2. DEFINITION OF NEUROTRANSMITTER
• Chemical released from nerve ending that
transmits impulses from one neuron(nerve
cell) to another neuron, or to a muscle cell.
3. NEUROTRANSMITTER
Act as both neurotransmitter and hormones
• Most neuron make two or more
neurotransmitter
• 50 or more neurotransmitter have been
identified
• 9 low molecular weight amines that serves as a
neurotransmitters eg. Glutamate, the major
excitatory transmitter
4.
5. Life Cycle of a Neurotransmitter
1) Synthesis of the transmitter
2) Packaging and storage in Synaptic
vesicles
3) If necessary, transport from the site of
synthesis to the site of release from
the nerve terminal
4) Release in response to an action potential
5) Binding to postsynaptic receptor proteins
6) Termination of action by
diffusion,destruction, or reuptake
into cells
6. NEUROTRANSMITTER RECEPTORS
• Once released, the neurotransmitter molecules diffuse across the
synaptic cleft
• When they “arrive” at the postsynaptic membrane, they bind to
neurotransmitter receptors
• Two main classes of receptors:
– Ligand-gated ion channels
• transmitter molecules bind on the outside, cause the channel to open and
become permeable to either sodium, potassium or chloride
– G-protein-coupled receptors
• G-protein-coupled receptors have slower, longer-lasting and diverse
postsynaptic effects. They can have effects that change an entire cell’s
metabolism
• or an enzyme that activates an internal metabolic change inside the cell
• activate cAMP
• activate cellular genes: forms more receptor proteins
• activate protein kinase: decrease the number of proteins
8. BIOGENIC AMINE
NEUROTRANSMITTERS
• The importance of biogenic amines is
demonstrated by their implication in the
pathophysiology and treatment of wide variety of
psychiatric and neurological disorders.
• These systems play critical roles in cognition
,memory,motivation and motor function and
arousal
• They are involved in slow synaptic transmission
9. • The biogenic amine neurotransmitters are the
catecholamines i.e.
• dopamine
• norepinephrine
• epinephrine
• The serotonin i.e.
• 5 hydroxy tryptamines
• acetyl choline
• histamines
11. AMINO ACID NEUROTRANSMITTERS
• Evidence suggests that Amino acid
neurotransmitters in particular GABA and
glutamic acid play an important role in
pathophysiology of broad range of psychiatric
disorders including schizophrenia ,bipolar
disorder, alzheimer’s disease and anxiety
disorders
• They are involved in fast synaptic transmission
• They are excitatory and inhibitory in action
17. DOPAMINE- INTRODUCTION
• Family -
Catecholamines(monoami
nes)
• 4-(2-aminoethyl)benzene-
1,2-diol
• Can act as inhibitory or
excitatory
• Central and peripheral
actions
• L-DOPA
• precursor of dopamine
• cross BBB
• L-dihydroxy Phenylalanine
18. SYNTHESIS
• Site of synthesis-
• neural tissue
adrenal medulla
• From AA- tyrosine
• Rate limiting enzyme
Tyrosine Hydroxylase
• HVA-Final metabolite
• pathway
21. DOPAMINE RECEPTORS
Metabotropic G-protein coupled receptors
D1 – like family:
◦ Includes subtypes D1 and D5
◦ Activation is coupled to Gs ; activates adenylyl cylcase
which leads to increase in concentration of cAMP
D2 – like family:
◦ Includes D2, D3 and D4
◦ Activation is coupled to Gi ; inhibits adenylyl cyclase
leading to decrease in concentration of cAMP
7
23. MECHANISM OF ACTION
• Dopamine cells fire in two modes either single
spiking or burst firing
• Different rates of firing probably code different
response
• At fastest scale, with burst firing dopamine can
signal a reward
• At slowest scale, the pacemaker activity of
dopamine neurons have been linked to a tonic
function on a variety of motor, coginitive and
motivational processes.
26. MESOLIMBIC PATHWAY
• The mesolimbic dopamine pathway, which
projects from the ventral tegmental area in the
brainstem to the nucleus accumbens in the
ventral striatum
• Involved in regulation of emotional behaviors
• Specifically, hyperactivity of this pathway is
believed to account for delusions and
hallucinations .
• This pathway is also involved in pleasure,reward,
and reinforcing behavior, and many drugs of
abuse interact here.
27.
28. MESOCORTICAL PATHWAY
• Arising from cell bodies in the ventral tegmental
area, but projecting to areas of the prefrontal
cortex, is known as the mesocortical dopamine
pathway
• Branches of this pathway into the dorsolateral
prefrontal cortex are hypothesized to regulate
cognition and executive functions
• whereas branches of this pathway into the
ventromedial parts of the prefrontal cortex are
hypothesized to regulate emotions and affect
29. DA & SCHIZOPHRENIA
Mesocortical
DLPFC- Cognitive and
negative symptoms
VLPFC- Cognitive and
affective symptoms
DOPAMINE HYPOTHESIS
Mesolimbic +ve symptoms
30. • Hyperactivity of the mesolimbic dopamine pathway
accounts for positive psychotic symptoms whether
those symptoms are part of the illness of
schizophrenia,or of drug-induced psychosis, or whether
they are positive psychotic symptoms accompanying
mania,depression, or dementia.
