Description of transmission of impulses in the neurons and diffrent neurotransmitters

1. Neurochemical transmission in
the brain
Dr Lateef M Khan
For M.Sc (Advanced Pharmacology- Pham 801)
20/1/2021

2. Importance of the topic
The mechanisms by which various drugs act in the CNS have not
always been clearly understood.
Dramatic advances have been made in the methodology of CNS
pharmacology.
It is now possible to study the action of a drug on individual cells
and even single ion channels within synapses.
 It is clear now that nearly all drugs with CNS effects act on
specific receptors that modulate synaptic transmission.
Very few agents such as general anesthetics and alcohol may have
nonspecific actions on membranes, but even these non–receptor-
mediated actions result in demonstrable changes in synaptic
transmission.

3. Importance of the topic
Secondly, for the study of CNS physiology, drugs are
among the most important tools.
Finally, describing the action of certain drugs in
specific clinical condition leads to the explanation of
the mechanism of the disease
For example, information about the action of
antipsychotic drugs on dopamine receptors has
provided the basis for important hypotheses regarding
the pathophysiology of schizophrenia.

4. Methods for the Study of CNS Pharmacology
Major progress in the study of CNS drugs was provided by the
development of new experimental techniques.
Invention of glass microelectrodes which permit
intracellular recording has made possible the first detailed
description of synaptic transmission.
Brain slice technique permitted an analysis of the physiology
and pharmacology of synapses.
The patch clamp technique
- permits the recording of current through single channels,
- Detailed electrophysiologic studies of the action of drugs on
both voltage- and transmitter-operated channels.

5. Methods for the Study of CNS Pharmacology
Histochemical, immunologic, and radioisotopic methods
have made it possible to map the distribution of specific
transmitters, their associated enzyme systems, and their
receptors.
Molecular cloning has had a major impact on our
understanding of CNS receptors.
These techniques make it possible to determine the precise
molecular structure of the receptors and their associated
channels.
Knockout mice (mice with mutated genes for specific receptors
or enzymes) can provide important information regarding the
physiologic and pharmacologic roles of these components.

6. Introduction
• The CNS comprises of the brain and spinal cord – continuous
with each other.
• Function of the brain is to interpret the sensory information
obtained from the internal and external environment and then
send the messages to the effector organs to work
appropriately.
• These functions are accomplished by billion of neurons which
communicates with each other by passage of impulses which
is termed as transmission.
• The transmission of impulse from one neuron to the other is
chemical in nature and these chemicals are called as
neurotransmitters.

7. However, several major differences exist between CNS
&ANS:
The pathway of the CNS is much more complex than that of
the autonomic nervous system, and the number of synapses in
the CNS is far greater.
The CNS, unlike the ANS contains powerful networks of
inhibitory neurons that are constantly active in modulating the
rate of neuronal transmission.
In addition, the CNS communicates through the use of more
than 10 different neurotransmitters. In contrast, the ANS uses
only two primary neurotransmitters, Ach and NE.

8. How the brain communicates
Neurotransmitters: The brain’s chemical messengers
Receptors: The brain’s chemical receivers
Transporters: The brain’s chemical recyclers

9. Synaptic cleft – a gap of 20-40 nm between
the two neurons

10. Otto Loewi’s Experiment

11. Steps involved in excitatory and inhibitory
neurotransmission.
1. When the AP arrives at the presynaptic terminal, it
initiates release of the excitatory or inhibitory transmitter.
Depolarization at the nerve ending and entry of Ca2+
initiate docking and then fusion of the synaptic vesicle
with the membrane of the nerve ending.
2. Combination of the excitatory transmitter with
postsynaptic receptors produces a localized
depolarization, the excitatory postsynaptic potential
(EPSP), through an increase in permeability to cations,
most notably Na+. The inhibitory transmitter causes a
selective increase in permeability to K+ or Cl–, resulting in
a localized hyperpolarization, the inhibitory postsynaptic
potential (IPSP).
3. The EPSP initiates a conducted AP in the postsynaptic
neuron; this can be prevented, however, by the
hyperpolarization induced by a concurrent IPSP.
The transmitter is metabolized by enzymatic destruction,
by reuptake into the presynaptic terminal or adjacent glial
cells, or by diffusion.

