B.L.

CONDE, MD, FPPA, FPNA

NEUROBIOLOGY
INTRO
DNA
GENES
5-HT
DOPA
BRAIN
12043
ATOM
AUT3
DOPAMIN
E
DOPAMINE
The
Neurodevelopmental
UST Theory of
Psychopathology in
Schizophrenia
 The lifetime risk for schizophrenia
correlated with genetic relatedness
Relationship to schizophrenic individual
Mono Twin 48%
Genes shared
100% Dyz Twin 17%
50% (first-degree Child 13%
relatives)
Sibling 9%

Parent 6%

Half sibling 6%

Grandchild 5%

Nephew/Niece 4%
25% (second-degree
Uncle/Aunt 2%
relatives)
12.5% (third-degree First Cousin 2%
relatives)
None (General Population) 1%

0% 10% 20% 30% 40% 50% 60%

Adapted from Gottesman 1991
 NEUROBIOLOGY
INTRO
DNA
GENES
5-HT
DOPA
BRAIN
12043
ATOM
AUT3
DOPAMINE
DOPAMINE

The MIND &

BRAIN DICHOTOMY
 NEUROBIOLOGY
INTRO
DNA
GENES
5-HT
DOPA
BRAIN
12043
ATOM
AUT3
DOPAMINE
DOPAMINE

BIOLOGICAL vs
PSYCHOLOGICAL
 The Basis of Contemporary
Neural Science

All mental processes are

biological and any alteration in
those processes is organic
 Questions
1. How do the biological processes of the brain
give rise to mental events ?

2. How do social factors modulate the biological

structure of the brain ?

3. To what degree is this biological process

determined by genetic and developmental
factors ?

4. To what degree is it environmentally or socially

determined ?
 NEUROBIOLOGY
INTRO
DNA
GENES
5-HT
DOPA
BRAIN
12043
ATOM
AUT3
DOPAMINE
DOPAMINE

GENES
vs
ENVIRONMENT
 NEUROBIOLOGY
INTRO
DNA
GENES
5-HT
DOPA
BRAIN
12043
ATOM
AUT3
DOPAMINE
DOPAMINE
The genetic blueprint are coded in the DNA, yet
the blueprints are modified and shaped by
environmental influences that the brain/mind
encounter in a person’s journey through life.
 The
NEURODEVELOPMENT
AL HYPOTHESIS
of
schizophrenia proposes
that a proportion of
schizophrenia is the result
of an early brain insult,
either pre or perinatal
which affects brain
development leading to
abnormalities which are
expressed in the adult
brain
 Neurodevelopmental hypothesis of
schizophrenia suggests that genetics
and/or epigenetic events that occur
during critical periods of neuronal
growth may negatively influence brain
development
A meta-analysis of 40 MRI studies
described the following
abnormalities in
Volume reduction
Whole brain (3%)
Temporal lobes (left – 6
%, right 9.5%)
Amygdala/Hippocampal complex
(left – 6.5%, right 5.5%)
Volume is increased in the lateral ventricles
(left – 44%, right - 44%)
Gray matter is reduced but white
Retrospective data provide evidence
that women in their 2nd trimester (not
1st or 3rd) of pregnancy have an
increased risk of offsprings
developing schizophrenia
 Neuropathological data from brain
tissue in schizophrenia suggest that a
subgroup of schizophrenia may have
disturbances related to 2nd trimester
neuronal development

Arnold & Trojanowski, 1996

Burney et al, 1995
Chua & Murray, 1996
Jacob & Beckmann, 1986
Kovelman & Scheibel 1984
Weinberger, 1995
Aberrant expression of developmental
and plasticity-associated markers
(NCAM 9 GAP-43)

Sulcal-gyral abnormalities have

been reported in some post-mortem
studies of schizophrenic brains.
Anatomical Evidence
That May Support a
Neuro-Developmental
Defect
1. Ventricular enlargement in
schizophrenia may be indicative of a
more serious form of illness

a. Poor neuropsychological test

(Johnstone et al, 1976)

b. Treatment resistant (Weinberger et al, 1980)

c. More negative symptoms (Arderlasen et al, 1982)
2. Hippocampus
a. Finding of cellular architectural disarray
(Kovelman &
Scheibel, 1984)

b. Decrease in neuronal volume

(Heckers et al, 1991)

c. Reduction in pyramidal cell density

(Jeste & Lohr, 1989)

d. Decreases in neuronal sign in subiculum

& CA1 (Arnold et al, 1995)
 These suggest a neurodevelopmental
process rather than a
neurodegenerative one because:

