Lecture

1. MD Psych - Neurophysiology
1. Electrophysiology
2. Synapse & NMJ
3. Neurotransmitters
4. Sensory functions
5. Physiology of Pain
6. Main Motor system
7. Basal Ganglia
8. Cerebellum
9. Posture
10.Higher functions
11.Sleep, arousal
12.Memory and emotions
13.Evoked potentials
Prof. Vajira Weerasinghe
Senior Professor of Physiology
Faculty of Medicine, University of
Peradeniya &
Consultant Neurophysiologist,
Teaching Hospital, Peradeniya
www.slideshare.net/vajira54
vajira54@gmail.com

2. • www.slideshare.net/vajira54
• vajira54@gmail.com
• .edu
• …..ac.uk

3. Membrane potential
• Excitable tissues have more
negative RMP
( - 70 to - 90 mV)
Non-excitable
Red cell
GIT
excitable
neuron
muscle
• Non-excitable tissues
have less negative RMP
( - 5 to -10 mV)
All biological membranes have a resting
membrane potential across the membrane
with the inside being more negative than the
outside

4. Factors contributing to RMP
• One of the main factors is K+ efflux which causes
negativity inside the membrane (Nernst Potential:
-94mV) through leak channels (there are more K+
leak channels than Na+ leak channels)
• Na+/K+ pump causes more negativity inside the
membrane (3 Na+ removed with 2 K+ replaced,
excess negativity inside)
• Negatively charged protein remaining inside due
to impermeability contributes to the negativity
inside the membrane
• Contribution of Na+ influx is little (Nernst
Potential: +61mV) and causes less negativity
inside the membrane
• Net result: -70 mV inside

5. Na/K pump
• Active transport system for Na+/K+ exchange using
energy
• It is an electrogenic pump since 3 Na+ influx coupled
with 2 K+ efflux
• Net effect of causing negative charge inside the
membrane
3 Na+
2 K+
ATP ADP
What is the action
of Na+/K+ pump
blockers?
QUIZ

6. -70
+35
RMP
Hyperpolarisation
Slow depolarisation
Threshold -55
Action potential
Time (ms)
(mV)
Opening of
Voltage gated
Na+ channel
Closure of Voltage gated Na+ channel
& opening of voltage gated K+ channel
Closure of voltage gated K+ channel
Compare nerve AP
with AP of SA node
and cardiac muscle
QUIZ
6

7. • At rest: the activation gate is closed
• At threshold level: activation gate opens
– Na+ influx will occur
– Na+ permeability increases to 500 fold
• when reaching +35, inactivation gate closes
– Na+ influx stops
• Inactivation gate will not reopen until resting membrane potential is reached
outside
inside
outside
inside
-70 Threshold level +35
Na+ Na+
outside
inside
Na+m gate
h gate
What is the
action of
voltage gated
Na+ channel
blockers?
QUIZ

8. • At rest: K+ channel is closed
• At +35
– K+ channel open up slowly
– This slow activation causes K+ efflux
• After reaching the resting phase, still some K+
channels may remain open: causing further
hyperpolarisation
outside
inside
outside
inside
-70 At +35
K+ K+
n gate
During
repolarisation
phase, at -55 mV
Na+ channels do
not open again.
What is the reason?
QUIZ
-70
+35

9. Propagation of AP
• When one area is depolarised
• A potential difference exists between that site
and the adjacent membrane
• A local current flow is initiated
• Local circuit is completed by extra cellular fluid

10. AP propagation along myelinated nerves
• Local current will flow one node to another
• Thus propagation of A.P. is faster. Conduction
through myelinated fibres also faster.
• Known as Saltatory Conduction

11. 11

13. 13

14. Demyelinating disorders
• Peripheral demyelination
– Guillain Barre Syndrome (GBS) or Acute Inflammatory Demyelinating
Polyneuropathy (AIDP)
– Chronic Inflammatory Demyelinating Polyneuropathy (CIDP)
– Multifocal Motor Neuropathy (MMN)
– Multifocal Acquired Demyelinating Sensorimotor Neuropathy (MADSAM)
– Distal Acquired Demyelinating Symmetric Neuropathy (DADS)
– POEMS (Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal gammopathy,
Skin changes)
• Central demyelination
– Multiple Sclerosis (MS)
– Optic neuritis
– Acute disseminated encephalomyelitis (ADEM)
– Adrenoleukodystrophy

15. Applied physiology
• Decreasing the external Na+ concentration reduces the size of
the action potential but has little effect on the resting membrane
potential
• If the extracellular level of K+ is increased (hyperkalemia),the
resting potential moves closer to the threshold for eliciting an
action potential, thus the neuron becomes more excitable
• If the extracellular level of K+ is decreased (hypokalemia),the
membrane potential is reduced and the neuron is
hyperpolarized

