The following neurotransmitters are described : dopamine ,serotonin,norepinephrine,acetylcholine,epinephrine,GABA,glutamate

1. NEUROTRANSMITTERS
Sakshi Maheshwari
M.Phil clinical psychology
2021-23

2. NEURON

3. ELECTRICAL TRANSMISSION CHEMICAL TRANSMISSION

4. NEUROTRANSMITTERS
Neurotransmitters and neuromodulators are the
molecules responsible for the transmission of
information on chemical synapses.
For a molecule to be considered as
a neurotransmitter :
(i) must be stored in vesicles together with the
enzymes responsible for its synthesis
(ii) must be released in response to an increase in
intracellular Ca2+
(iii) the exogenous administration of the
neurotransmitter should elicit the same response
as it were endogenously produced.

5. • History
• Synthesis and breakdown
• Brain areas
• pathways
• receptors
• Functions in psychological domain
• Disturbances in psychiatric disorders
• Pharmacological treatment(agonist/antagonist)

6. DOPAMINE
• 1910 : first synthesized by George Barger and James Ewens
at Wellcome Laboratories in London, England
• 1957 :first identified in the human brain by Katharine Montagu ,
named dopamine because it is a monoamine whose precursor in
the Barger-Ewens synthesis is 3,4-dihydroxyphenylalanine
(levodopa or L-DOPA).
• 1958: function as a neurotransmitter was first recognized
by Arvid Carlsson and Nils-Åke Hillarp at the Laboratory for
Chemical Pharmacology of the National Heart Institute
of Sweden
• 2000 :Carlsson awarded Nobel Prize in Physiology or
Medicine for showing that dopamine is not only a precursor of
norepinephrine (noradrenaline) and epinephrine (adrenaline),
but is itself a neurotransmitter

7. SYNTHESIS BREAKDOWN

8. FUNCTIONS
• Inside the brain, dopamine plays important roles in executive
functions, motor control, motivation, arousal, reinforcement,
and reward as well as lower-level functions including lactation, sexual
gratification. The dopaminergic cell groups and pathways make up the
dopamine system which is neuromodulatory
• plays a starring role in motivating behavior. It gets released when we
take a bite of delicious food, when we have sex, after we exercise,
and, importantly, when we have successful social interactions.
• In an evolutionary context, it rewards us for beneficial behaviors and
motivates us to repeat them.

9. Reward behaviour
Appetite
phase(approach)
The motivational or desirable aspect of rewarding
stimuli is reflected by the approach behavior that
they induce
Consumption phase
the pleasure from intrinsic rewards results
from consuming them after acquiring them.
A neuropsychological model which distinguishes these two components of an intrinsically rewarding stimulus is
the incentive salience model, where "wanting" or desire (less commonly, "seeking") corresponds to appetitive or approach
behavior while "liking" or pleasure corresponds to consummatory behavior.In human drug addicts, "wanting" becomes
dissociated with "liking" as the desire to use an addictive drug increases, while the pleasure obtained from consuming it
decreases due to drug tolerance

10. BRAIN AREAS
• Dopamine cells originate in the substantia
nigra, ventral tegmental area, caudal thalamus,
periventricular hypothalamus, and olfactory bulb.

11. • Dopaminergic terminals are found in the basal ganglia, the
nucleus acumbens, the olfactory tubercle, the amygdala, and the
frontal cortex.

12. Pathways
REWARD
Mesocortical Mesolimbic Nigrostraital
PROLACTIN
CONTROL
Tubero
infundibular

13. Receptor and
type
Synaptic action Distribution in
CNS
Neurons that
synthesize it in
CNS
Neurons in PNS Proposed clinical
relevance
D1-like
family(D1,D5)
Metabotropic ,
excitation (via
opening of Na+
channels)
Slow “everywhere”
(especially basal
ganglia and
prefrontal cortex)
Mesencephalaon
(substantia nigra
and ventral
tegmental area)
D1 agonists used
in Parkinson’s
disease
D2-like
family(D2,D3,D4
)metabotropic ,
inhibition ( via
opening of K+
channels)
Slow D2 antagonists
are
antipsychotics
D3 agonists used
in Parkinson’s
disease,restless
leg syndrome
RECEPTORS

14. MESOLIMBIC PATHWAY
• Involved in pleasure and reward. This pathway
begins at the ventral tegmental area (VTA) and
projects to nucleus accumbens (NA) and here
dopamine primarily mediates feelings of
pleasure and reward.
• over-stimulation can lead to cravings for the
item that stimulated the NA. These substances
directly increase dopaminergic activity within
the mesolimbic pathway, creating intense
feelings of euphoria.