They are present in both

newly diagnosed as well
as chronic schizophrenics
They appear to be non-
progressive
Cognitive deficits found in
schizophrenia show no
deterioration over the
course of the illness
 Gliosis

• Is the neural scarring following brain

lesions other than those that occur
early in neurodevelopment

• Characteristic of neurodegenerative
disorder
 Relative lack of evidence for
neurodegenerative defect in schiziphrenia

Measurement of gliosis indicative of

neurodegeneration in brain tissue fail
to demonstrate that
neurodegeneration plays a role
 There is NO extensive
gliosis seen in brains of
schizophrenic patients

There is failure to develop

normal cerebral
asymmetries, which are
normally formed during
the second trimester of
pregnancy

Pathological changes appear to

affect the left side of the brain
more severely than the right.
 Psychotic Relapses and
Progressive
Neurodegeneration
• Several MRI follow-up studies since 1995 were
done in first-episode psychosis and after
subsequent psychotic relapses
• Findings include:
• 1) ↓ brain volume (about 1-2% after each
relapse)
• 2) ↑ ventricular size
• 3) ↓ frontal lobe volume
• 4) ↓ temporal lobe volume
• Extensive and widespread cortical tissue loss was
also reported after psychosis in adolescents

Nasrallah HA. 2002.

MRI of Ventricular System

Nasrallah HA. 2002.

 Multiple Relapses May Lead to
Continuing Neurodegeneration

• Deterioration in schizophrenia is probably the result

of neurodegeneration

• Many patients who stop treatment and then relapse

fail to regain prior level of function
• Early intervention is key
• Antipsychotics may improve long-term outcome by
counteracting neurodegeneration
References: Lieberman JA, et al. J Clin Psychiatry1996;57(suppl
9) 5-9.
Sheitman BA, et al. Psychiatric Res. 1998:32:143-150.
Compelling evidences come from
studies of cytoarchitecture which
demonstrated that neurons among
schizophrenic brains were

MISPLACED,
MIS-SIZED and
DISORGANIZED.
 The Premorbid Child
If schizophrenia is
caused by an
aberration in the
developing brain, then
it is reasonable to
expect the presence
of some subtle
abnormalities of
neural function and
developmental
anomalies in early life.
It is hypothesized that genetic defects
predispose the brain to be affected by
intrauterine or perinatal environmental events.

Alternatively,
genetic control of
brain development
maybe disrupted
by adverse
environmental
events.
 The Premorbid Child
• Higher incidence of neuromotor abnormalities

• Delayed developmental milestones

• Behavioral & intellectual abnormalities

• Within 1st 2 year, reduced responsiveness, less

positive affect, less eye contact

• 75% “soft” neurological signs – abnormal gait,

disgraphaesthesia, tics, twitches
 Mechanisms of Delayed
Onset

• After peaking during childhood, synaptic

density in human frontal cortex decline by
30-40% by adulthood

– Selective neuronal death

– Progressive synaptic elimination
 Mechanisms of Delayed
Onset

Maldevelopment in utero sets the

stage for secondary disorganization in
adolescence
 Mechanisms of Delayed
Onset

The lesions remain dormant until

normal brain maturation in
adolescence leads to the use of
neuronal circuits that are poorly
developed in children
 Mechanisms of Delayed
Onset

In humans, myelination in circuitry to or

from hippocampus is only complete in
adolescence
Clare Holtman
April 2000
 First Episode
Schizophrenia

• Enlargement of ventricular system

• Reduction of total brain size
• Reduction of hippocampal size
• No reduction of temporal lobe or
amygdala volumes
International researcher from USA, UK,
and Australia reported longitudinal
temporal horn lengthening and
abnormalities in paracingulate sulcus
asymmetry in 2 studies among
adolescents with schizophrenia
 Canadian study found significantly
lower total gray matter volumes in 17
young schizophrenia patients (mean
age 20 years) compared to 16 healthy
controls
 etiological Factors
Risk factors:
Nutrition
Seasonality
Infection or
infectious
agents
Obstetric
complications
4 lines of evidence support prenatal nutritional
deficiencies or a plausible set of risk factors for
SCHIZOPHRENIA
Their effects are not
incompatible with the
epidemiology of
schizophrenia
They have adverse effects in
brain development
General malnutrition results
in neurological anomalies
of brain regions
implicated in
schizophrenia
Prenatal malnutrition affects
maternal systems critical
to the developing fetal
nervous system
 NEUROBIOLOGY
INTRO
DNA
GENES
5-HT
DOPA
BRAIN
12043
ATOM
AUT3
DOPAMINE

