Chemical transmission in the nervous system

1. NEUROTRANSMITTERS

2. INTRODUCTION
• Neurotransmitters are endogenous chemicals that transmit
signals from a neuron to a target cell across a synapse
• Synapses are the junctions where neurons release a chemical
neurotransmitter that acts on a postsynaptic target cell, which
can be another neuron or a muscle or gland cell
• Some chemicals released by neurons have little or no direct
effects on their own but can modify the effects of
neurotransmitters. These chemicals are called
neuromodulators.

3. Criteria That Define a Neurotransmitter

4. THE FATHER OF NEUROSCIENCE
• Otto Loewi (German
pharmacologist)
• Discovered the chemical nature of
neurotransmission (Acetylcholine)
across synapse
• Loewi was awarded the Nobel
Prize in Physiology (1936)

5. The Experiment :

6. Identified neurotransmitters and neuromodulators can be divided
into two major categories:
SMALL-MOLECULE TRANSMITTERS
Monoamines (eg, Acetylcholine, Serotonin, Histamine),
Catecholamines (Dopamine, Norepinephrine Epinephrine)
Amino Acids (eg, Glutamate, GABA, Glycine).
LARGE-MOLECULE TRANSMITTERS.
Include a large number of peptides called neuropeptides including
substance P, enkephalin, vasopressin, and a host of others.
There are also other substances thought to be released into the
synaptic cleft to act as either a transmitter or modulator of synaptic
transmission. These include purine derivatives like Adenosine,
Adenosine Triphosphate (ATP) and Nitric Oxide (NO).

7. Neurotransmitter receptors
Two broad classes:
LIGAND-GATED ION CHANNELS
Open immediately upon neurotransmitter binding
G PROTEIN–COUPLED RECEPTORS.
Neurotransmitter binding to a G protein–coupled receptor induces the
opening or closing of a separate ion channel protein over a period of
seconds to minutes. These are “slow” neurotransmitter receptors.
Each ligand has many subtypes of receptors : selective effect at
different sites
Presynaptic receptors, or Autoreceptors : provide feedback control

8. • Receptors are concentrated in clusters in postsynaptic structures close
to the endings of neurons that secrete the neurotransmitters specific
for them. This is generally due to the presence of specific binding
proteins for them.
In the case of nicotinic acetylcholine receptors at the neuromuscular
junction, the protein is rapsyn
In the case of excitatory glutamatergic receptors, a family of PB2-
binding proteins is involved.
GABAA receptors are associated with the protein gephyrin, which also
binds glycine receptors, and
GABAC receptors are bound to the cytoskeleton in the retina by the
protein MAP-1B.

9. DESENSITIZATION
Prolonged exposure to their ligands causes most receptors to
become unresponsive. This can be of two types:
Homologous desensitization, with loss of responsiveness
only to the particular ligand and maintained responsiveness
of the cell to other ligands
Heterologous desensitization, in which the cell becomes
unresponsive to other ligands as well.

10. Reuptake
• From the synaptic cleft back into the cytoplasm of the neuron
The reuptake systems employ two families of transporter proteins:
Members include transporters for norepinephrine, dopamine,
serotonin, GABA, and glycine, as well as transporters for proline,
taurine, and the acetylcholine precursor choline. In addition, there
may be an epinephrine transporter.
The other family is made up of at least three transporters that
mediate glutamate uptake by neurons and two that transport
glutamate into astrocytes.

11. • There are in addition two vesicular monoamine transporters, VMAT1
and VMAT2, that transport neurotransmitters from the cytoplasm to
synaptic vesicles. They are coded by different genes but have
extensive homology:
Both have a broad specificity, moving dopamine, norepinephrine,
epinephrine, serotonin, and histamine from the cytoplasm into
secretory granules.
Both are inhibited by reserpine, which accounts for the marked
monoamine depletion produced by this drug.
Like the neurotransmitter membrane transporter family, they have 12
transmembrane domains, but they have little homology to the other
transporters.
• There is also a vesicular GABA transporter (VGAT) that moves GABA
and glycine into vesicles and a vesicular acetylcholine transporter.