15. NIGROSTRAITAL PATHWAY
• originates in the substantia nigra par compacta and
ascends to innervate the corpus striatum (caudate,
putamen, and globus pallidus), it modulates the
output of the corpus striatum. The destruction of the
nigrostriatal cells in Parkinson's disease produces
marked motor deficits.
• Additionally, D2 antagonists, such as first-generation
antipsychotics, interfere with the nigrostriatal
pathway and can cause extrapyramidal symptoms.
These movement disorders may include spasms,
contractions, tremors, motor restlessness,
parkinsonism, and tardive dyskinesia (irregular/jerky
movements)

16. MESOCORTICAL PATHWAY
• dopaminergic projections within the mesocortical
pathway originate in the VTA. From the VTA, action
potentials travel to areas in the prefrontal cortex
(PFC). The PFC is highly involved in cognition,
working memory, and decision making . Thus, when
dysfunction within this pathway occurs, individuals
may experience poor concentration and the inability
to make decisions.
• amphetamines, can upregulate the release of
dopamine in the mesocortical pathway, which in
turn increases cognition and activity in the PFC but
may have unintended side effects in the mesolimbic
pathway.

17. TUBEROINFUNDIBULAR PATHWAY
• mediates the control of milk production during lactation. It
originates in the periventricular and arcuate nuclei of the
hypothalamus and project to the median eminence of the
hypothalamus where they release DA into the capillary
plexus of the hypophyseal-portal system. DA travels to the
anterior pituitary where it inhibits the release of prolactin
• Prolactin enables milk production and has important
functions in metabolism, sexual satisfaction (countering
the arousal effect of dopamine), and the immune system.
• Blockage of the D2 receptors, common with antipsychotic
medications, prevent dopamine’s inhibitory function, thus
increasing prolactin levels in the blood.
• Increases in prolactin can affect menstrual cycles, libido,
fertility, bone health, or galactorrhea

18. Dopamine hypothesis in schizophrenia
The DA theory of schizophrenia is
based on the observation that DA
antagonists are effective antipsychotic
drugs. Their capacity to inhibit DA
receptors correlates well with their
antipsychotic efficacy. Currently,
clinical studies are attempting to
develop DA antagonists with specific
DA receptor subtype efficacy that will
most effectively decrease the
antipsychotic symptoms without
influencing other DA actions, such as
movement control.

19. Dopamine activity in Parkinson’s disease
Although dopamine is normally broken down by an oxidoreductase
enzyme, it is also susceptible to oxidation by direct reaction with
oxygen, yielding quinones plus various free radicals as
products.The rate of oxidation can be increased by the presence
of ferric iron or other factors. Quinones and free radicals
produced by autoxidation of dopamine can poison cells, and
there is evidence that this mechanism may contribute to the cell
loss that occurs in Parkinson's disease and other conditions.
It is now well accepted that decreased DA in the substantia nigra
and striatum is the critical lesion in Parkinson's disease. Autopsy
shows that nearly all DA is lost during the course of this disease,
apparently due to the degeneration of DA neurons. l-DOPA is used
to treat this disease's symptoms because it can be converted to DA
by AADC in the cells in the vicinity of the degenerated nerve
endings to replace the missing endogenous DA.