• Hyperactivity of mesolimbic dopamine neurons may
also play a role in aggressive and hostile symptoms in
schizophrenia and especially if serotonergic control of
dopamine is aberrant in patients who lack impulse
control.
31.
32. • Cognitive and some negative symptoms of
schizophrenia may be due to a deficit of
dopamine activity in mesocortical projections
to dorsolateral prefrontal cortex
• whereas affective and other negative
symptoms of schizophrenia may be due to a
deficit of dopamine activity in mesocortical
projections to ventromedial prefrontal cortex
33. • Anthony grace hypothesized that people
with schizophrenia demonstrate abnormal
intra synaptic level of dopamine in 1) Tonic
state 2) phasic state
• Intra synaptic DA decreased in tonic state
and increased in phasic state.
34. ROLE OF DOPAMINE IN MOOD
DISORDER
• Decreased mesocortical and mesolimbic
dopamine activity has implications in cognitive
and motor disturbances that are associated
with depression
• While increased mesocortical and mesolimbic
dopamine activity leads to mania
35. DOPAMINE AND ADDICTION
• The dopaminergic projection to ventral
striatum has often been implicated in the
mechanisms for addiction
• Increased loco motor activity and stereotypy
caused due to psycho stimulant involve
dopamine release in striatum
36.
37. Nucleus Accumbens
Occurs due to increased release of dopamine
caused by the psychotropic substances like
morphine
heroin
Cannabis
cocaine
nicotine
38. • Cocaine binds to presynaptic dopamine
transporter, thus inhibit dopamine reuptake
• Amphetamines not only inhibit dopamine
uptake, but also reverse function of dopamine
transporter
• Caffeine increases dopamine release in shell
of nucleus accumbens
• Tetra hydro cannabinol also increase
dopamine level in nucleus accumbens
39.
40. • Modulation of prefrontal cortical function,and
therefore regulation of attention and behavior,
relies on the optimum release of dopamine (DA)
and norepinephrine(NE)
• If the systems are properly “tuned,”then D1
receptor stimulation can reduce the noise and
α2A receptor stimulation can increase the signal
to result in proper prefrontal cortex functioning.
• This will result inadequate guided attention ,
focus on a specific task, and adequate control of
emotions and impulses.
41.
42. • In ADHD, imbalances in NE and DA circuits in the
prefrontal cortex cause inefficient information
processing in prefrontal circuits, and thus the
symptoms of ADHD
• When there is low release of both DA and NE .It leads
to low stimulation of both D1 and α2A receptors on
the spines of these pyramidal neurons
• Deficient DA and NE input will lead to increased noise
and decreased signal, respectively, thus preventing a
coherent signal from being sent
• This could cause hyperactivity, inattention, impulsivity.
43.
44. NEGROSTRIATAL PATHWAY
• Projects from dopaminergic cell bodies in the brainstem
substantia nigra to the basal ganglia or striatum
• The nigrostriatal dopamine pathway is a part of the
extrapyramidal nervous system and controls motor
movements.
• Deficiencies in dopamine in this pathway cause movement
disorders
• Dopamine deficiency in the basal ganglia also can produce
akathisia (a type of restlessness), and dystonia(twisting
movements especially of the face and neck).
• These movement disorders can be replicated by drugs that
block D2 receptors in this pathway,
45. PARKINSONS DISEASE
• Substantial loss of Dopamine
in the striatum (70 – 80%)
• characterized by rigidity,
akinesia/bradykinesia (i.e.,
lack of movement or slowing
of movement), and tremor
• Treatment strategy includes
increasing dopamine levels by
administering L-Dopa, nerve
grafting with dopamine
containing cells and deep brain
stimulation
46.
47. TUBEROINFUNDIBULAR PATHWAY
• The dopamine neurons that project from
hypothalamus to anterior pituitary are part of the
tuberoinfundibular dopamine pathway .
• These neurons are active and inhibit prolactin
release.
• In the postpartum state, however, the activity of
these dopamine neurons is decreased. Prolactin
levels can therefore rise during breastfeeding so that
lactation will occur.
• If the functioning of tuberoinfundibular dopamine
neurons is disrupted by lesions or drugs, prolactin
48. DOPAMINE AND SEROTONIN
• The serotonin system inhibits dopaminergic
function at the level of the origin of dopamine
system in mid brain as well as as at terminal
dopaminergic fields in the forebrain
• Serotonergic antagonists release the dopamine
system from this disinhibition
• This disinhibition may increase neuroleptic
induced extrapyramidal symptoms and a similar
disinhibition in prefrontal cortex may ameliorate
negative symptoms