13. Excitatory neurotransmitters:

14. Inhibitory neurotransmitters

15. The criteria for the identification of central transmitters
The transmitter must be present in the neurons from which the
presynaptic terminals arises.
The transmitter must be released from the presynaptic nerve on
stimulation.
When applied experimentally to target cells, the effects of the
recognized transmitter must be identical to the effects of
stimulating the presynaptic pathway.
Specific pharmacological agonists and antagonists should mimic
and antagonize, respectively, the measured functions of the
recognized transmitter.

16. Targets for drugs acting on CNS
Identified targets for centrally acting drugs include ion channels
that mediate change in excitability induced by neurotransmitters,
neurotransmitter receptors to which drugs bind to produce
biological responses, and transport proteins that re - accumulate
released transmitter.
The membrane transporters, including those selective for
norepinephrine, dopamine, or serotonin (NET, DAT, and SERT),
accumulate released transmitter and package it for reuse.
 Inhibition of reuptake increases the concentration and duration
of stay of transmitter in the synaptic space; serotonin selective
reuptake inhibitors used for the treatment of depression and
cocaine, which inhibits the reuptake of DA, have dramatic effects.

17. /serotonin
Vmat
transporter
stimulation
DA/5HTHow some drugs of abuse cause dopamine release:
• opioids narcotics (activate opioid receptors)
• nicotine (activate nicotine receptors)
• marijuana (activate cannabinoid receptors)
• alcohol (activate GABA receptors; an inhibitory
transmitter)
Drug :
• cocaine
• ritalin
vesicle Neuronal terminal

18. • Release DA from vesicles and reverse
transporter
Drug Types:
• Amphetamines
-methamphetamine
-MDMA (Ecstasy)
Vmat
transporter
serotonin/
DA/5HT

19. 1.Neurotransmitters are
synthesized from precursors under
the influence of enzymes
2. Stored in vesicles
3.Neurotransmitter molecules that
leak from their vesicles are
destroyed by enzymes
4. Action potential cause vesicle to
fuse with synapse and release
neurotransmitters
5. Some of it binds with auto
receptor and inhibit subsequent
neurotransmitter release
6.Rest of it bind to post synaptic
receptors.
7.Released neurotransmitters are
deactivated either by re uptake or
enzyme degradation.

20. 20

21. TYPES OF NEUROTRANSMITTERS
BOTH
Acetylcholine
Nor epinephrine
EXCITATORY
Glutamate
Aspartate
Nitric oxide
INHIBITORY
Glycine
GABA
Serotonin
Dopamine

22. Neurohormones
Hypothalamic neurons release their hormones to the pituitary,
where they regulate the release of trophic hormones (i.e., ACTH,
FSH, GH, LH, prolactin) into the blood.
The anterior and posterior pituitary secretes a variety of
hormones and releasing factors.
Neuromodulators
They originates from non-synaptic sites, yet influences the
excitability of nerve cells.
Substances such as CO and ammonia, arising from active
neurons or glia, are potential modulators acting through non-
synaptic actions.
 Similarly, circulating steroid hormones, steroids produced in the
nervous system (i.e., neurosteroids), locally released adenosine,
and other purines, eicosanoids, and nitric oxide (NO) are regarded
as modulators.

23. Neurotrophic Factors
Neurotrophic factors are substances produced within the CNS by
neurons, astrocytes, microglia, invading peripheral inflammatory or
immune cells that assist neurons in their attempts to repair damage.
Seven categories of neurotrophic peptides are recognized:
1. Nerve growth factor
2. Brain-derived neurotrophic factor,
3. Neuropoietic factors, which have effects both in brain and in
myeloid cells
4. Growth factor peptides, such as epidermal growth factor,
transforming growth factors
5. Fibroblast growth factors
6. Insulin-like growth factors
7. Platelet-derived growth factors

24. GLUTAMATE
Glutamate & GABA interlinked

25. Glutamate receptors
• Ionotropic (fast): Na+ in
– AMPA: fast excitatory signals
– Kainate: fast excitatory, autoreceptor
• Ionotropic (slow): Na+, Ca2+ in
– NMDA: sustained, high-frequency excitatory
signals
• Metabotropic (slow): K+ out; Ca2+ in

26. Main sites of drug action on
NMDA and GABAA receptor

27. 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

28. 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

29. GABA
• GABA functions as an inhibitory transmitter in
many different CNS pathways.
• About 20% of CNS neurons are GABAergic;
• GABA serves as a transmitter at about 30% of
all the synapses in the CNS.