20. Dopamine in ADHD
• There are genetic links between dopamine receptors, the dopamine transporter, and
ADHD, in addition to links to other neurotransmitter receptors and transporters.
• The most important relationship between dopamine and ADHD involves the drugs that
are used to treat ADHD.
• Some of the most effective therapeutic agents for ADHD are :
1. psychostimulants such as methylphenidate (Ritalin, Concerta)
2. amphetamine (Evekeo, Adderall, Dexedrine), drugs that increase both dopamine and
norepinephrine levels in the brain.
• The clinical effects of these psychostimulants in treating ADHD are mediated through
the indirect activation of dopamine and norepinephrine receptors,
specifically dopamine receptor D1 and adrenoceptor α2 , in the prefrontal cortex

21. Dopamine in MOOD DISORDERS
• Data suggests that dopamine activity may be
reduced in depression and increased in mania
• Recent theories indicate that mesolimbic pathway
maybe dysfunctional in depression and D1 receptors
may be hypoactive

23. AGONISTS & ANTAGONISTS
AGONISTS ANTAGONISTS
Cocaine Chlorpromazine
(antipsychotic)
heroin Metaclopramide(nausea
and vomiting)
Ropinirole(parkinson’s
agonist : levadopa therapy)
Bromocriptine : To treat
side effects of
antipsychotics

24. NOREPINEPHRINE
• Early 20th century : Walter Cannon, who had popularized the
idea of a sympathoadrenal system preparing the body for fight
and flight, and his colleague Arturo Rosenblueth developed a
theory of two sympathins, sympathin E (excitatory)
and sympathin I (inhibitory), responsible for these actions.
• 1934:Zénon Bacq suggested noradrenaline might be a
sympathetic transmitter.
• 1939:Hermann Blaschko and Peter Holtz independently
identified the biosynthetic mechanism for norepinephrine in the
vertebrate body.
• 1945 : Ulf von Euler published the first of a series of papers that
established the role of norepinephrine as a neurotransmitter.
• Stanley Peart was the first to demonstrate the release of
noradrenaline after the stimulation of sympathetic nerves.

25. SYNTHESIS(CNS) SYNTHESIS(PNS)
•In the peripheral nervous system, chromaffin cells
in the adrenal medulla (following the same steps
as mentioned above) synthesize norepinephrine.
•Once synthesized, they get stored in chromaffin
granules.
•Norepinephrine can be released into the
bloodstream or be converted to epinephrine by
phenylethanolamine-N-methyl transferase
.
• The release of these hormones into the
bloodstream is stimulated by acetylcholine which
binds nicotinic receptors located in the adrenal
medulla

26. BREAKDOWN

27. FUNCTIONS
• general function is to mobilize the brain and body for action.
• release is lowest during sleep, rises during wakefulness, and reaches much
higher levels during situations of stress or danger, in the so-called fight-or-
flight response
• In the brain, it increases arousal and alertness, promotes vigilance, enhances
formation and retrieval of memory, and focuses attention
• it also increases restlessness and anxiety
• Sympathetic nervous system : the effect of norepinephrine on each target
organ is to modify its state in a way that makes it more conducive to active
body movement, often at a cost of increased energy use and increased wear
and tear.

28. BRAIN AREAS
• In the brain, noradrenaline is produced in locus coeruleus,
located in the pons.
• Outside the brain, norepinephrine is used as a neurotransmitter
by sympathetic ganglia located near the spinal cord or in
the abdomen, as well as Merkel cells located in the skin.
• It is also released directly into the bloodstream by the adrenal
glands(medulla).

29. PATHWAYS
• Projections to
neocortex,hippocampus,thalamus,
midbrain tectum
• Activity varies with level of
wakefullness. Firing rate responsive
to novel/stressful stimuli(largest
response to stimuli that disrupt
ongoing behviour and reorient
attention)
Locus
ceruleus
• Projections to ventral pons and
medulla,overlapping with LC. Both
innervate amygdala,septum,spinal
cord.
• Hypothalamus,lower brainstem
predominant
Lateral
tegmental
noradrenergic
nuclei

30. RECEPTORS
Receptor name Synaptic action Distribution in
CNS
Neurons
synthesizing in
CNS
Distribution in
PNS
Clinical relevance
α (α 1-α
2),metabotropic
β (β1-β2)
,metabotropic
Slow
Slow
“everywhere’ Locus coeruleus
and diffuse cell
groups in reticular
formation
Sympathetic
ganglia
Assist in initiating
of metabolic
activity of
messenger cells in
brain pathways

31. Role in Anxiety disorders
• Chronic symptoms of anxiety(panic
attacks,insomnia,startle,hyperarousal ) are characteristic of increased
noradrenergic function
• Experiments in primates have shown stimulation of locus ceruleus
produces fear response and ablation blocks the ability to form fear
response
• Less consistent finding is elevated noradrenergic metabolite in CSF of
anxiety disorder patients

32. Other PSYCHIATRIC DISORDERS
Depression
• Evidence suggest that activation of β 2
receptors decrease amount of
norepinephrine released
• SNRIs are antidepressants that treat
depression by increasing the amount of
serotonin and norepinephrine available
to postsynaptic cells in the brain.
• Tricyclic antidepressants (TCAs) increase
norepinephrine activity as well.