16. Nerve fibre types
16

17. Nerve fibre types
17

18. Nerve fibre types
18

19. Nerve fibre types
19

20. Nerve fibre types
20

21. Nerve fibre types
21

22. Nerve fibre types
22

23. Membrane stabilisers
• Membrane stabilisers (these decrease excitability)
• Increased serum Ca++
– Hypocalcaemia causes membrane instability and spontaneous activation
of nerve membrane
– Reduced Ca level facilitates Na entry
– Spontaneous activation
• Decreased serum K+
• Local anaesthetics
• Acidosis
• Hypoxia
• Membrane destabilisers (these increase excitability)
• Decreased serum Ca++
• Increased serum K+
• Alkalosis
• Caffeine
• strychnine

24. Synapse
• Synapse is a gap between two neurons
• More commonly chemical
• Rarely they could be electrical (with gap junctions)
– which are pores (as shown in the electron micrograph)
constructed of connexin proteins

25. Different types of synapses
25

26. Types of synapses
• Axo-dendritic synapse
• Most common
• Axon terminal branch (presynaptic
element) synapses on a dendrite
• Axo-somatic synapse
• Axon terminal branch synapses on
a soma (cell body)
• Axo-axonic synapse
• Axon terminal branch synapses on
another axon terminal branch (for
presynaptic inhibition)
• Dendro-dendritic synapse
• Dendrite synapsing on another
dendrite (localised effect) 26

27. Details of presynaptic events
• in the resting state, the presynaptic membrane has resting membrane
potential
• when an action potential arrives at the end of the axon
• the adjacent presynaptic membrane is depolarised
• voltage-gated Ca2+ channels open and allow Ca2+ influx (driven by [Ca2+]
gradient)
• elevated [Ca2+] activates synaptic proteins
(SNARE proteins: Synaptobrevin, Syntaxin, SNAP 25) and triggers
vesicle mobilization and docking with the plasma membrane
• vesicles fuse with presynaptic plasma membrane and release
neurotransmitter molecules (about 5,000 per vesicle) by exocytosis
• neurotransmitter molecules diffuse across the cleft & bind with postsynaptic
receptor proteins
• neurotransmitter molecules are eliminated from synaptic clefts via
pinocytotic uptake by presynaptic or glial processes and/or via enzymatic
degradation at the postsynaptic membrane
• molecules are recycled
• subsequently, presynaptic plasma membrane repolarises

28. Ca2+ Ca2+
SNARE
proteins
28

29. IONOTROPIC RECEPTORS
• Neurotransmitter molecule binds to the receptor
• Cause a ligand-gated ion channel to open
• Become permeable to either sodium, potassium or chloride
• Accordingly depolarisation (excitation) or hyperpolarisation (inhibition)
• Quick action, short lasting

30. • Neurotransmitter attaches to G-protein-coupled receptors (GPCR) which has slower, longer-
lasting and diverse postsynaptic effects
• They can have effects that change an entire cell’s metabolism
• Activates enzymes that trigger internal metabolic change inside the cell
• Activate cAMP
• Activate cellular genes: forms more receptor proteins
• Activate protein kinase: decrease the number of proteins
• Sometimes open up ion channels also
Metabotropic Receptors

31. Postsynaptic activity
• Synaptic integration
– On average, each neuron in the brain receives about 10,000
synaptic connections from other neurons
– Many (but probably not all) of these connections may be
active at any given time
– Each neuron produces only one output
– One single input is usually not sufficient to trigger this output
– The neuron must integrate a large number of synaptic inputs
and “decide” whether to produce an output or not
– Constant interplay of excitatory and inhibitory activity on the
postsynaptic neuron produces a fluctuating membrane
potential that is the algebraic sum of the hyperpolarizing and
depolarizing activities
– Soma of the neuron thus acts as an integrator

32. 32

33. Other synaptic activities
• Postsynaptic inhibition
– eg. GABA activates GABA A receptors on the postsynaptic
membrane and opens up Cl- channels and causes
hyperpolarisation and inhibition
• Presynaptic inhibition
– eg. GABA activates GABA B receptors on the presynaptic
membrane and through G proten activation opens up K+ channels
and causes hyperpolarisation and inhibition
• Autoreceptors
– eg. Ach released from the presynaptic membrane activates
autoreceptors for Ach on the presynaptic membrane and causes
feedback inhibition
• Renshaw cell inhibition
– Spinal motor neuron activates a collalteral neuron which secrete
glycine and which inhibit activity of the spinal motor neuron
• Retrograde signalling
– Neurotransmitter secreted from the postsynaptic membrane act
on the receptor on the presynaptic membrane and through G
protein activation causes inhibition