12. Monoamineissynthesizedinthe
cytoplasmandthesecretorygranules
(1)anditsconcentrationinsecretory
granulesismaintained
(2)bythetwovesicularmonoamine
transporters(VMAT).Themonoamine
issecretedbyexocytosisofthegranules
(3),anditacts
(4)onreceptors(Y-shapedstructures
labeledR).Manyofthesereceptorsare
postsynaptic,butsomearepresynaptic
andsomearelocatedonglia.In
addition,thereisextensivereuptake
intothecytoplasmofthepresynaptic
terminal
(5)viathemonoamine
neurotransmittertransporter(NTT)for
themonoaminethatissynthesizedin
theneuron.

13. Reuptake is a major factor in terminating the action of
transmitters, when inhibited, the effects of transmitter release
are increased and prolonged. This has clinical consequences.
Several effective antidepressant drugs are inhibitors of the
reuptake of amine transmitters.
Cocaine is believed to inhibit dopamine reuptake.
Glutamate uptake into neurons and glia is important because
glutamate is an excitotoxin that can kill cells by overstimulating
them. There is evidence that during ischemia and anoxia, loss of
neurons is increased because glutamate reuptake is inhibited.

14. Acetylcholine
Acetylcholine, which is the
acetyl ester of choline, is
largely enclosed in small,
clear synaptic vesicles in
high concentration in the
terminal boutons of
cholinergic neurons

15. • Acetylcholine is the transmitter at the neuromuscular junction, in
autonomic ganglia, and in postganglionic parasympathetic nerve-
target organ junctions and some postganglionic sympathetic
nerve-target junctions. It is also found within the brain, including
the basal forebrain complex and pontomesencephalic cholinergic
complex . These systems may be involved in regulation of sleep-
wake states, learning, and memory.

17. • Cholinergic neurons actively
take up choline via a
transporter. Choline is also
synthesized in neurons.
• The enzyme choline
acetyltransferase is found in
high concentration in the
cytoplasm of cholinergic
nerve endings. Acetylcholine
is then taken up into synaptic
vesicles by a vesicular
transporter (VAChT).
• Removed via Hydrolysis to
choline and acetate, a
reaction catalyzed by the
enzyme
ACETYLCHOLINESTERASE.

18. Acetylcholine Receptors
Muscarinic
Nicotinic

19. Muscarinic receptors
• Muscarine, the alkaloid responsible for the toxicity of toadstools, has little
effect on the receptors in autonomic ganglia but mimics the stimulatory
action of acetylcholine on smooth muscle and glands.
• These actions of acetylcholine are therefore called muscarinic actions, and
the receptors involved are muscarinic cholinergic receptors.
• They are blocked by the drug atropine.
• Five types, encoded by five separate genes, have been cloned.
• The exact status of M5 is uncertain, but the remaining four receptors are
coupled via G proteins to adenylyl cyclase, K+ channels, and/or
phospholipase C .
• M1 is abundant in the brain.
• The M2 receptor is found in the heart.
• The M4 receptor is found in pancreatic acinar and islet tissue.
• The M3 and M4 receptors are associated with smooth muscle.

20. Nicotinic receptors
• In Sympathetic Ganglia, the actions of Ach are unaffected by
atropine but MIMICKED BY NICOTINE. Consequently, these actions
of Ach are nicotinic actions and the receptors are nicotinic
cholinergic receptors.
• Nicotinic receptors are subdivided into those at neuromuscular
junctions and those found in autonomic ganglia and the central
nervous system
• Both muscarinic and nicotinic acetylcholine receptors are found in
large numbers in the brain.
• The nicotinic acetylcholine receptors are members of a superfamily
of ligand-gated ion channels

21. • Each nicotinic cholinergic receptor is made up of five subunits that form a
central channel which, when the receptor is activated, permits the passage
of Na+ and other cations. A prominent feature of neuronal nicotinic
cholinergic receptors is their high permeability to Ca2+.
• The 5 subunits come from a menu of 16 known subunits, α1–α9, β1–β5, γ , δ
and ε , coded by 16 different genes.
• THE MUSCLE TYPE NICOTINIC RECEPTOR found in the fetus is made up of
two α1 subunits, a β1 subunit, a γ subunit, and a δ subunit . In adult,the γ
subunit is replaced by a δ subunit, which decreases the channel open time
but increases its conductance.
• The nicotinic cholinergic RECEPTORS IN AUTONOMIC GANGLIA usually
contain α3 subunits in combination with others.
Many of the nicotinic cholinergic receptors in the brain are located
presynaptically on glutamate-secreting axon terminals, and they facilitate the
release of this transmitter. However, others are postsynaptic. Some are located
on structures other than neurons, and some seem to be free in the interstitial
fluid, that is, they are perisynaptic in location.

