2. What are Antidepressants?
• Drugs that are used to relieve or prevent psychic
depression.
• Work by altering the way in which specific
chemicals, called neurotransmitters, work in our
brains (i.e. in the case of depression, some of the
neurotransmitter systems don’t seem to be
working properly).
• They increase the activity of these chemicals in
our brains
4. Amine Hypothesis
• 1950: Reserpine Induce depression
• Study: Reserpine depletes storage or amine neurotransmitters
such as serotonin and norepinephrine
• Break-through: MAOI and TCA
• Then: Depression Amine-dependent synaptic
transmission
(Antidepressants Amine by means of reuptake and
metabolism)
• Conclusion: Major model for the subsequent antidepressants,
except Buproprion.
5. • The precise cause of affective disorders
remains elusive.
• Evidence implicates alterations in the firing
patterns of a subset of biogenic amines in
the CNS, Norepinephrine (NE) and
Serotonin (5-HT).
↓ Activity of NE and 5 -HT systems?.
Biogenic Theory of Depression
13. Information integration
cognition, thought,
mood, emotion
Cerebral cortex
Sensory input Motor output
acetylcholine norepinephrine
serotonin dopamine histamine
Information integration
cognition, thought,
mood, emotion
Cerebral cortex
Sensory input Motor output
14. Arousal:
1. Processing signals relate to plain & pleasure. Regulating
body homeostasis
2. Emotion and feeling
3. Attention
4. Wakefulness & sleep
5. learning
The construction of consciousness.
25. Particular modulator transmitters should not be
regarded as purely excitatory or inhibitory.
Their exact action depends on context.
On the same cell, they can be either excitatory or
inhibitory depending on the state of the cell.
27. NE System
Almost all NE pathways in the brain originate from the cell
bodies of neuronal cells in the locus coereleus in the
midbrain, which send their axons diffusely to the cortex,
cerebellum and limbic areas (hippocampus, amygdala,
hypothalamus, thalamus).
• Mood: -- higher functions performed by the
cortex.
• Cognitive function: -- function of cortex.
• Drive and motivation: -- function of brainstem
• Memory and emotion: -- function of the
hippocampus and amygdala.
• Endocrine response: -- function of hypothalamus.
α and β receptors.
29. Reuptake of NE
Monoamine oxidase, located on outer membrane
of mitochondria; deaminates catecholamines free in
nerve terminal that are not protected by vesicles
Selective inhibitor,
reboxetine
Cocaine blocks the NET
Antidepressant
MAO Inhibitors
Stimulant
32. time
GABA
response
GABA
GABA + NE
GABA + cAMP
Noradrenergic potentiation of cerebellar Purkinje cell responses
to GABA: cAMP as intracellular intermediary.
35. Why does a small amount of stress help you learn better?Why does a small amount of stress help you learn better?
But, too much chronic, severe stress DEPRESSION
37. After LTP
More glutamate receptors
= bigger response
After several hours…….
Presynaptic Postsynaptic
LTP decays
38. Unless β-adrenergic activation of postsynaptic cell takes place…
NE
Glu
cAMP
PKA
Inhibition of
protein phosphatase I
Active during memory
formation
Stabilization of LTP
39. β-adrenergic receptor activation helps memories
-better memories when you are paying attention
because of higher emotional stimulation
41. Serotonin System
As with the NE system, serotonin neurons located
in the pons and midbrain (in groups known as
raphe nuclei) send their projections diffusely to the
cortex, hippocampus, amygdala, hypothalamus,
thalamus, etc. --same areas implicated in
depression. This system is also involve in:
• Anxiety.
• Sleep.
• Sexual behavior.
• Rhythms (Suprachiasmatic nucleus).
• Temperature regulation.
• CSF production.
44. Noradrenergic Control of Serotonergic Release
NE
5-HT
NE
α2-AR
α1-AR
1 2 3
Mianserin
5-HT1
5-HT2
5-HT3
Receptors
45. Serotonin - a chemical manifestation of personality
High level of serotonin: compulsives
obsessive-compulsive disorders
e.g. compulsive hand-washing
Low levels of serotonin: depression, suicide.
Listening to Prozac, P.D. Kramer, 1993
Humans
The purpose of antidepressants is to increase the levels of
circulating neurotransmitters in the synapse.
49. Genetic variation in the gene promoter region of the
serotonin transporter.
risk factor for anxiety, alcoholism, mood disorders
slight differences in level of expression
52. Dopamine pathways do many things:
Control flow of blood through the brain
Motor control (nigrostriatal) system
Behavioural control
Dopamine is the brain’s motivational chemical. It works on
glutamate synapses to modulate their excitability.
A shortage of brain dopamine causes an indecisive
personality, unable to initiate even the body’s own
movement. Parkinson’s disease. Time stops.
L-DOPA therapy. ‘Awakenings’ film. (Oliver Sachs)
Excess dopamine, more arousal. Attention defecit
disorder. May cause schizophrenia.
Dopamine’s action is essential for drug addiction.
54. Other neuromodulators (NE, serotonin) probably
work in a similar way to dopamine
They assist with the selection/maintenance of different
neural ensembles.
58. Polymorphisms of genes involved in aminergic
(dopamine/serotonin) neurotransmission
Effects on personality?
Dopamine D4 receptor - novelty seeking
Promoter of serotonin transporter gene - harm avoidance/anxiety
Genetics
59. D4 dopamine receptor
16 amino acid repeat sequence present in two
to 11 copies - minisatellite phrase
60. D4 dopamine receptor
The larger the number of repeats, the more
ineffective is the dopamine D4 receptor
in signalling
61. The larger the number of loop 3 repeats, the more ineffective
the dopamine D4 receptor in signalling
“Long” D4DR genes imply low responsiveness to dopamine
“short” D4DR gene imply high responsiveness
The idea
People with “long” D4DR genes have low responsiveness to
dopamine, so they need to take a more adventurous approach to
life to get the same dopamine “buzz” that short-gened people get
from simple things.
Obviously, this is just one possible factor of many.
Don’t oversimplify!
Genetics