DOPAMINE

NATURE VS
NURTURE
A Synthetic Model for the
Development of Mental
Illness
CAUSES
MULTIPLE INTERACTING FACTORS

VIRUSES
GENES BIRTH INJURY

GENE
EXPRESSION PERSONAL
EXPERIENCES

TOXINS
NUTRITION

Andreasen, NC: Brave New Brain. P36, 2001

A Synthetic Model for the
Development of Mental
Illness
CAUSES
MULTIPLE INTERACTING FACTORS

VIRUSES
GENES BIRTH INJURY

GENE
EXPRESSION PERSONAL
EXPERIENCES

TOXINS
NUTRITION

Andreasen, NC: Brave New Brain. P36, 2001

 A Synthetic Model for the
Development of Mental
Illness
CAUSES
MULTIPLE INTERACTING FACTORS

BRAIN STRUCTURE AND FUNCTION

e.g., brain development and degeneration, plastic changes
in response to experience, brain chemistry, changes in
response to medications, changes in response to
psychotherapy

Andreasen, NC: Brave New Brain. P36, 2001

A Synthetic Model for the
Development of Mental
Illness
CAUSES
MULTIPLE INTERACTING FACTORS

BRAIN STRUCTURE AND FUNCTION

MIND FUNCTIONS
e.g., memory, emotion, language,
attention, arousal, consciousness

Andreasen, NC: Brave New Brain. P36, 2001

 A Synthetic Model for the
Development of Mental
Illness
CAUSES
MULTIPLE INTERACTING FACTORS

BRAIN STRUCTURE AND FUNCTION

MIND FUNCTIONS

THE UNIQUE PERSON IN A SPECIFIC SOCIAL WORLD

e.g., individual behavior and response in a specific
personal and social environment
Andreasen, NC: Brave New Brain. P36, 2001
 A Synthetic Model for the
Development of Mental
Illness
CAUSES
MULTIPLE INTERACTING FACTORS

BRAIN STRUCTURE AND FUNCTION

MIND FUNCTIONS

THE UNIQUE PERSON IN A SPECIFIC SOCIAL WORLD

A SPECIFIC MENTAL ILLNESS

e.g., schizophrenia, mood disorders, dementias, anxiety disorders
Andreasen, NC: Brave New Brain. P36, 2001
• How does a single Single Cell
cell, the fertilized
egg, give rise to
each of the
differentiated cell
types comprising
the nervous
system?

The nervous system

begins to develop
late in the process
of embryogenesis
Embryogenesis
Endoderm – innermost layer gives
rise to the gut, lungs and liver
Mesoderm – the middle layer,
gives rise to connective tissue,
muscles and the vascular
system
Ectoderm – the outer most later,
gives rise to the CNS and PNS
The initial step in the
development of
neuronal tissue is the
induction of the neural
plate.
Once cells of the neural plate are
induced, they rapidly acquire
specialized properties that
depend on the position they
initially occupy within the neural
plate
Once cells of the neural plate are induced, they
rapidly acquire specialized properties that
depend on the position they initially occupy
within the neural plate
Once cells of the neural plate are induced, they
rapidly acquire specialized properties that
depend on the position they initially occupy
within the neural plate
1
• The fate of the induced neural
2 cells is controlled by 2
independent signaling systems:
3 – Medial to lateral axis which
eventually becomes the dorso-
ventral axis of the neural tube
– Antero-posterior axis that divides
the neural tube into its four-region
rosto-caudal subdivision
1 • The fate of the induced
neural cells is controlled
by 2 independent
2 signaling systems:
– Medial to lateral axis which
3 eventually becomes the
dorso-ventral axis of the
neural tube
– Antero-posterior axis that
divides the neural tube into
its four-region rosto-caudal
subdivision
 Andreasen, NC: Brave New Brain. P45, 2001