23. Serotonin
• Serotonin is formed in the
body by hydroxylation and
decarboxylation of the
essential amino acid
TRYPTOPHAN
• Tryptophan hydroxylase in
the human CNS is slightly
different from the
tryptophan hydroxylase in
peripheral tissues, and is
coded by a different gene.

24. SEROTONIN (5-
HYDROXYTRYPTAMINE; 5-
HT) is present in highest
concentration in blood
platelets and in the
gastrointestinal tract, where
it is found in the
enterochromaffin cells and
the myenteric plexus.
It is also found within the
brain stem in the midline
raphé nuclei which project to
portions of the
hypothalamus, the limbic
system, the neocortex, the
cerebellum, and the spinal
cord There is evidence for a relationship between
behavior and brain serotonin content.

25. • After release from
serotonergic neurons, much
of the released serotonin is
recaptured by an active
reuptake mechanism and
inactivated by MONOAMINE
OXIDASE (MAO) to form 5-
hydroxyindoleacetic acid (5-
HIAA).
• This substance is the
principal urinary metabolite
of serotonin, and its urinary
output is used as an index of
the rate of serotonin
metabolism in the body

26. Serotonergic Receptors
• 5-HT1 - 5-HT7 receptors
• Most of these are G protein-coupled receptors
• 5-HT1 => 5-HT1A, 5-HT1B, 5-HT1D, 5-HT1E, & 5-HT1F
• 5-HT2 => 5-HT2A, 5-HT2B, & 5-HT2C
• 5-HT2A receptors mediate platelet aggregation and smooth muscle
contraction.
• 5-HT3 receptors are ligand-gated ion channels present in the GIT & the
area postrema & are related to vomiting.
• 5-HT4 receptors are also present in the GIT, where they facilitate
secretion and peristalsis, & in the brain.
• 5-HT5 => 5-HT5A & 5-HT5B
• 5-HT6 & 5-HT7 are distributed throughout the limbic system, and the 5-
HT6 receptors have a high affinity for antidepressant drugs.

27. Histamine
• Histamine is formed by decarboxylation of the amino acid
histidine .

28. • Histaminergic neurons have their cell bodies in the
tuberomammillary nucleus of the posterior hypothalamus, and their
axons project to all parts of the brain, including the cerebral cortex
and the spinal cord.
• Histamine is also found in cells in the gastric mucosa and in heparin-
containing cells called mast cells that are plentiful in the anterior and
posterior lobes of the pituitary gland as well as at body surfaces.
• The three known types of histamine receptors— H1, H2, and H3—are
all found in both peripheral tissues and the brain.
• Mostof the H3 receptors are presynaptic, and they mediate
inhibition of the release of histamine and other transmitters via a G
protein. H1 receptors activate phospholipase C, and H2 receptors
increase the intracellular cAMP concentration.
• Evidence links brain histamine to arousal, sexual behavior, blood
pressure, drinking, pain thresholds, and regulation of the secretion of
several anterior pituitary hormones.

29. Catecholamines
• Norepinephrine, Epinephrine, & Dopamine
• The chemical transmitter present at most sympathetic
postganglionic endings is norepinephrine. It is stored in the
synaptic knobs of the neurons that secrete it in characteristic small
vesicles that have a dense core.
• NOREPINEPHRINE and its methyl derivative, EPINEPHRINE, are
secreted by the adrenal medulla
• Tyrosine hydroxylase, which catalyzes the RATE LIMITING step, is
subject to feedback inhibition by dopamine and norepinephrine,
thus providing internal control of the synthetic process.
• The cell bodies of the norepinephrine-containing neurons are
located in the locus ceruleus and other medullary and pontine
nuclei .

30. RATE LIM STEP

33. Catabolism of Catecholamines
• Removed from the synaptic cleft by binding to postsynaptic receptors,
binding to presynaptic receptors , reuptake into the presynaptic
neurons, or catabolism. Reuptake is a major mechanism in the case of
norepinephrine.
• Epinephrine and norepinephrine are metabolized to biologically
inactive products by oxidation and methylation. The former reaction is
catalyzed by MAO and the latter by catechol -O –methyltransferase
(COMT).
• EXTRACELLULAR epinephrine and norepinephrine are for the most
part O-methylated, and measurement of the concentrations of the O-
methylated derivatives normetanephrine and metanephrine in the
urine is a good index of the rate of secretion of norepinephrine and
epinephrine.
• The O-methylated derivatives that are not excreted are largely
oxidized, and 3-methoxy-4-hydroxymandelic acid (vanillylmandelic
acid, VMA) is the most plentiful catecholamine metabolite in the
urine. Small amounts of the O-methylated derivatives are also
conjugated to sulfate and glucuronide.