34. Dendritic spine
• Small button like extensions like “door knobs”
found on the dendritic processes that contain
post-synaptic densities
• Axo-dendritic synapses terminates in these
• Dendritic spines are known to change shape,
to the extend of appearing and disappearing
entirely & is the basis of memory
• A mechanism underlying memory loss in
Alzheimer's disease involves a loss
of dendritic spines in hippocampal pyramidal
cells
• Ca channels, NMDA receptors are present in
these
• Long-term potentiation (LTP) at Hebbian
synapses in hippocampal region CA1 occurs
involving NMDA receptors in these sites

35. Neuromuscular junction

36. NMJ function
• Pre-synaptic membrane
• Ca2+ channels
• SNARE proteins
• Acetylcholine release
• Postsynaptic membrane
• Acetylcholine receptors
• Ligand-gated Na+ channels
• Synaptic cleft
• cholinesterase

37. Ach vesicle docking
• With the help of Ca entering the presynaptic
terminal
• Docking of Ach vesicles occur
• Docking:
– Vesicles move toward & interact with
membrane of presynaptic terminal
• There are many proteins necessary for this
purpose
• These are called SNARE (soluble NSF
attachment protein receptor) proteins
– Syntaxin, synaptobrevin, SNAP25
• Botulinum toxin cleaves all three SNARE proteins
• Tetanus toxin causes cleavage of synaptobrevin
• Deficiency of SNARE proteins has been linked
with schizophrenia causing altered dopamine or
glutamate release
• Ii is also linked with psychosis

38. NMJ
• Postsynaptic membrane contain nicotinic
acetylcholine receptor
• This receptor contains several
sub units (2 alpha, beta, gamma,
delta)
• Ach binds to alpha subunit
• Na+ channel opens up
• Na+ influx occurs
• End Plate Potential (EPP)
•This is a graded potential
•Once this reaches the threshold
level
•AP is generated at the
postsynaptic membrane

39. NMJ blocking
• Useful in general anaesthesia to facilitate inserting tubes
• Muscle paralysis is useful in performing surgery
• Commonly used to paralyze patients requiring intubation
whether in an emergency as a life-saving intervention or for a
scheduled surgery and procedure
• Indications for intubation during an emergency
– failure to maintain or protect the airway
– failure to adequately ventilate or oxygenate
– anticipation of a decline in clinical status

40. Earliest known NMJ blocker - Curare
• Curare has long been used in South America as
an extremely potent arrow poison
• Darts were tipped with curare and then
accurately fired through blowguns made of
bamboo
• Death for birds would take one to two minutes,
small mammals up to ten minutes, and large
mammals up to 20 minutes
• NMJ blocker used in patients is tubocurarine

41. Non-depolarising blocking agents
– Competitive
– Act by competing with Ach for the Ach receptors
– Binds to Ach receptors and blocks
– Prevent Ach from attaching to its receptors
– No depolarisation
– Late onset, prolonged action
– Ach can compete & the effect overcomes by an excess Ach
– Anticholinesterases can reverse the action
– eg.
• Curare
• Atracurium
• Rocuronium
• Vencuronium

42. Depolarising blocking agents
– non-competitive, chemically act like Ach
– Bind to motor end plate and once depolarises
– Persistent depolarisation leads to a block
• Due to inactivation of Na channels
– Phase I block
• After a depolarizing agent binds to the motor end plate receptor, the agent remains
bound and thus the end plate cannot repolarize
• during this depolarizing phase the transient muscle fasciculation occur
• Absence of fade to tetanic stimulation
– Phase II block
• After adequate depolarization has occurred, phase II (desensitizing phase) sets in and
the muscles are no longer receptive to acetylcholine released by the motor neurons
• It is at this point that the depolarizing agent has fully achieved paralysis
• Fade after tetanic stimulation
– Ach cannot compete
– Quick action start within 30 sec, recover within 3 min and is complete within 12–
15 min
– Hydrolysed by plasma cholinesterase (also called pseudocholinesterase)
produced in the liver
– Prolonged blockade is seen in liver disease or pregnancy
– Inhibition of plasma cholinesterase occurs with OP compounds
– eg. Succinylcholine
– Side effect: hyperkalaemia
– Bind to nicotinic and muscarinic Ach, causes bradycardia
– Contraindicated in burns

43. Na+
Acetylcholine
Depolarization
Na+
- - - -+ + + +
- - - -
+ + + +
+ + + +
+ + + +- - - - - - - -
43

44. Na+
AcetylcholineTubocurarine
Na+
+ + + +
- - - -- - - -
+ + + +
Competitive neuromuscular blocking drugs
44

45. Na+
Depolarized
Na+
PHASE I
Membrane depolarizes
resulting in an initial
discharge which
produces transient
fasciculations followed
by flaccid paralysis
- - - -
+ + + ++ + + +
- - - - - - - -+ + + + + + + +
- - - -- - - -
Depolarizing Neuromuscular blocking drugs