30. GABA Receptors
• Two types of GABA Receptors:
– GABA-A
a) Cl- influx through Ionotropic receptor
- fast IPSP
• “fast” response (1msec)
• Benzodiazepines, barbiturates
– GABA-B
• G-protein coupled receptor
• K+activate channel ,
• reduce Ca2 conductance,
• inhibit adenyl cyclase
• - slow & long lasting IPSP
• “slow” response (1sec)

32. GABAergic drugs
 GABAA receptor ligands :
1) Agonist /positive allosteric modulators –
- Alcohol
- Barbiturates
- BZD
- Non BZD
- IV anesthetics – etomidate, propofol
- volatile anesthetics – halothane
2) Antagonist/ negative allosteric modulators –
- flumazenil

33. GABAB receptor

34. GABAergic drugs
 GABAB receptor ligands :
- Agonist – baclofen
 GABA reuptake inhibitors:
- tiagabine
 GABA transaminase inhibitors :
- valproate, vigabatrin
 GABA analogues :
- gabapentin, progabide

35. Clinical uses – GABA related drugs
1) As antiepileptics
2) As anesthetics
3) Sedative hypnotics ( BZD, barbiturates)
- anxiety
- insomnia
- sedation & amnesia
- component of anesthesia
- control of ethanol or sedative-hypnotic
withdrawal state
- muscle relaxants

36. Clinical uses – GABA related drugs
4) Migraine headache prophylaxis –
- valproate, topiramate
5) Post herpetic neuralgia – gabapentin
6) Spasmolytics :stroke, cerebral palsy, multiple sclerosis
- baclofen, diazepam

37. Monoamine Transmitters
◦ Noradrenaline (Norepineprine)
◦ Dopamine
◦ 5 HT (Serotonin)
◦ Acetylcholine
◦ Histamine

38. NOREPINEHRINE
The basic processes responsible for the synthesis, storage, release and reuptake of
noradrenaline are the same in the brain as in the periphery.
Noradrenaline Function
Noradrenergic transmission functions in
the 'arousal' system, controlling wakefulness and alertness,
blood pressure regulation
control of mood (functional deficiency contributing to depression).
Noradrenaline excess
 Anxiety
 ADHD
 Panic attacks
 Depression
 Sleep disturbances

39. 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
o Locus coeruleus (LC),
located in the pons.
o Descending control of
pain pathways

40. Dopamine
• 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)

41. 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 - dopamine deficiency- Parkinsons Disease

42. Dopamine Pathways & Function – Cont’d
Mesolimbic pathway: Overactivity of the mesolimbic pathway has
been implicated in development of positive symptoms of
schizophrenia. The negative and some cognitive symptoms of
schizophrenia have been associated with a reduction of dopamine
activity in the mesocortical pathways.
Mesocortical pathway:The mesocortical pathway also originates
from the midbrain ventral tegmental area and innervates areas of
the frontal cortex. It has been implicated in aspects of learning ,
memory and reward.
Tuberohypophyseal pathway
The tuberoinfundibular pathway projects from the hypothalamus to
the anterior pituitary gland and controls prolactin secretion.
Regulate secretions of pituitary gland
Prolactin release (inhibited)
Growth hormone release (stimulated)

43. Dopaminergic pathways
Adapted from Inoue and Nakata. Jpn J Pharmacol. 2001;86:376.
Nigrostriatal
pathway
(part of EP system)
Tuberoinfundibular pathway
(inhibits prolactin release)
Me Mesocortical pathway socortil
pathway
Mesolimbic
pathway

44. Dopamine Receptors
There are five dopamine receptor subtypes.
Dopamine receptors
– 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 are mediated mainly by
receptors of the D2 family - schizophrenia

45. Serotonin (5-HT)
5-HT - 1% in brain , 99% in gut.
Molecular biological approaches have led to identification of 14
distinct mammalian 5-HT receptor subtypes -5HT1-5HT7
Lysergic acid diethylamide (LSD) is a potent partial agonist
at 5-HT2 receptors
Selective serotonin reuptake inhibitors constitute an important
group of antidepressant drugs.