33. Attention-deficit/hyperactivity disorder
• Norepinephrine, along with dopamine, has come to be recognized as
playing a large role in attention and focus. For people with ADHD,
psychostimulant medications such as Ritalin ,Adderall are prescribed
to help increase levels of norepinephrine and dopamine.
• Atomoxetine (Strattera) is a selective norepinephrine reuptake
inhibitor, and is a unique ADHD medication, as it affects only
norepinephrine, rather than dopamine.

34. Anti-Inflammatory agent role in Alzheimer’s Disease
• The norepinephrine from locus ceruleus cells in addition to its
neurotransmitter role locally defuses from "varicosities". As such it provides
an endogenous anti-inflammatory agent in the microenvironment around the
neurons, glial cells, and blood vessels in the neocortex and hippocampus.
• Up to 70% of norepinephrine projecting cells are lost in Alzheimer’s Disease.
It has been shown that norepinephrine stimulates mouse microglia to
suppress Aβ-induced production of cytokines and their phagocytosis of Aβ
suggesting this loss might have a role in causing this disease

35. Schizophrenia
• Anhedonia is a significant feature
• A selective neuronal degeneration within norepinephrine
reward system could account for this symptom
Alzheimer’s disease
• Decreased activity suggested by decrease in norepinephrine
containing neurons in locus ceruleus,affects cognition

36. AGONISTS & ANTAGONISTS
AGONISTS ANTAGONISTS
Phenylephrine(alpha 1) phenoxybenzamine
Clonidine(alpha 2) TCAs
Dobutamine(beta 1) SNRIs
Amphetamines(CNS stimulants)

37. EPINEPHRINE/ADRENALINE
• 1901 : Jōkichi Takamine patented a purified extract from
the adrenal glands which was trademarked by Parke,
Davis & Co in the US. The British Approved
Name and European Pharmacopoeia term for this drug
is hence adrenaline.
• 1897: the pharmacologist John Abel had already
prepared an extract from adrenal glands , and coined
the name epinephrine to describe it (from the
Greek epi and nephros, "on top of the kidneys"). In the
belief that Abel's extract was the same as Takamine's (a
belief since disputed), epinephrine became the generic
name in the US,and remains
the pharmaceutical's United States Adopted
Name and International Nonproprietary Name (though
the name adrenaline is frequently used

38. FUNCTIONS
• Memory
• It has been found that adrenergic hormones, such as adrenaline, can produce
retrograde enhancement of long-term memory in humans.
• The release of adrenaline due to emotionally stressful events, which is
endogenous adrenaline, can modulate memory consolidation of the events,
ensuring memory strength that is proportional to memory importance.
• Post-learning adrenaline activity also interacts with the degree of arousal
associated with the initial coding.
• There is evidence that suggests adrenaline does have a role in long-term
stress adaptation and emotional memory encoding specifically.
• Adrenaline may also play a role in elevating arousal and fear memory under
particular pathological conditions including post-traumatic stress disorder

39. SEROTONIN(5-HT)
• 1935 : Italian Vittorio Erspamer showed an
extract from enterochromaffin cells made
intestines contract. Some believed it
contained adrenaline, but two years later,
Erspamer was able to show it was a previously
unknown amine, which he named "enteramine“
• 1948 : Maurice M. Rapport, Arda Green,
and Irvine Page of the Cleveland
Clinic discovered a vasoconstrictor substance
in blood serum, and since it was a serum agent
affecting vascular tone, they named it
serotonin
1–2% in
the CNS
About 8% is found in
platelets
90% of the human body's total
serotonin is located in
the enterochromaffin cells in
the GI tract, where it regulates
intestinal movements

40. SYNTHESIS BREAKDOWN

41. BRAIN AREAS
•neurons of the raphe nuclei are the principal
source of 5-HT release in the brain. There are
nine raphe nuclei, designated B1-B9 all of which
are located along the midline of the brainstem,
and centered on the reticular formation.
•Axons from the neurons of the raphe nuclei
form a neurotransmitter system reaching almost
every part of the central nervous system.
•Axons of neurons in the lower raphe nuclei
terminate in the cerebellum and spinal cord ,
while the axons of the higher nuclei spread out in
the entire brain.