46. Repolarized
PHASE II
Membrane repolarizes
but the receptor is
desensitized to effect
of acetylcholine
+ + + +- - - -+ + + +- - - -
- - - -+ + + +
- - - -+ + + +
Depolarizing Neuromuscular blocking drugs

47. Anticholinesterases
• AchE inhibitors
– Inhibit AchE so that Ach accumulates and causes
depolarising block
• Reversible
– Competitive inhibitors of AChE
• eg. physostigmine, neostigmine, edrophonium used to diagnose and
treat myasthenia
• Irreversible
– Binds to AChE irreversibly
• eg. Insecticides (organophosphates), nerve gases (sarin)

48. NMJ disorders
• Myasthenia gravis (MG)
– Antibodies to Ach receptors
– Post synaptic disorder
• Lambert Eaton myasthenic syndrome (LEMS)
– Presynaptic disorder (antibodies against Ca channels)
• Neuromyotonia (Isaac’s syndrome)
– Down-regulation of K+ channels, hyperexcitability due to prolonged
depolarisation
• Botulism
– Presynaptic disorder
– Binds to the presynatic region, cleaves SNARE proteins and prevent
release of Ach
• Tetanus
– Presynaptic disorder
– Blockade of neurotransmitter release (GABA & glycine) of spinal
inhibitory neurons causes hyper-excitable tetanic muscle contractions

49. Botulinum toxin
• Most potent neurotoxin known
• Produced by bacterium Clostridium botulinum
• Causes severe diarrhoeal disease called botulism
• Action:
– enters into the presynaptic terminal
– cleaves proteins (syntaxin, synaptobrevin, SNAP 25) necessary for Ach
vesicle release with Ca2+
• Chemical extract is useful for reducing muscle spasms, muscle
spasticity and even removing wrinkles (in cosmetic and plastic
surgery)

50. 50

51. Organophosphates
• Phosphates used as insecticides
• Action
– AchE inhibitors
– Therefore there is an excess Ach
accumulation
– Depolarising type of postsynaptic
block
• Used as a suicidal poison
• Causes muscle paralysis and death
• Nerve gas (sarin)

52. Myasthenia gravis
• Serious neuromuscular disease
• Antibodies form against acetylcholine nicotinic
postsynaptic receptors at the NMJ
• Characteristic pattern of progressively reduced
muscle strength with repeated use of the muscle and
recovery of muscle strength following a period of rest
• Present with ptosis, fatiguability, speech difficulty,
respiratory difficulty
• Treated with cholinesterase inhibitors

53. Muscle contraction
• Depolarisation of the muscle membrane
spreads through the muscle
• Causes muscle contraction
• Excitation - contraction coupling
– Excitation : electrical event
– Contraction : mechanical event

54. Mechanism of Ca release
• AP spreads through t tubule into the muscle tissue
• Close to the sarcoplasmic reticulum, AP activates
dihydropyridine DHP receptor (dihydropyridine blocks these
Ca channels) located in the T tubule
• DHP receptor is physically close to a Ryanodine receptor
located on the sarcaplasmic reticulum
• Releases Ca from sarcoplasmic reticulum
• Ca flows to the myoplasm in the vicinity of actin & myosin
• In cardiac muscle cell
– L type Ca channel present in the DHP receptor causes
Ca2+ entry from outside
– This Ca activates ryanodine receptor
– Releases Ca from sarcoplasmic reticulum
– calcium induced calcium release occurs
• L type Ca channels are blocked by calcium channel
blockers used for hypertension
• Ryanodine receptors are known to be present in the brain
(hippocampus)
• Cognitive dysfunction may be related to RyR induced Ca
release In Alzheimer’s and PTSD

55. Neuromuscular junction in smooth muscle
• There is intrinsic innervation in smooth muscles eg. In GI tract, extrinsic
innervation from autonomic nervous system
• There is no specialized connection between the nerve fiber and the smooth
muscle cell
• The nerve fibers essentially passes "close" to the smooth muscle cells and
releases the neurotransmitter
• The neurotransmitter can bind to any one of the nearby smooth muscle cells
• many different neurotransmitters can be released from the many different
nerves that innervate smooth muscle cells
• They could be excitatory or inhibitory
• eg. Ach, norepinephrine, nitric oxide, prostacyclin, endothelin
• There is nothing equivalent to the motor endplate in smooth muscle,
therefore receptors for the neurotransmitters are located throughout the
smooth muscle membrane
• Smooth muscle can be made to contract by hormones and paracrine agents