46. 5-HT Receptors in the CNS

47. 5-HT Functions
• Functions associated with 5-HT pathways:
– Mood and emotion
– Appetite
– Sleep/wakefulness
– Control of sensory pathways, including nociception
– Body temperature control
– Vomiting

48. STR
TH
Raphe Nuclei

49. Serotonin imbalance
• Depression
• Anxiety
• Obsessions and
Compulsions
• Pain Sensitivity
• Aggression
• Sleep Disorders

51. 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
• 5-HT3 receptor antagonists, - ondansetron - antiemetic
agents
• 5-HT2A/2C receptor antagonists Antipsychotic drugs -
clozapine
• 5-HT4 receptor antagonist :Metoclopramide
Gastrokinetic and anti emetic

52. 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:
 Forebrain nuclei which send a diffuse projection
◦Degeneration – Alzheimer’s Dementia
Septohippocampal projection
Short interneurons in the striatum and nucleus
accumbens.

53. Acetylcholine pathways

54. 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.

55. Chlinomimetic Drugs
Acetylcholinesterase Inhibitor: Alzheimers disease
Tacrine
Donepezil
Galantamine
Rivastigmine
Muscarinic Cholinergic Receptor Antagonists:
Trihexyphenidyl and Benztropine

56. Histamine
Most of the histaminergic neurons are located in the ventral
posterior hypothalamus; they give rise to long ascending and
descending tracts that are typical of the patterns characteristic
of other aminergic systems.
 The histaminergic system is thought to affect arousal, body
temperature, and vascular dynamics.
Unlike the monoamines and amino acid transmitters, there
does not appear to be an active process for reuptake of
histamine after its release.
 Inhibition of H1 receptors causes drowsiness, an effect that
limits the use of H1 antagonists to treat allergic reactions.
The development of H1 antagonists with low CNS
penetration has reduced the incidence of these side effects.

57. Alcohol & neurotransmitters
• It binds directly to receptors for ACh,
serotonin, GABA and glutamate.
• It enhances the effects of the GABA,
– Enhancing an inhibitor make things sluggish.
– The neuron activity is diminished- sedative effects of alcohol.
• Alcohol inhibits glutamate receptor function.
– This causes discoordination, slurred speech, staggering, memory
disruption, and blackout.
• Alcohol raises dopamine levels.
– This leads to excitement, pleasure and later addiction.

58. Nicotine & Neurotransmitters
• Nicotine activates cholinergic neurons in many different regions
throughout the brain simultaneously.
– In addition also increases - release of Glutamate.
– Stimulation of cholinergic neurons promotes the release of
dopamine.
– The production of dopamine causes feelings of pleasure.

59. DISEASES ASSOCIATED WITH
NEUROTRANSMITTERS
NEUROTRANSMITTER
• Acetylcholine
• Dopamine
• GABA
• Serotonin
• Glutamate
DISEASE
• Alzheimer’s
• Parkinson’s disease
• Schizophrenia
• Epilepsy
• Migraines
• ADD
• Depression
• Migraine
• stroke

60. RECENT DEVELOPMENTS
• A team of scientists from University of Barcelona in 2011,
has discovered that D-aspartic acid (D-Asp) is a novel
neurotransmitter that could potentially be used in the fight
against neurological diseases such as Parkinson's and
schizophrenia.
• According to a new study led by researchers at the Ohio State
University Comprehensive Cancer Center in 2011, doses of
a neurotransmitter dopamine might offer a way to boost the
effectiveness of anticancer drugs and radiation therapy.

61. Conclusion
Drugs that act in the central nervous system (CNS) are valuable
therapeutically.
 They can, e.g., relieve pain, reduce fever, suppress disordered
movements, induce sleep or arousal, reduce appetite, and reduce or
eliminate the tendency to vomit.
Selectively acting drugs can be used to treat anxiety, depression,
mania, or schizophrenia and do so without altering consciousness
Socially acceptable stimulants and anti-anxiety agents contribute
to emotional stability, relief of anxiety, and pleasure.

62. Conclusion – cont’d
However, the excessive use of such drugs can affect lives
adversely when uncontrolled, self-administration leads to
physical dependence or to toxic side effect.
The nonmedical self-administration of CNS-active drugs—
recreational pharmacology—is widespread.
CNS pharmacologists have two overlapping goals: to explain
the mechanisms that operate in the normal CNS, and to develop
drugs to correct pathophysiological events in the abnormal
CNS.
Advances in molecular biology and neurobiology are
facilitating the development of drugs that can selectively treat
diseases of the CNS.