Stages of Development
• Neuronal formation
• Neuronal proliferation
• Proliferation of dendrites and spines
• Synaptogenesis
• Myelination
• Pruning
• Apoptosis
 Neuronal Fate in the
Mammalian Cortex
The neurons of the cerebral cortex are
generated in the ventricular zone, an
epithelial layer of progenitor cells that line
the ventricular wall.
Neuronal Fate in the
Mammalian Cortex
Once they have left the cell
cycle, the immature neurons
migrate out of the ventricular
zone to form the cortical plate,
which eventually becomes the
gray matter of the cerebral
cortex
Neuronal Fate in the
Mammalian Cortex

Once they have left the cell

cycle, the immature
neurons migrate out of the
ventricular zone to form the
cortical plate, which
eventually becomes the
gray matter of the cerebral
cortex
Neuronal Fate in the
Mammalian Cortex

Once they have left the cell

cycle, the immature neurons
migrate out of the ventricular
zone to form the cortical
plate, which eventually
becomes the gray matter of
the cerebral cortex
 Neuronal Fate in the
Mammalian Cortex

G1 S G2 M
The plane of
division of
progenitor cells
in the
ventricular zone
influences their
fate
 Neuronal Fate in the
Mammalian Cortex

G1 S G2 M
The plane of
division of
progenitor cells in
the ventricular
zone influences
their fate
 Neuronal Fate in the
Mammalian Cortex

G1 S G2 M
The plane of
division of
progenitor cells in
the ventricular
zone influences
their fate
Neuronal
differentiation 1
G
does not stop
when a cell

S
leaves the cell

G 2
cycle and

/
M
migrates to its
final position.
For a mature
neuron to
participate in
neuronal circuitry,
it must express
many specialized
properties, the
most important
being a chemical
transmitter that
permits the cell to
signal to other
neurons.
 NEUROTROPHIC FACTOR
HYPOTHESIS

TARGET CELL OF
NEUROTROPHIC FACTOR

Rita Levi-Montalcini observed that

death of neurons is a normal
occurrence during embryonic
development.
 Andreasen, NC: Brave New Brain. P45, 2001

Stages of Development

• Neuronal formation
• Neuronal proliferation
• Proliferation of dendrites and spines
• Synaptogenesis
• Myelination
• Pruning
• Apoptosis
The two most plausible developmental
processes which may help explain the
subplate marker disturbances are
defects in either neuronal migration or
programmed cell death
 NEUROTROPHIC FACTOR
HYPOTHESIS

TARGET CELL OF
NEUROTROPHIC FACTOR

Deprivation of neurotrophic
factors activates a cell death
program in neurons
 Guidance of Axons to their
Targets

Paul Weiss proposed that

proper connections survive
because they are the ones in
which the axons and target
match patterns of electrical
activity
Guidance of Axons to their
Targets

Roger Sperry,
a student of Weiss,
forwarded the
CHEMOSPECIFICITY
HYPOTHESIS
The cellular environment
provides a complex set of
commands to the growing
axon.
 Axons of retinal ganglion cells
follow a complex path to the optic
tectum

7
6
5 8
3
2 4
1

10
 The Guidance of Axons to
their Targets

TECTUM

TARGET
ZONE

Axons from the retina terminate and arborize to

their termination site in the tectum
The Guidance of Axons to their Targets

AXONAL ENTRY
The Guidance of Axons to their Targets

AXONAL EXTENSION
The Guidance of Axons to their Targets

AXONAL CORRECTION
The GROWTH CONE is a sensory-motor structure
that regenerates and responds to guidance cues:

Elongating axons terminate in a

protuberance called the GROWTH CONE.

In 1890s, Santiago Ramon y Cajal,

the greatest of all developmental
neurobiologists, proposed that the
growth cone was responsible for
axonal path finding
 Extracellular Matrix Adhesion

+
+
+
+

++++++ -
+ + +++ -
+ ++ -
++ +++
++++
+
+++
+++ -
++ +
++ +
+ +
+++++++++
++ +
- ----- -- -
--- -
--
- -
----- -------
- --- ---
-- - -
- - - - - --
----- -
 Cell Surface Adhesion

+
+
+
+

+++ -
+ +
+ + ++++ -
+ + +
++ ++ -
++++
+
++++
+++ -
++ +
++ +
+ +
++++++++++
++
- ----- -- -
--- -
--
- -
----- -------
- --- ---
-- - -
- - - - - --
----- -
 Fasciculation