42. PATHWAYS
Rostral
(B5-B9,ascending)
distributed throughout
the midbrain. A cluster
of cells located medially
and another located
dorsally provide over
80% of the 5-HT
innervation of the
forebrain.
Caudal
(B1-B4,descending)
located close to the
midline and project
caudally to the spinal
cord dorsal and ventral
horns as well as the
intermediolateral cell
column
These pathways are
believed to mediate the
role of 5-HT in sensory,
motor and autonomic
functions, respectively.

43. FUNCTIONS
• Implicated in mood, appetite, sleep, learning, and memory.
• Serotonin is important in the regulation of appetite, and appears to act
in a pathway that monitors the carbohydrate intake, acting as a negative
regulator of the motivation to ingest carbohydrate. This response
appears to be mediated by 5-HT in the hypothalamus and has led to the
use of serotonin uptake blockers, such as fenfluramine, as obesity pills
• Increased serotonergic firing observed during rhythmic motor
behaviours suggesting that it modulates some forms of motor output

44. • Many clinical observations and animal behavioral studies support the conclusion
that serotonin is an important factor in aggressive behavior and the expression
of dominance versus submissive behavior.
For example the use of pharmacological agents to decrease levels of 5-HT at
synapses in animal studies consistently demonstrates that low 5-HT is associated
with both increased aggressiveness and decreased dominance.
Similarly, the measurement of 5-HT metabolites in CSF and blood of patients or
experimental animals shows that low 5-HIAA predicts aggressiveness as well as risk
taking and a lower social rank.
This correlation between decreased 5-HT activity and increased aggression was
recently supported by the observation that 5-HT1B receptor knock-out mice have a
marked increase in aggressive behavior.

45. Receptor
and type
Synaptic
action
Distributi
on in CNS
Neurons
synthesizi
ng in CNS
Neurons
in PNS
Clinical
relevance
5-
HT1A,metabo
tropic, K+
Slow,
inhibition
‘everywhere’ Raphe
nuclei(brain
stem)
Same as above
5-HT2 ,
metabotropic
Slow,excitatio
n
5-HT3
,ionotropic
,Na+
Fast
,excitation
Assists in passing
of ions required for
activity of the
neurotransmitter
RECEPTORS

46. Serotonin Hypothesis in DEPRESSION
• Almost 50yrs ago ,it proposes at its simplest that diminished activity of serotonin
pathways play causal role in depression. This notion was based on depressogenic
effects of amine depleting agents ,actions of antidepressant drugs.
• Although ,best evidence comes from studies of “trytophan depletion” where in diet
the amino acid is purposely lowered.
• In healthy people ,no clinically significant mood changes found
• Recovered patients free of medication can show brief,clinically relevant,depressive
symptomatology
• This evidence suggests impairing serotonin can cause clinical depression in some
circumstances,but is neither necessary nor sufficient

47. Serotonin in ANXIETY DISORDERS
• Different type of acute stress result in increased 5-HT in
prefrontal cortex,nucleus accumbens,amygdala
• Several reports indicate that meta-chlorophenylpiperazine ,a
drug with multiple serotonergic and nonserotonergic
effects,which cause release of serotonin ,cause increased anxiety
• Mostly mixed results have been found ,like lower levels of 5-HT in
panic disorder patients .

48. • Obsessive Compulsive Disorder. 5-HT dysfunction has been associated with obsessive
compulsive disorder. Accordingly, selective 5-HT uptake blockers are used as a therapy for this
condition.
• Eating Disorders. Also controversial is the use of the drug fenfluramine to treat eating disorders
because of the toxic effects that occur in some individuals. Fenfluramine blocks 5-HT reuptake
into nerve terminals.
• Schizophrenia. current hypothesis posit serotonin excess cause both positive and negative
symptoms . Antagonist activity of 2nd gen antipsychotics to decrease positive symptoms have
contributed to this proposition.
• Insomnia. The role of 5-HT in sleep regulation has lead to the hypothesis that reduced levels 5-
HT may induce insomnia. Some clinicians are treating patients with 5-HT uptake blockers for
this ailment.