56. Type Neurotransmitter
Amines Serotonin (5HT), Dopamine, Norepinephrine, Acetylcholine, Histamine
Amino acids Gamma-aminobutyric acid (GABA), Glycine, Glutamate, Aspartate
Opioids Beta-endorphin, Enkephalins, Dynorphin, Nociceptin, Kyotorphin
Neurokinins Substance P, Neurokinin A, B
Endocannabinoids Endocannabinoids (Anandamide, 2AG)
Mixed types Nitric oxide and Carbon monoxide (CO)
ATP, ADP
CART (cocaine and amphetamine regulated transcript)
Neuropeptide Y
Orexin
Other Angiogensin, Calcitonin, Glucagon, Insulin, Leptin, Atrial natriuretic factor,
Estrogens, Androgens, Progestins, Thyroid hormones, Cortisol. Hypothalamic
releasing hormones, Corticotrophin-releasing hormone (CRH), Gonadotropin
releasing hormone (GnRH), Luteinizing hormone releasing hormone (LHRH),
Somatostatin, Thyrotropin releasing hormone (TRH), Growth hormone releasing
hormone (GHRH), Pituitary peptides, Corticotrophin (ACTH), Growth
hormone (GH), Lipotrophin, Alpha-melanocyte-stimulating hormone(alpha-MSH),
Oxytocin, Vasopressin, Thyroid stimulating hormone (TSH), Prolactin,
Gut hormones Cholecystokinin (CCK), Gastrin, Motilin, Pacreatic polypeptide, Secr
etin, Vasoactive intestinalpeptide (VIP), Bombesin, Bradykinin, Carnosine,
Calcitonin G related peptide, Delta sleep factor, Galanin, Focretin, Melanocyte
concentration hormone
NEUROTRANSMITTERS
56

57. Glutamate
– The most abundant and the main excitatory neurotransmitter in the brain
– Responsible for 75% excitatory neurotransmission in the CNS
– Ca2+ is necessary for release
– Reuptake to the presynaptic terminal by glutamate transporter or via glial cells
– receptors
• Ionotropic receptors: AMPA (Na+), Kainate (Na+), NMDA (Ca2+ and Na+)
• NMDA receptor is normally blocked by Mg2+
• When glutamate binds to AMPA receptors, Na channel open up, Na influx occurs,
membrane is depolarised, depolarisation removes Mg2+, then glutamate and
glycine binding to NMDA receptor will open up Na+ and Ca2+ channels, Ca2+
influx, activates protein kinases and several actions
• Metabotropic glutamate receptors: second messenger system, act thru inositol
phosphate and cAMP, present in presynaptic and postsynaptic
– Increased levels of glutamate causes neuronal excitotoxicity, known to be involved in
Alzheimer’s disease, NMDA antagonists are used as a treatment
– Aspartate is an agonist
– NMDA receptor activity is involved in memory processes known as long term
potentiation
– Glutamate is a mediator of pain impulse pathway, NMDA receptor antagonists are
used as pain reducing drugs
– present in cortical projection to striatum (basal ganglia). Present in the stretch reflex

58. Acetylcholine (Ach)
• First neurotransmitter discovered in 1914
• Secreting neurons are called cholinergic neurons
• Secreted at the neuromuscular junction (skeletal muscle contraction),
autonomic ganglia (both sympathetic and parasympathetic),
parasympathetic postganglionic nerve endings and in central pathways in
the basal forebrain and brainstem (memory, arousal, attention, rapid eye
movement (REM) sleep
• receptors
– nicotinic (NN: autonomic ganglia, NM: NMJ) – ionotropic receptors Na+
influx
– muscarinic (parasympathetc terminal)
» sub types: M1(brain), M2(heart), M3(glands, smooth muscle), M4, M5
» Metabotropic receptors with G protein and second messenger cAMP and K+ channel
opening
• Agonist: nicotine, muscarine (toad poison)
• Inhibitors: NMJ blockers competitive: curare (plant poison), atracurium, depolarising:
succinylcholine, botulinum toxin (food poison), organophosphate (insecticide), atropine
(muscarinic blocker), neostigmine (AchE inhibitor)
• Loss of Ach neurons in Alzheimer’s patients: donepezil (anticholinesterase, increases Ach level)
• Pilocarpine (muscarinic chollinergic eye drops used in glaucoma)