Pioneer Neuron
+
+
+
+

++ + -
++++++++ -
+ ++ -
++ ++
++++
+
++++
+ -
++ +++
++ +
+ +
+++++++++
++ + - - -
- -
-- -- - - -
--- ---
---- ------
-
- --- ---
-- - -
- - - - - --
----- -
 Chemoattraction

+
+
+
+

-
+ + + -
++++++++ -
+ +
+
++ ++
+ + -
++++ +
++ ++
++
++ +
+
+ +
+++++++++
+ + - -- - --
-- - - - -
--- ---
---- ------
-
- --- ---
-- - -
- - - - - --
----- -
 Contact Inhibition

+
+
+
+

-
+ + + -
++++++++ -
+ ++
++ ++
+ -
+++ +++
+ ++ +++
+
++ +
+ +
+++++++++
+ + -- -
- -
-- -- - - -
--- ---
---- -------
- --- ---
-- - -
- - - - - --
----- -
 Chemorepulsion

+
+
+
+

-
+ + + -
++++++++
+ ++ -
++ ++
+ -
+++ +++
+ ++ +++
+
++ +
+ +
+++++++++
+ + -- -
- -
-- -- - - -
--- ---
---- -------
- --- ---
-- - -
- - - - - --
----- -
Compelling evidences come from
studies of cytoarchitecture which
demonstrated that neurons among
schizophrenic brains were

MISPLACED,
MIS-SIZED and
DISORGANIZED.
 Functional
Hypothesis for
Schizophrenia
Etiology
 Davis, et al, 1991

DOPAMI NE
HYPOTH ESIS

Hyperdopaminergic state
in subcortical area may underlie
the positive symptoms of
schizophrenia -
 Adapted from Weinberger, 1987

Neuroanatomical Model of
Schizophrenia: Prefrontal Inhibition

PREFRONTAL CORTEX PREFRONTAL CORTEX

(-) (-)

LIMBIC AREAS LIMBIC AREAS

(-) (-)

Brainstem Dopaminergic neurons

NORMAL STATE SCHIZOPHRENIA

 Davis, et al, 1991

DOPAMI NE
HYPOTH ESIS

Hypodopaminergic state
in cortex may underlie
the negative symptoms of schizophrenia -
The Four Major Dopaminergic
Tracts in the Brain

MESOCORTICAL SYSTEM
? Involved in the
NEGATIVE symptoms of
Schizophrenia

MESOLIMBIC SYSTEM
? Involved in the
POSITIVE symptoms of
Schizophrenia
Functional Neuroanatomy of
Hallucinations in
Schizophrenia

VENTRAL ANTERIOR
MAGNOCELLULAR
DIVISION OF THE
THALAMUS

PUTAMEN
INFERO-
SUBSTANTIA
TEMORAL
NIGRA CORTEX
 Ellinwood, 1967; Post, 1980

Dopaminergic Model of
Psychosis

• Psychostimulant psychosis results

with increasing doses of
amphetamines over prolonged use.
 Dopaminergic Model of
Psychosis

• Psychostimulant psychosis results

with increasing doses of
amphetamines over prolonged use.
 Dopaminergic Model of
Psychosis

• Initial effects are

1. Euphoria
2. Enhanced attention
3. Psychomotor agitation
 Dopaminergic Model of
Psychosis

• On repeated exposure, there are

1. Perceptual changes
2. Suspiciousness
3. Repetitive behavior
 Dopaminergic Model of
Psychosis

• Chronic use leads to:

1. Dysphoria
2. Paranoid delusions
3. Increased distractability
4. Ideas of reference
5. Auditory, visual, tactile hallucinations
 Dopaminergic Model of
Psychosis

The key characteristic of

psychostimulant psychosis is
sensitization, inducing cross-
sensitization with other drugs or
environmental stressor.
 Dopaminergic Model of
Psychosis

• Kalivas, in 1995, showed that sensitization

is associated with increased stimulant-
induced dopamine release in the axon
terminals.