49. AGONISTS & ANTAGONISTS
AGONISTS ANTAGONISTS
SSRIs(prozac,lexapro
SNRIs

50. ACETYLCHOLINE
• 1867 : Adolf von Baeyer resolved the
structures of choline and acetylcholine and
synthetized them both, referring to the latter
as "acetylneurin" in the study.
• 1906 : Acetylcholine was first noted to be
biologically active in when Reid Hunt (1870–
1948) and René de M. Taveau found that it
decreased blood pressure in exceptionally
tiny doses

51. SYNTHESIS BREAKDOWN

52. BRAIN AREAS & PATHWAYS
• In the brainstem acetylcholine originates
from the Pedunculopontine
nucleus and laterodorsal tegmental
nucleus collectively known as the
mesopontine tegmentum area or
pontomesencephalotegmental complex
• .In the basal forebrain, it originates from
the basal nucleus of Meynert and
medial septal nucleus

53. RECEPTORS
Receptor name Synaptic action Distribution in
CNS
Neurons
synthesizing in
CNS
Neurons in PNS Clinical relevance
Nicotinic
,ionotropic , Na+
Muscarinic ( G-
coupled proteins)
Fast,excitation Cerebral
cortex,spinal
cord(and other
places)
Motoneurons,pre
ganglionic
autonomic
neurons,basal
nucleus,septal
nuclei,nuclei in
reticular
formation of
brain stem
- All
parasympathetic
target organs
(cardiac and
smooth muscle)
Excitatory
Excitatory and
inhibitory

54. Cholinesterase inhibitor
• Many ACh receptor agonists work indirectly by inhibiting the
enzyme acetylcholinesterase. The resulting accumulation of
acetylcholine causes continuous stimulation of the muscles,
glands, and central nervous system, which can result in fatal
convulsions if the dose is high

55. FUNCTIONS
• Acetylcholine is the neurotransmitter used at the neuromuscular junction—in other
words, it is the chemical that motor neurons of the nervous system release in order to
activate muscles. This property means that drugs that affect cholinergic systems can
have very dangerous effects ranging from paralysis to convulsions.
• Acetylcholine is also a neurotransmitter in the autonomic nervous system, both as an
internal transmitter for the sympathetic nervous system and as the final product
released by the parasympathetic nervous system
• In the brain, acetylcholine functions as a neurotransmitter and as a neuromodulator.
The brain contains a number of cholinergic areas, each with distinct functions; such as
playing an important role in arousal, attention, memory and motivation
• Acetylcholine is involved in a variety of functions including pain, recent memory,
nicotine addiction, salivation, locomotion, regulation of circadian rhythm and
thermoregulation.

56. Memory
• Acetylcholine has been implicated in learning and memory in several ways.
• The anticholinergic drug, scopolamine, impairs acquisition of new information in
humans and animals.
• In animals, disruption of the supply of acetylcholine to the neocortex impairs the
learning of simple discrimination tasks
• comparable to the acquisition of factual information and disruption of the supply of
acetylcholine to the hippocampus and adjacent cortical areas produces forgetfulness,
comparable to anterograde amnesia in humans

57. Acetylcholine in ALZHEIMER’S
• Acetylcholine is hypothesized to be hypoactive.
• Studies report specific degeneration of cholinergic neurons in nucleus
basalis of meynert
• Support comes from antagonists(eg: scopolamine ,atropine) which
impair cognitive abilities ,agonists(eg : physostigamine) enhance
cognitive abilities
• It has also been demonstrated that brain cholinergic neurons play a
critical role in Huntington’s chorea and in the generation of epileptic
seizures.

58. • Schizophrenia
• Postmortem studies have demonstrated decreased muscarinic
and nicotinic receptors in caudate-putamen,hippocampus and
selected regions of pre frontal cortex.
• These receptors play role in cognition,which is impaired in
schizophrenia.