34. • In the
NORADRENERGIC
NERVE TERMINALS, on
the other hand, some
of the norepinephrine is
constantly being
converted by
intracellular MAO to the
physiologically inactive
deaminated derivatives,
3,4-dihydroxymandelic
acid (DOMA) and its
corresponding glycol
(DHPG). These are
subsequently converted
to their corresponding
O-methyl derivatives,
VMA and 3-methoxy-4-
hydroxyphenylglycol
(MHPG).

35. α & β Receptors
• Epinephrine and norepinephrine both act on and receptors,
with norepinephrine having a greater affinity for α-adrenergic
receptors and epinephrine for β-adrenergic receptors.
• G protein-coupled receptors, and each has multiple forms

36. Dopamine
• In certain parts of the brain, catecholamine synthesis stops at
dopamine
• Active reuptake of dopamine occurs via a Na+- and Cl–-dependent
dopamine transporter.
• Dopamine is metabolized to inactive compounds by MAO and COMT
in a manner analogous to the inactivation of norepinephrine
• Dopaminergic neurons are located in several brain regions including
the nigrostriatal system, which projects from the substantia nigra to
the striatum and is involved in motor control, and the mesocortical
system.
• The mesocortical system projects to the nucleus accumbens and
limbic subcortical areas, and it is involved in reward behavior and
addiction.
• Studies by PET scanning in normal humans show that a steady loss
of dopamine receptors occurs in the basal ganglia with age. The loss
is greater in men than in women.

38. Dopamine Receptors
• Five different dopamine receptors have been cloned, and several of
these exist in multiple forms.
• Most, but perhaps not all, of the responses to these receptors are
mediated by heterotrimeric G proteins.
• Overstimulation of D2 receptors is thought to be related to
schizophrenia.
• D3 receptors are highly localized, especially to the nucleus accumbens

39. Glutamate
• The amino acid glutamate is the main excitatory transmitter in the brain
and spinal cord( 75% of the excitatory transmission in the brain. )
• Glutamate is formed by reductive amination of the Krebs cycle
intermediate α-ketoglutarate in the cytoplasm.
• The reaction is reversible, but in glutaminergic neurons, glutamate is
concentrated in synaptic vesicles by the vesicle-bound transporter BPN1.
• The cytoplasmic store of glutamine is enriched by three transporters that
import glutamate from the interstitial fluid, and two additional
transporters carry glutamate into astrocytes, where it is converted to
glutamine and passed on to glutaminergic neurons.
• Released glutamate is taken up by astrocytes and converted to
glutamine, which passes back to the neurons and is converted back to
glutamate, which is released as the synaptic transmitter.
• Uptake into neurons and astrocytes is the main mechanism for removal
of glutamate from synapses

40. The glutamate–glutaminecycle through
glutaminergicneurons and astrocytes.

41. Glutamate Receptors
Two types:
METABOTROPIC RECEPTORS
IONOTROPIC RECEPTORS
THE METABOTROPIC RECEPTORS
• G protein-coupled receptors that increase intracellular IP3 and DAG
levels or decrease intracellular cAMP levels.
• Eleven subtypes
• Presynaptic & postsynaptic, and widely distributed in the brain.
• They appear to be involved in the production of synaptic plasticity,
particularly in the hippocampus and the cerebellum.
• Knockout of the gene for one of these receptors, one of the forms of
mGluR1, causes severe motor incoordination and deficits in spatial
learning.

42. THE IONOTROPIC RECEPTORS
• Ligand-gated ion channels.
• There are three general types, each named for the congeners of
glutamate to which they respond in maximum fashion.
Kainate receptors (kainate is an acid isolated from seaweed)
Simple ion channels that, when open, permit Na+ influx and K+ efflux
4 AMPA subunits have been identified
AMPA receptors ( amino-3-hydroxy-5-methylisoxazole-4-
propionate)
Two populations : one is a simple Na+ channel and one also passes
Ca2+.
5 kainate subunits have been identified
NMDA receptors (N-methyl-D-aspartate).