59. GABA
• Gamma amino butyric acid
• The main inhibitory neurotransmitter in the brain
• Responsible for 40% inhibitory neurotransmission in the CNS
• Present in both presynaptic and postsynaptic inhibition
• Reuptake up GABA transporter
• receptors
– GABA A receptor (ionotropic): postsynaptic, open up Cl- channel,
hyperpolarisation, inhibition, alcohol, antiepieptics (barbirurates),
benzodiazepine (diazepam), activate these receptors
– GABA B receptor (metabotropic): presynaptic , G protein coupled action,
increase K+ efflux, inhibit Ca2+ influx through presynaptic Ca2+
channels
– GABA C receptor is also known to be present
• Increased GABA activity causes sedative effect
• Main neurotransmitter which produces sleep
• GABA decreases serotonergic, noradrenergic, cholinergic and histaminergic
neuronal activity to cause Non-REM (rapid eye movement) sleep

60. GABA
• Secreted by the neurons originating in striatum terminating in globus pallidus & substantia nigra
• faulty GABAergic neurotransmission has been implicated in a broad range of neuropsychiatric
disorders including anxiety disorders, schizophrenia, alcohol dependence, and seizure
disorders
• Endogenous GABA binds to GABA-a receptors in the basolateral amygdala and inhibits anxiety
responses
• Alterations in GABAergic transmission can result in severe disturbances in brain activity and a
deficit in GABAergic transmission can lead to epileptogenesis.
• Some metabolic alterations in GABA levels in the brain occur coincidentally with some
degenerative brain diseases, Huntington’s chorea and Parkinsonism
• GABA transport inhibitors, competitive inhibition of GABA and substrate inhibitor of GABA are
used to treat epilepsy

61. Glycine
• An inhibitory neurotransmitter in the spinal cord
• It is also known to be present in retina
• Co-activates NMDA receptor with gulutamate
• It has ionotropic receptor: Activate Cl- channels and cause
hyperpolarisation
• Action of glycine is antagonised by strychnine
• Strychnine poisoning causes muscle spasms, convulsions and
muscle hyperactivity
• Reuptake by transporter
• Parallel circuits potentiate GABA inhibition

62. Norepinephrine & epinephrine
• present in the autonomic nerves, brain stem, hypothalamus, locus ceruleus
of the pons
• Reuptake by transporter
• Metabolised by MAO (monoamine oxidase); MAO inhibitors are used as
antidepressants
• Increases BP and HR
• Control the overall activity of the brain and the mood
• Excitatory or inhibitory depending on the receptor
• Receptors
– α1A, α1B, α1D, α2A, α2B, α2C, 1, 2, 3
• Metabotropic receptors G protein coupled, second messenger: cAMP or Ca2+ and
protein kinase
– with norepinephrine having a greater affinity for α-adrenoceptors and
epinephrine for β-adrenoceptors
• Locus ceruleus is the principal site of norepinephrine in the brain, involved in
arousal, stress reaction, attention, sleep-wake cycle
• In antidepressants, serotonin-norepinephrine reuptake inhibitors (SNRIs) are
used by blocking transporters

63. Dopamine
• Dopamine (DA) is present in several important areas and pathways in the brain involved in reward pathway
– Ventral tegmental area (VTA) of the midbrain
– Nucleus accumbens (NA) of basal forebrain (brain pleasure centre)
– Mesocortical pathway from midbrain to prefrontal cortex
– Mesolimbic pathway from midbrain to limbic system
– Nigrostriatal pathway from substantia nigra to striatum in the limbic system
• Involved in motor control, dopamine levels are low in Parkinson disease
• Involved in reward behavior and addiction and in psychiatric disorders such as schizophrenia
• Receptors (metabotropic)
– D1, D2, D3, D4 D5
– D1-like (D1 and D5) increases cAMP and D2-like (D2, D3 and D4) decreases cAMP
– Overstimulation of D2 receptors may lead to schizophrenia
• Autoreceptors are present, Reuptake by dopamine transporter , MAO degrade dopamine
• Drug addiction is due to increased dopamine levels
– Cocaine and methamphetamine act by inhibiting dopamine transporters and thereby increasing
dopamine level in the brain to a unimaginably high levels ,
– Opioids and heroin act directly on DA neurons or inhibit GABA inhibition of DA neurons
– Cannabis and marijuana activate endocannabinoids which act presynaptically , inhibit GABA, increases
DA levels
– Nicotine: More complex mechanism increasing DA
• Most drugs of addiction blocks the transporters and thereby increases DA levels to a very high levels causing
euphoria and “high” but persistent drug use with addiction causes tolerance and dependence and subsequent
damage to the brain

64. • Nigrostriatal dopamine pathway:
– From substantia nigra to striatum, is
part of the extrapyramidal nervous
system and controls motor function and
movement.
• Mesolimbic dopamine pathway
– From midbrain ventral tegmental area to
the nucleus accumbens in the ventral
striatum, a part of the limbic system of
the brain thought to be involved in many
behaviours such as pleasurable
sensations and motivation, the powerful
euphoria of drugs of abuse, as well as
delusions and hallucinations (positive
symptoms) of psychosis.
• Mesocortical dopamine pathway:
– From midbrain ventral tegmental area
and sends its axons to areas of the
prefrontal cortex, where they may have
a role in mediating cognitive symptoms
and executive function (dorsolateral
prefrontal cortex) and affective
symptoms (ventromedial prefrontal
cortex) of schizophrenia.
• Tuberoinfundibular dopamine pathway
– From hypothalamus to anterior pituitary
gland and controls prolactin secretion.