59. AGONISTS & ANTAGONISTS
AGONIST ANTAGONISTS
Black widow spider venom ( increase release of Ach
causing muscle spasm)
Botox(toxin that cause muscle paralysis by blocking Ach
release from motor neuron)
nicotine

60. GLUTAMATE
• 1952 : The first suggestion that glutamate might function as a
transmitter came from T. Hayashi , who was motivated by the
finding that injections of glutamate into the cerebral ventricles
of dogs could cause them to have seizures.
• Other support for this idea soon appeared, but the majority of
physiologists were skeptical, for a variety of theoretical and
empirical reasons. One of the most common reasons for
skepticism was the universality of glutamate's excitatory effects
in the central nervous system, which seemed inconsistent with
the specificity expected of a neurotransmitter.
• Other reasons for skepticism included a lack of known
antagonists and the absence of a known mechanism for
inactivation.
• A series of discoveries during the 1970s resolved most of these
doubts, and by 1980 the compelling nature of the evidence was
almost universally recognized.

61. SYNTHESIS & BREAKDOWN

62. BRAIN AREAS & PATHWAYS

63. RECEPTORS
Receptor name Synaptic action Distribution in
CNS
Neurons
synthesizing in
CNS
Neurons in PNS Clinical relevance
AMPA
,ionotropic,Na+
NMDA,ionotropic,
Ca2+,Na+
MGluR1-5
,metabotropic
Fast,excitation
Fast,excitation
Slow,excitation/in
hibition
“everywhere” “everywhere” Spinal ganglion
cells

64. FUNCTIONS
• Because the glutamate receptor proteins are
expressed on the surface of the cells in such a way
that they can only be activated from the outside, it
follows that glutamate exerts its neurotransmitter
function from the extracellular fluid.

65. • Because glutamate is the major mediator of excitatory signals as well as of nervous
system plasticity, including cell elimination, it follows that glutamate should be
present at the right concentrations in the right places at the right time.
• It further follows that cells should have the correct sensitivity to glutamate and
have energy enough to withstand normal stimulation, and that glutamate should
be removed with the appropriate rates from the right locations.
• Both too much glutamate and too little glutamate are harmful. Excessive activation
of glutamate receptors may excite nerve cells to their death in a process now
referred to as “excitotoxicity”.

66. • Glutamate receptors are involved in a physiological phenomenon
called long-term potentiation (LTP) - a cellular model of learning and
memory. The NMDA receptor activation is an absolute requirement
for LTP induction, however, AMPA and metabotropic glutamate
receptors also play important roles.
• GLU is one of the first molecules produced during fetal life and plays
a critical role in brain development and in organ development
because it is a building block for protein synthesis and for
manufacturing muscle and other body tissue.

67. PSYCHIATRIC DISORDERS
Schizophrenia
• The NMDA receptor ion channel allows both sodium and calcium when opened (not
just sodium as with AMPA and kainate). This is important because calcium is
associated with cognition and neuroplasticity, both of which are impaired in
schizophrenia and other major psychiatric disorders, implicating NMDA receptor
dysfunction in those disorders.
• The GLU hypothesis of schizophrenia grew out of the observation that
phencyclidine, a drug of abuse that is a potent NMDA antagonist (50-fold stronger
than ketamine), can trigger in healthy individuals a severe psychosis
indistinguishable from schizophrenia, with positive and negative symptoms,
cognitive impairment, thought disorder, catatonia, and agitation.

69. Mood disorders
• there appears to be increased activity of NMDA receptors in both unipolar and
bipolar depression.
• Several NMDA antagonists have been shown in CCTs to be highly effective in rapidly
reversing severe, chronic depression that did not respond to standard
antidepressants.
• Also worth noting is that ketamine, an NMDA antagonist which has emerged as an
ultra-rapid acting antidepressant, is an anesthetic, suggesting that perhaps it may
help mitigate the pain symptoms that often accompany major depression.

70. AGONISTS & ANTAGONISTS
AGONISTS ANTAGONISTS

71. GABA
• 1900s : was first described
• 1950s :presence and participation as a
neurotransmitter in the mammalian CNS.
During the following two decades, many
studies established its mechanism of action,
as well as its inhibitory activity in the cerebral
cortex
• We, currently, know that GABA is distributed
in most areas of the brain and participates in
40% of the inhibitory synapses of adult
vertebrates.