43. NMDA receptors
• A cation channel: permits passage of relatively large amounts of
Ca2+
• Glycine facilitates its function by binding to it, & appears to be
essential for its normal response to glutamate.
• When glutamate binds to it, it opens, but at normal membrane
potentials, its channel is blocked by a Mg2+ ion.
• Phencyclidine and ketamine, which produce amnesia and a feeling
of dissociation from the environment, bind to another site inside
the channel. Most target neurons for glutamate have both AMPA
and NMDA receptors.

44. • Kainate receptors are located presynaptically on GABA-secreting
nerve endings and postsynaptically at various localized sites in the
brain. Kainate and AMPA receptors are found in glia as well as
neurons, but it appears that NMDA receptors occur only in
neurons
• The concentration of NMDA receptors in the hippocampus is high,
and blockade of these receptors prevents long-term potentiation,
a long-lasting facilitation of transmission in neural pathways
following a brief period of high-frequency stimulation. Thus, these
receptors may well be involved in MEMORY AND LEARNING.

45. NMDA receptor

46. GABA
• Major inhibitory mediator in the brain, including being
responsible for presynaptic inhibition.
• Formed by decarboxylation of glutamate . The enzyme
glutamate decarboxylase (GAD), is present in nerve endings in
many parts of the brain.

47. • Metabolized primarily by transamination to succinic semialdehyde
and thence to succinate in the citric acid cycle. GABA transaminase
(GABA-T) catalyzes the transamination.
• In addition, there is an active reuptake of GABA via the GABA
transporter. A vesicular GABA transporter (VGAT) transports GABA
and glycine into secretory vesicles

48. GABA Receptors
• Three subtypes of GABA receptors have been identified: GABAA,
GABAB, and GABAC
• The GABAA and GABAB receptors are widely distributed in the CNS,
whereas in adult vertebrates the GABAC receptors are found
almost exclusively in the retina.
• The GABAA and GABAC receptors are ion channels made up of five
subunits surrounding a pore . In this case, the ion is Cl– .
• The GABAB receptors are metabotropic ,coupled to heterotrimeric
G proteins that increase conductance in K+ channels, inhibit
adenylyl cyclase, and inhibit Ca2+ influx.
• Increases in Cl– influx and K+ efflux and decreases in Ca2+ influx all
hyperpolarize neurons, producing an IPSP. The G protein mediation
of GABAB receptor effects is unique in that a G protein
heterodimer, rather than a single protein, is involved.

50. • There is a chronic low-level stimulation of GABAA receptors in the CNS
that is aided by GABA in the interstitial fluid. This background
stimulation cuts down on the "noise" caused by incidental discharge of
the billions of neural units and greatly IMPROVES THE SIGNAL-TO-NOISE
RATIO in the brain. It may be that this GABA discharge declines with
advancing age, resulting in a loss of specificity of responses of visual
neurons.
• The increase in Cl– conductance produced by GABAA receptors is
potentiated by benzodiazepines, drugs that have marked anti-anxiety
activity and are also effective muscle relaxants, anticonvulsants, and
sedatives. Benzodiazepines bind to the α subunits.
• At least in part, barbiturates and alcohol also act by facilitating Cl–
conductance.
• Metabolites of the steroid hormones progesterone and
deoxycorticosterone bind to GABAA receptors and increase Cl–
conductance.
• It has been known for many years that progesterone and
deoxycorticosterone are sleep-inducing and anesthetic in large doses,
and these effects are due to their action on GABAA receptors.

51. Glycine
• Glycine has both excitatory and inhibitory effects in the CNS.
• When it binds to NMDA receptors, it makes them more sensitive.It
appears to spill over from synaptic junctions into the interstitial fluid,
and in the spinal cord, for example, this glycine may facilitate pain
transmission by NMDA receptors in the dorsal horn.
• Glycine is also responsible in part for direct inhibition, primarily in the
brain stem and spinal cord. Like GABA, it acts by increasing Cl–
conductance. Its action is antagonized by strychnine.
• The clinical picture of convulsions and muscular hyperactivity
produced by strychnine emphasizes the importance of postsynaptic
inhibition in normal neural function.