65. Serotonin
• Chemically: 5Hydroxy tryptamine (5HT)
• present in high concentration in platelets and in the GIT, within the brain stem in the midline raphé nuclei,
which project to a wide area of the CNS including the hypothalamus, limbic system, neocortex, cerebellum
and spinal cord
• After secretion, reuptake by serotonin transporter (SERT)
• Once inside the presynaptic terminal it is metabolised by MAO
• Receptors
– Metabotropic : 5HT1 (A,B,D,E,F), 5HT2 (A,B,C), 5HT4, 5HT5 (A,B), 5HT6, 5HT7
– Ionotropic : 5HT3
• Regulate arousal, mood and social behavior, appetite and digestion, sleep, memory, and sexual desire
• Low levels are known to be involved in depression
• Selective serotonin reuptake inhibitors (SSRI) blocks serotonin transporter and increases serotonin levels or
SNRI (Serotonin Norepinephrine reuptake inhibitors) are also used
• Serotonin is involved in migraine (serotonin agonists are used)
• Serotonin antagonists are used for vomiting
• Tricyclic antidepressants (TCAs) inhibit the reuptake of norepinephrine serotonin
• Monoamine oxidase (MAO) metabolises 5HT.MAO inhibitors are used as antidepresants
• 5HT1A acts as autoreceptor
• 5HT1 B,D,F receptors are stimulated by antimigraine drug sumatriptan
• 5-HT2A receptor has been implicated in the cognitive process of working memory. Useful in schizophrenia
• 5-HT 2C receptor stimulation produce anxiogenic and anorectic effects from interactions with the
hypothalamic melanocortin and leptin pathways
• 5HT3 antagonist act as strong antiemetic agent (Ondansetron)
• 5-HT4 receptors modulate the release of acetylcholine and dopamine and implicated in cognition and
anxiety.
• Increasing the levels of serotonin in the brain can alleviate OCD symptoms

66. Serotonin
• Selective-serotonin
reuptake inhibitors
(SSRIs) – used to
treat depression
66

67. Cocaine acts as a monoamine agonist by
blocking the reuptake transporter enzyme

68. Opioid Peptides
• Peptides originally known to be similar to morphine
• Different types of
–  Endorphin: present in pituitary, earliest discovered opioid peptide
– enkephalins: met-enkephalin, leu-enkephalin: present at substantia gelatinosa in the spinal
cord & brain stem reticular nuclei, widely distributed
– Dynorphin: recently discovered
• Opioid peptides are involved in the descending pain inhibitory pathway
• Nociceptin
– Similar to dynorphin A, bind to nociceptin receotor
• Kyotorphin
– it acts by releasing an met-enkephalin, lower in patients with persistent pain, is a
neuromodulator
• receptors: , , : metabotropic, GPCR
• Activation of μ receptors increases K+ conductance, hyperpolarizing central neurons and
primary afferents. Activation of κ receptors and δ receptors closes Ca2+ channels
• Opioid act on the brainstem and inhibit GABA inhibition on spinal cord pain inhibitory action or
directly act on spinal cord
• Presynaptic or postsynaptic inhibition occurs
• Opioid system is involved in pain modulation, stress, appetite regulation, learning, memory,
motor activity, immune function
• Opioids addiction is due to their action through reward pathway (VTA etc) and dopamine
•

69. Histamine
• present in pathways from hypothalamus to cortical areas & spinal cord
• receptors: H1, H2, H3 (all present in brain)
• functions related to arousal, sexual behaviour, drinking, pain
• H1 receptors:
• Apart from periphery these receptors are distributed in the thalamus, cortex, and cerebellum.
H1 receptor is the mediator of allergy, sedation and weight gain produced by a number of
antipsychotic and antidepressant drugs.
• H2 receptors:
• Apart from periphery, H2 receptors are widely expressed in the neocortex, hippocampus,
amygdala, and striatum and produces excitatory effects in neurons of the hippocampal
formation and thalamus. Several studies indicates that the stimulation of these receptors
produces antinociceptive effects.
• H3 receptors:
• These are located presynaptically on axon terminals. Those located on histaminergic terminals
act as autoreceptors. In addition, H3 receptors are located on nonhistaminergic nerve terminals,
where they act as heteroreceptors to inhibit the release of a variety of neurotransmitters -
including norepinephrine, dopamine,acetylcholine, and serotonin. Particularly high levels of H3
receptor binding are found in the frontal cortex, striatum,amygdaloid complex, and substantia
nigra. Antagonists of H3 receptors have been proposed to have appetite suppressant,arousing,
and cognitive-enhancing properties.
• H4 receptors:
• It has identified recently and is detected predominantly in the periphery, in regions such as the
spleen, bone marrow, and leukocytes.