72. SYNTHESIS & BREAKDOWN

73. BRAIN AREAS & PATHWAYS
• Studies in animal models indicate the presence of GABAergic
neurons in regions such as the amygdala, hippocampus,
hypothalamus, prefrontal cortex, olfactory bulb, retina, and
spinal cord, this observation was corroborated also in human
studies

74. PATHWAYS

75. RECEPTORS
Receptor
name
Synaptic
action
Distribution
in CNS
Neurons
synthesizing
in CNS
Neurons in
PNS
Clinical
relevance
GABA
,ionotropic
,Cl-
GABA(b)
,metabotropi
c ,K+,Ca2+
Fast,inhibitio
n
Slow,inhibitio
n
ubiquity Gut,ganglia

76. FUNCTIONS
• The proper functioning of the CNS depends on the balance between the excitatory and inhibitory
neurotransmitter systems. The excitatory system is regulated by glutamate, while the inhibitor
system is regulated by GABA through interneurons, which modulate the excitatory level
generated by glutamate release. These interneurons control the flow of information and the
synchronization of the cerebral cortex, despite the existence of a 1:5 proportion with
glutamatergic neurons. Suggesting, that the numerical balance between neurons and
interneurons determines brain functionality, in the case of the cerebral cortex, the proportion 1:5
indicates that this region is mainly excitatory.
• This wide expression of the GABAergic cells indicates that this inhibitory neurotransmitter is
involved in many functions in the CNS , for instance, the thalamocortical pathway, which
regulates primordial functions such as behavior, motor control, mood, sleep, and among others.
• When GABA attaches to a protein in your brain known as a GABA receptor, it produces a calming
effect. This can help with feelings of anxiety, stress, and fear. It may also help to prevent seizures.

77. PSYCHIATRIC DISORDERS
Epilepsy
• It is known that the mechanisms regulated by the
GABAA receptor participate in the partial or generalized
generation of tonic-clonic seizures. Pharmacological and gene
expression studies suggest a role in the prevention of seizures by
blocking the regulation of GABAA receptors with specific
antagonists.

78. Schizophrenia
• It has been found that there is a loss of GABAergic neurons in hippocampus.
• The use of benzodiazepines in combination with antiepileptic drugs reduces
considerably the symptoms of schizophrenia and anxiety. On the other hand, the
administration of valproate with neuroleptics controls efficiently irritability
symptoms and violent behaviors.
• The genes that encode GABAB R1 are located within the loci of schizophrenia,
suggesting the participation of this receptor in this disorder

79. Depression
• In recent years, different reports showed evidence about the association between GABA and
depression. For example, a decrease of this neurotransmitter in the cerebrospinal fluid of
patients with depression has been reported
• Magnetic resonance spectroscopy in depressive patients showed a reduction in GABA levels,
mainly in the occipital cortex (OCC) and in some areas of the prefrontal cortex (PFC).
• Studies indicate changes in the regulation of the genes which encoding GABA receptors. For
example, Choudary and col. showed the deregulation of the b3, g2, and d subunits in the
frontal cortex.
• In this regard, the postmortem analysis by PCR of different brain regions from suicide victims
with depression showed alterations in the a5, g1, and g2 subunits of the dorsolateral and
lateral inferior PFC..
• Fatemi and col. found an increase in the a2, a2, g3, and e subunits in the cerebellum of non-
suicidal patients with depression

80. Anxiety
• According to a 2006 article, two very small studies found that
participants who took a GABA supplement had increased feelings of
relaxation during a stressful event than those who took a placebo or L-
theanine, another popular supplement.
• The article also notes that the relaxing effects were felt within an hour of
taking the supplement

81. Stress and fatigue
• A 2011 study in Japan examined the effects of a beverage containing either 25
mg or 50 mg of GABA on 30 participants. Both beverages were linked to
reduced measures of mental and physical fatigue while doing a problem-
solving task.
• Another study from 2009 found that eating chocolate containing 28 mg of
GABA reduced stress in participants performing a problem-solving task. In
another study, taking capsules containing 100 mg of GABA reduced measures
of stress in people completing an experimental mental task.

82. AGONISTS & ANTAGONISTS
AGONISTS ANTAGONISTS
alcohol

83. FUNCTIONS