52. RECEPTOR
• The glycine receptor responsible for inhibition is a Cl– channel.
• It is a pentamer made up of two subunits:
The ligand-binding α subunit
The structural β subunit.
• Recently, solid evidence has been presented that three kinds of
neurons are responsible for direct inhibition in the spinal cord:
neurons that secrete glycine,
neurons that secrete GABA, and
neurons that secrete both.
Presumably, neurons that secrete only glycine have the glycine
transporter GLYT2, those that secrete only GABA have GAD, and
those that secrete glycine and GABA have both. This third type of
neuron is of special interest because the neurons seem to have
glycine and GABA in the same vesicles.

53. Anesthesia
• Alcohols, barbiturates, and many volatile inhaled anesthetics
as well act on ion channel receptors and specifically on GABAA
and glycine receptors to increase Cl– conductance. Regional
variation in anesthetic actions in the CNS seems to parallel the
variation in subtypes of GABAA receptors.
• Other inhaled anesthetics do not act by increasing GABA
receptor activity, but appear to act by inhibiting NMDA and
AMPA receptors instead.
• Local anesthetics produce anesthesia by blocking conduction
in peripheral nerves via reversibly binding to and inactivating
Na+ channels. When depolarization and propagation are
interrupted, the individual loses sensation in the area supplied
by the nerve.

54. Large-Molecule Transmitters:
Neuropeptides
• Substance P & Other Tachykinins:
• Substance P is a polypeptide containing 11 amino acid residues that is
found in the intestine, various peripheral nerves, and many parts of
the CNS.
• It is one of a family of 6 mammalian polypeptides called tachykinins
that differ at the amino terminal end but have in common the carboxyl
terminal sequence.

55. • Substance P is found in high concentration in the endings of
primary afferent neurons in the spinal cord, and it is probably the
mediator at the first synapse in the pathways for pain transmission
in the dorsal horn.
• It is also found in high concentrations in the nigrostriatal system,
where its concentration is proportional to that of dopamine, and in
the hypothalamus, where it may play a role in neuroendocrine
regulation
• In the intestine, it is involved in peristalsis.

56. Opioid Peptides
Peptides that bind to opioid receptors are called opioid peptides.
The ENKEPHALINS are found in nerve endings in the gastrointestinal
tract and many different parts of the brain, and they appear to
function as synaptic transmitters. They are found in the substantia
gelatinosa and have analgesic activity when injected into the brain
stem. They also decrease intestinal motility.
METABOLISM
Enkephalins are metabolized primarily by two peptidases
• Enkephalinase A, which splits the Gly-Phe bond, and
• Enkephalinase B, which splits the Gly-Gly bond.
• Aminopeptidase, which splits the Tyr-Gly bond, also contributes to
their metabolism.

57. RECEPTORS
• µ , κ , δ
• All three are G protein-coupled receptors, and all inhibit adenylyl
cyclase.
• Activation of µ receptors increases K+ conductance, hyperpolarizing
central neurons and primary afferents. Activation of κ and δ
receptors closes Ca2+ channels.

58. Physiologic effects of opiate
receptor stimulation

59. Receptor affinity

60. Other Polypeptides
SOMATOSTATIN is found in various parts of the brain, where it
apparently functions as a neurotransmitter with effects on sensory input,
locomotor activity, and cognitive function.
• In the endocrine pancreas, it inhibits insulin secretion and the secretion
of other pancreatic hormones
• In the gastrointestinal tract, it is an important inhibitory gastrointestinal
regulator.
A family of five different SOMATOSTATIN RECEPTORS have been
identified (SSTR1 through SSTR5).
• All are G protein-coupled receptors. They inhibit adenylyl cyclase and
exert various other effects on intracellular messenger systems.
• It appears that SSTR2 mediates cognitive effects and inhibition of
growth hormone secretion, whereas SSTR5 mediates the inhibition of
insulin secretion.

61. • VASOPRESSIN & OXYTOCIN are not only secreted as hormones but
also are present in neurons that project to the brain stem and spinal
cord
• The brain contains BRADYKININ, ANGIOTENSIN II & ENDOTHELIN
• The gastrointestinal hormones VIP, CCK-4, and CCK-8 are also found
in the brain. There are two kinds of CCK receptors in the brain, CCK-
A and CCK-B.
• GASTRIN, NEUROTENSIN, GALANIN, AND GASTRIN-RELEASING
PEPTIDE are also found in the gastrointestinal tract and brain

62. CALCITONIN GENE-RELATED PEPTIDE (CGRP)
• Is a polypeptide that exists in two forms : CGRPα and CGRPβ
• CGRP is present in the gastrointestinal tract, found in primary afferent
neurons, neurons that project impulses to the thalamus, and neurons
in the medial forebrain bundle. It is also present along with substance
P in the branches of primary afferent neurons that end near blood
vessels.
• Its injection causes vasodilation.
• CGRPα and the calcium-lowering hormone calcitonin are both
products of the calcitonin gene.