70. Neurokinins
• Substance P
• found in primary nerve ending in the spinal cord
• mediator of pain in the spinal cord
• Present in intestine, various peripheral nerves
and many parts of the CNS
• Neurokinin A and neurokinin B are similar to
Sub P
• Receptors: Neurokinin NK1, NK2 and NK3:
metabotropic receptor

71. Nitric oxide (NO)
• is a neurotransmitter in the central, peripheral, and enteric nervous
systems
• Inhibitory (smooth muscle relaxation)
• It has a role in a variety of neuronal functions including learning and
memory processes, cortical arousal, nociception, food intake, penile
erection, yawning, blood vessel dilatation and immune response
• Neurons synthesize NO as a response to the activation of N-methyl-
D-aspartate (NMDA) receptors by the excitatory amino acid
glutamate
• NO is generated in the neuronal cells by the enzyme nitric oxide
synthase (NOS) with calcium and calmodulin as cofactors
• NO has been described as an unconventional neurotransmitter,
because it is not stored in synaptic vesicles and not released upon
membrane depolarization but released as soon it is synthesized

72. Endocannabinoids
• The endocannabinoid system (ECS) is a widespread neuromodulatory
system that plays important roles in central nervous system (CNS)
development, synaptic plasticity, and the response to endogenous and
environmental insults.
• The ECS is comprised of cannabinoid receptors, endogenous cannabinoids
(endocannabinoids), and the enzymes responsible for the synthesis and
degradation of the endocannabinoids
• The most abundant cannabinoid receptor is the CB1 cannabinoid receptors,
however CB2 cannabinoid receptors
• Exogenous cannabinoids, such as tetrahydrocannabinol (Cannabis),
produce their biological effects through their interactions with cannabinoid
receptors.
• 2-arachidonoyl glycerol (2-AG) and arachidonoyl ethanolamide
(anandamide) are the best-studied endogenous cannabinoids.

73. • CGRP (Calcitonin gene related peptide):
– Present in the pain pathway
– Involved in migraine
– Monoclonal antibodies against CGRP useful in migraine
• ATP
– Present in ANS
– Binds to P2X receptors, which are ligand-gated ion channel receptors
– Present in dorsal horn, may be involved in pain pathway
• CART (cocaine and amphetamine regulated transcript)
– hypothalamus and midbrain enriched neurotransmitter with an antioxidant property
– can be found in mitochondria, which is the main source of reactive oxygen species
– Systemic administration of CART has been found to ameliorate dopaminergic neuronal loss and improve
motor functions in PD
– It is a potential neurotrophic factor and is involved in the regulation of hypothalamic-pituitary-adrenal axis
and stress response as well as in energy homeostasis. CART is also highly expressed in limbic system
– Possess antidepressant properties
• Neuropeptide Y
– influences many physiological processes, including cortical excitability, stress response, food intake,
circadian rhythms, and cardiovascular function
– increases eating and promotes obesity
– Neuropeptide Y inhibits orexin
– Leptin inhibits neuropeptide Y
• Orexin (hypocretin)
– Involved in arousal, wakefulness, and appetite
– Narcolepsy is caused by a lack of orexin in the brain due to the destruction of the cells that produce it

74. Neuromodulators
• Neurotransmitters transmit an impulse from one
neuron to another
• Neuromodulator modulate regions or circuits of the
brain
• They affect a group of neurons, causing a modulation
of that group
• Neuromodulators alter neuronal activity by amplifying
or dampening synaptic activity
– eg. dopamine, serotonin, acetylcholine, histamine, glutamate

75. Channelopathies
• In excitable cells
– periodic paralysis (K + channel, Na + channel)
– myasthenia (nicotinic Ach receptor with a ligand Na channel)
– myotonia (K + channel)
– malignant hypothermia (Ryanodine Receptor, a Ca 2+
channel),
– long QT syndrome (Na + and K + channel)
• In nonexcitable cells
– cystic fibrosis (Cl - channel)
– Bartter’s syndrome (K + channel)