuals are usually lethargic and unresponsive to external
stimuli.
• Depression results from a functional deficiency of noradrenaline in certain
parts of the brain, while mania results from an excess.
– Blood pressure regulation
• Clonidine, methyldopa – centrally acting hypotensive drugs
• Decrease the discharge of sympathetic nerves emerging from the CNS.
• Drugs acting on noradrenergic transmission
– Antidepressants, antihypertensive drugs

26. • Neurotransmitter & precursor of noradrenaline.
• Three main dopaminergic pathways
– Nigrostriatal pathway – motor control
– Mesolimbic or mesocortical – emotional & drug
induced reward systems
– Tuberohypophyseal (pathway from hypothalamus to
pituitary gland) – control secretions
• Receptors – 5 subtypes – D1-D5

27. • Diseases or conditions associated with dopamine
– Schizophrenia (D2) ? Dopamine overactivity
– Parkinsonism (deficiency of nigrostriatal dopaminergic
neurones)
– Behavioral effects associated with drugs that act on dopamine
• Dopamine releasing agents (amphetamine)
• Dopamine agonist (apomorphine)
– As dopamine regulates hormone released from anterior pituitary
• Inhibition of prolactin release
– Stimulation of dopamine r/c in CTZ – causes Nausea and
vomiting
– Inhibition of dopamine r/c in CTZ – antiemetics

29. • Synthesis, storage, release, reuptake and degradation
of 5-HT in the brain are similar to periphery.
• Functions associated
– Various behavioral responses (eg. hallucination)
– Feeding behaviour
– Control of mood and emotion
– Control of sleep/wakefullness
– Control of sensory pathways (eg. nociception)
– Control of body temperature
– Vomiting
• Receptors
– 5-HT1A, … 5-HT1D, 5-HT2, 5-HT3

30. • Drugs acting on 5-HT receptors
– Triptans (eg. sumatriptan ) – 5-HT agonist – for migraine
– Selective serotonin reuptake inhibitors – SSRI (Eg. fluoxetine –
for depression)
– Ondansetron – 5-HT3 agonist – for chemotherapy induced
emesis
– Some as appetite suppressants
– Some as appetite stimulants

31. • Synthesis, storage, release, reuptake and degradation of 5-HT in the brain
are similar to periphery.
• Widely distributed in the CNS
• Diseases associated
– Neurodegenerative diseases (dementia, Parkinson’s disease) associated with
abnormalities in cholinergic pathways
• Receptors (nicotinic & muscarinic)
• Muscarinic receptors – mediate main behavioral effects and on learning
and short term memory
• Drugs
– Muscarinic antagonist – can cause amnesia

32. • Wide spread distribution in CNS
• Receptors – H1, H2 and H3
• Function
– H1 and H3 – excitatory
– H2 – inhibitory
• Drugs
– Histaminergic receptors are active during working hours
– H1 receptor antagonists – strongly sedative.
– H1 receptor antagonists – antiemetic

33. • Target
– Enzymes (glutamate dehydrogenase) .. Increase glycine
level
– ion channels .. (sodium channels via GABA receptors)
– receptors (GABA r/c, glutamate r/c, dopamine r/c)
– transport proteins.

34. • http://www.experientiadocet.com/2013_01_01_archive.html
• http://www.nature.com/nrn/journal/v7/n3/box/nrn1870_BX1.html
• http://jonlieffmd.com/blog/are-microglia-the-most-intelligent-brain-cells
• http://journals.cambridge.org/fulltext_content/ERM/ERM5_15/S14623994
03006252sup002.htm
• Lullmann, Heinz, Mohr, Kalus (2005). Colour Atlas of Pharmacology. 3rd ed.
Germany: Georg Thieme Verlag.
• Rang, HP, Dale, MM, Ritter, JM, Flower, RJ, Henderson, G (2012). Rang and
Dale's Pharmacology. 7th ed. London: Elsevier Churchill Livingstone.