63. NEUROPEPTIDE Y
• Is a polypeptide containing 36 amino acid residues that acts on at
least two of the 4 known G protein-coupled receptors: Y1, Y2, Y4, and
Y5.
• Neuropeptide Y is found throughout the brain and the autonomic
nervous system.
• When injected into the hypothalamus, this polypeptide increases
food intake, and inhibitors of neuropeptide Y synthesis decrease
food intake.
• Neuropeptide Y-containing neurons have their cell bodies in the
arcuate nuclei and project to the paraventricular nuclei

64. Other Chemical Transmitters
PURINE & PYRIMIDINE TRANSMITTERS
• ATP, URIDINE, ADENOSINE, AND ADENOSINE METABOLITES
are neurotransmitters or neuromodulators.
ADENOSINE
is a neuromodulator that acts as a general CNS depressant and
has additional widespread effects throughout the body.
• 4 receptors: A1, A2A, A2B, and A3. G protein-coupled &
increase (A2A and A2B) or decrease (A1 and A3) cAMP
concentrations.
• The stimulatory effects of coffee and tea are due to blockade
of adenosine receptors by caffeine and theophylline.

65. ATP
• ATP has now been shown to mediate rapid synaptic responses in the
autonomic nervous system and a fast response in the habenula.
• ATP binds to P2X receptors which are ligand-gated ion channel
receptors; seven subtypes (P2X1–P2X7) have been identified.
• P2X receptors have widespread distributions throughout the body;
for example, P2X1 and P2X2 receptors are present in the dorsal horn,
indicating a role for ATP in sensory transmission.
• ATP also binds to P2Y receptors which are G protein-coupled
receptors. There are eight subtypes of P2Y receptors: P2Y1, P2Y2,
P2Y4, P2Y6, P2Y11, P2Y12, P2Y13, and P2Y14
• It appears that soluble nucleotidases are released with ATP, and
these accelerate its removal after it has produced its effects.

66. CANNABINOIDS
• Two receptors with a high affinity for tetrahydrocannabinol (THC),
the psychoactive ingredient in marijuana, have been cloned.
• The CB1 receptor triggers a G protein-mediated decrease in
intracellular cAMP levels and is common in central pain pathways as
well as in parts of the cerebellum, hippocampus, and cerebral
cortex.
• The endogenous ligand for the receptor is ANANDAMIDE, a
derivative of arachidonic acid. This compound mimics the euphoria,
calmness, dream states, drowsiness, and analgesia produced by
marijuana.
• There are also CB1 receptors in peripheral tissues, and blockade of
these receptors reduces the vasodilator effect of anandamide.
• A CB2 receptor has also been cloned, and its endogenous ligand may
be palmitoylethanolamide (PEA). However, the physiologic role of
this compound is unsettled.

67. Gases
NITRIC OXIDE (NO)
• The compound released by the endothelium of blood vessels as
EDRF, is also produced in the brain.
• It is synthesized from arginine, a reaction catalyzed in the brain by
one of the three forms of NO synthase.
• NO synthase requires NADPH
• It activates guanylyl cyclase and, unlike other transmitters, it is a
gas, which crosses cell membranes with ease and binds directly to
guanylyl cyclase.
• It may be the signal by which postsynaptic neurons communicate
with presynaptic endings in long-term potentiation and long-term
depression.

68. Other Substances
PROSTAGLANDINS
• Are derivatives of arachidonic acid found in the nervous system, present
in nerve-ending fractions of brain homogenates and are released from
neural tissue in vitro. A putative prostaglandin transporter with 12
membrane-spanning domains has been described.
• However, prostaglandins appear to exert their effects by modulating
reactions mediated by cAMP rather than by functioning as synaptic
transmitters.
NEUROACTIVE STEROIDS
• They are not neurotransmitters in the usual sense.
• Evidence has now accumulated that the brain can produce some
hormonally active steroids from simpler steroid precursors, and the term
neurosteroids has been coined to refer to these products. Progesterone
facilitates the formation of myelin, but the exact role of most steroids in
the regulation of brain function remains to be determined.

69. Thank you…