• This appears to be a glutamate-dependent

process involving both NMDA and non-
NMDA receptors.
 Dopaminergic Model of
Psychosis

• Evidences:
• Post-WW II abuse of
methamphetamines
• Lieberman et al, in 1987, noted that
psychostimulant-naïve schizophrenics
become worse when taking
psychostimulants.
 Carlsson & Carlsson, 1990, Kalivas, 1995

Dopaminergic Model of
Psychosis

Sensitization is a function of
regulatory abnormalities within the
cortico-striato-thalamic circuitry.
 The Serotonin Hypothesis

• 5-HT projections inhibit DA at two

levels:
– At the midbrain, 5-HT inhibits the firing of
DA cells from the substantia nigra
– At the cortex and striatum, 5-HT inhibit
synaptic release of DA

Kapur and Remington, 1996

 Serotonergic Model of
Psychosis
• In 1954, Gadduan observed LSD-
induced psychosis that showed some
similarity to 5-HT. This was the first
indication of a link between a specific
neurotransmitter and psychosis
 Serotonergic Model of
Psychosis
• LSD demonstrated partial agonist
effect on 5-HT2A receptors
• Mark and Aghajanian, 1996
 Serotonergic Model of
Psychosis
• 5-HT2A receptors, which mediate
hallucinogenic effects play modulatory
roles within local cortical circuits.
 The Role of Glutamate

• Glutamate communicates with two

receptors: AMPA and NMDA

• LTP is enhanced by glutamate

activation of NMDA receptors.
 Glutaminergic Model of
Psychosis

• Luby in 1959 proposed the

“phencyclidine model” of psychosis
 Glutaminergic Model of
Psychosis

• Effects of PCP and ketamine are

amply similar to schizophrenia
 Glutaminergic Model of
Psychosis

• Rosembaum et al, in 1959, Cohen et

al, 1962 compared LSD and PCP
cognitive effects in healthy subjects
compared to schizophrenics.
 Phenomenology of the
Model Psychoses

Signs/ 5-HT Psycho- NMDA

Symptoms Hallucinogens stimulants Antagonists
Psychotic Symptoms
Delusions + ++ +
Hallucinations ++ + +
Others ++ 0 ++
Negative Symptoms
Blunted affect + - ++
Withdrawal + - ++
Anhedonia - - -

Adapted from Andreasen, 1995

 Phenomenology of the
Model Psychoses
Signs/ 5-HT Psycho- NMDA
Symptoms Hallucinogen stimulants Antagonists
s
Disorganization

Thought d/o + + ++
Abstraction 0 0 ++
Attention + + +
Reduced PPI + + +
Others (impaired)

Working memory ? ? +
Declarative
memory + +/- ++
Eye movement
Executive ? ? +
functions +/- +/- ++

Adapted from Andreasen, 1995

 Glutaminergic Model of
Psychosis

• Amphetamine-produced paranoia
psychosis are associated with relative
sparing of cognitive and thought
disorder
 Glutaminergic Model of
Psychosis

• NMDA antagonist psychosis is associated

with disorganized thought and behavior,
impaired cognitive function and negative
symptoms.

• This closely parallels the undifferentiated

and disorganized subtypes of
schizophrenia.
 Glutaminergic Model of
Psychosis

• Paranoid schizophrenia is the most

neuroleptic-sensitive
 Biochemical Changes associated
with Schizophrenia

• Normal or decreased dopamine metabolite in CSF

• Increased striatal D2 receptors
• Altered expression of D3 and D4 mRNA in specific
cortical regions
• Decreased cortical glutamate
• Increased cortical glutamate receptors
• Decreased glutamate uptake sites in cingulate cortex
• Decreased GAD mRNA in prefrontal cortex CG
• Increased GABAA binding sites in cingulate cortex

Byne et al, 1999

 Davis, et al, 1991

DOPAMINE HYPOTHESIS

• Hypodopaminergic state in cortex may

underlie the negative symptoms of
schizophrenia, while the
hyperdopaminergic state in the
subcortical area underlie the positive
symptoms.
 Six types of Dopamine
Receptors
Presyanptic
Dopaminergic IP3
Neuron

D3
PKC
Cortical or DAG D3
Mesolimbic target
PIP2
neuron

D2, D3, D4 D1, D5

Gi
ATP ADP
 Dopaminergic Pathways and site
of action of various psychoactive
substances
NM
Inhibition of reuptake
Deaminated
(cocaine, amphetamine.
products
benztropine
Inhibition of breakdown COMT
(pargyline)

Tyrosine hydroxylase Increase of

Inhibition of
synthesis MAO
synthesis
(L-DOPA) Interference with
DOPA blocking of autoreceptors
Dopamine (α-methyltyrosine Stimulation of
vesicular storage
(antipsychotics, release of DA at
(reserpine,
perphenazine, haloperidol) nerve terminals receptor
tetrabenazine)
(amphetamine,
tyramide)
 Adapted from Synder, 1986
Chlorpromazine acting on
Dopamine Receptors
DOPAMINE

CHLORPROMAZINE
 Indirect effects ofR.anti-
Adapted from Zigmond

schizophenia drugs on
dopamine receptors
DOPAMINERGIC
NEURON
Drugs acts here

Schizophrenia (-) NEURON

acts here USING
(-) NEURO-
TRANSMITTER
(-) B

NEURON USING
NEUROTRANSMITTER A
POSTSYNAPTIC CELL
Serotonergic Innervation of
the Frontal Cortex

GABA
(-)
G G
GABA
(-)
(+)
2A 2A
(+)

GLUTAMATE
5-HT
Serotonergic Innervation of
the Piriform Cortex

GABA
(-)
2A G

(+) (+)
2B

GLUTAMATE
5-HT
ORIGINAL DOPAMINE HYPOTHESIS

VERSUS

RECENT AND COMPLEX ROLE OF

DOPAMINE
 Original Dopamine
Hypothesis
• DA metabolite and receptor in post-
mortem brain do not support this
hypothesis (Davis et al, 1991)
• Some schizophrenic patients do not
respond to drugs that block dopamine
activity
• Negative symptoms of schizophrenia
are refractory to such drugs
 Complexity of Dopamine
• DA interact with many other
neurotransmitter system (Davis, et al, 1991)
• DA is differentially regulated in different
brain regions – hypodopaminergic in the
cortex; hyperdopaminergia in subcortical
areas
• Phenomenon of depolarization blockade A9
and A10.
• Concept of hypofrontality
Is there hyperdopaminergia in
schizophrenia?
 Is there
hyperdopaminergia in
schizophrenia?
• Grace (1991) presented a model
pertinent to dopamine function
between the prefrontal cortex and
subcortical areas based on 2 events:
– Transient or phasic dopamine release
caused by DA firing
– Sustained or tonic release requested by
prefrontal cortical areas
 Is there
hyperdopaminergia in
schizophrenia?
New Model Hypothesis:
• Tonic subcortical release of DA would
be reduced by decreased activity of
cortical efferents leading to an
upregulation of subcortical DA
receptors, leading to an exaggerated
DA response triggered by phasic DA
release.
 NMDA Receptor
Hypofunction Hypothesis:
DA inhibit glutamate release
• NMDA activation causes neuronal
degeneration
• NMDA antagonists may ameliorate
the symptoms of degeneration
 NMDA Receptor
Hypofunction Hypothesis:
• NAN and NAP are inhibited by DA
antagonists and GABA agonists
Olney and Farber, 1995
 NMDA Receptor
Hypofunction Hypothesis:
• Olney proposes that NMDA receptors
tonically drive GABAergic neurons
that inhibit excitatory amino acid
neurons.
 NMDA Receptor
Hypofunction Hypothesis:
• NMDA receptor (NRH) hypofunction
would diminish GABAergic inhibition
over excitatory inputs to the cortex
 NMDA Receptor
Hypofunction Hypothesis:
The role of the thalamus
• THALAMIC PROJECTIONS -
• Javitt et al., 1994 – treated chronic
schizophenics with glycine – a
potentiator of NMDA-receptor
mediated neurotransmission.
 The Concept of
BRAIN PLASTICITY

Donald Hebb
– In 1949, observed
that our ability to
change our brain
through new data
and then to learn
occurs because of
changes at the
neuronal cell levels.
 The Concept of
Long-Term Potentiation

A process by which
the size of a
neuronal response
increases after
stimulation. This is
probably one of the
basis of learning.
David Hubel and
Torsten Wiesel
• Both persons
explained how
experience in the
environment affect
brain development
– a different
perspective of brain
plasticity.
 Two important components of
brain plasticity

• Critical periods
• Activity-dependent changes
Surface of the Cerebrum
The Brain in
Alfred T. Kamajian
 Medial View of cerebral hemisphere with
major limbic structures indicated

Ring of limbic cortex

Corpus callosum Posterior

cingulate
Anterior
Anterior nucleus
cingulate Fornix

Stria terminalis
Septal nuclei
Anterior
commissure
Subcallosal Hippocampal
gyrus formation

Hypothalamus
Olfactory bulb
Olfactory tract
Mammillary body
Entorhinal cortex
Piriform cortex
Amygdala