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Overview
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Huntington’s Disease
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Degeneration of caudate nucleus and putamen
Uncontrollable movements, jerky limb movements
Progressive, cognitive and emotional changes
Gene that codes the huntingtin protein (htt) (chromosome 4)
No cure
Death (10-15 years)
Alzheimer’s Disease
 Amyloid Plaque
 Neurofibrillary Tangle
 APP gene – chromosome 21
 Protective value of intellectual activity
 Cholingeric agonists (acetylcholinesterase inhibitors)
 NMDA receptor antagonist (memantine)
Multiple Sclerosis
 Autoimmune disorder, attacks myelin
 Interferon β
 Glaterimer acetate (copaxone)
Schizophrenia
and the
Affective
Disorders
Chapter 16
Schizophrenia
 Description
 Schizophrenia is a serious mental disorder characterized by
disordered thoughts, delusions, hallucinations, and often
bizarre behaviors.
Schizophrenia
 “Splitting of psychic
functions”
 Refers to the breakdown of
integration of emotion,
thought, and action
 Affects 1% of the population
 A diverse disorder – multiple
types exist with varied
profiles
Scientific American (2008)
See Table 16.1
Schizophrenia Symptoms
POSITIVE SYMPTOMS
Hallucinations
Auditory/olfactory
COGNITIVE SYMPTOMS
Attention
Low psychomotor speed
Delusions
Persecution/grandeur/control
Deficits in learning and memory
Thought disorders
Disorganized, irrational
Poor problem solving
 Negative and Cognitive symptoms
are closely related, may involve
dysfunction in similar brain areas
 Negative and Cognitive symptoms
are not specific to schizophrenia
Poor abstract thinking
NEGATIVE SYMPTOMS
Anhedonia
Flat affect
Motor Deficits
Little Speech (poverty of speech)
Social withdrawal
Diagnosis
► The recurrence of only 2 symptoms for one month
► 1 symptom is necessary if the person exhibits delusions
that are particularly bizarre or hallucinations that include 1
voice providing a running commentary or 2 voices
conversing
Schizophrenia
► Biological Basis
 Classification - according to onset
► acute
► chronic – gradual onset, progressive deterioration
► ~ 1/3 of those diagnosed will show progressive
deterioration & become chronic schizophrenics
Behavioural Genetics
Heritability: statistic which gives an estimate of the
total variance in a trait that is attributable to genetic
variation in a group
 Maximum value of the estimate is 1.0 (which is equivalent
to 100%)
 Important: Because a trait is heritable, does NOT mean it
cannot be altered by the environment
Example:
 Height is a heritable trait
 Table manners is not
Schizophrenia: Heritability
 Heritability
 Schizophrenia is a
heritable trait
 Not likely to be a
single gene (dominant
or recessive)
 Several genes or
susceptibility
hypothesis
Schizophrenia.com
Schizophrenia: Heritability
Fig. 16.1
 Susceptibility hypothesis (genetic propensity, not necessarily
expressed)
 Risk for Sz is 17% in children with a Sz parent but ALSO in children of
unaffected MZ parents – risk is being passed on in genes. Lack of expression
of Sz in normal MZ co-twins tells us that environment is important to Sz.
Schizophrenia: Heritability
 Also linked: paternal age
 Children of older fathers
 Copying error in DNA replication (spermocytes); high amount of
replication (divides everyone 16 days after puberty)
 Genes identified:
 No single gene
 DISC1: Disrupted in schizophrenia
 Neuronal migration
 Neurogenesis
 Function of PSD in excitatory neurons, function of mitochondria
 EPIGENETICS:
 Mechanisms that control the expression of genes (environmental control e.g.
toxins)
 http://www.youtube.com/watch?v=kp1bZEUgqVI
Antipsychotic Drugs
 Much of our understanding of schizophrenia is a
consequence of the drugs that are able to treat it
 Chlorpromazine
 Henri Laborit: drug reduced anxiety and shock
 Developed to treat neuroses and psychoses (not always
effective)
 Calms many agitated schizophrenics
 Block DA receptors
Dopamine Theory of Schizophrenia
 1960 – link between dopamine and Parkinson’s
disease established
 Antipsychotic drug side effects suggests role for
dopamine – drugs work by decreasing dopamine
levels; positive symptoms of schizophrenia are
associated with dopamine overactivity
 Reserpine depletes brain of dopamine and other
monoamines by making vesicles leaky
 Amphetamine, cocaine and L-dopa are dopamine agonists
and produce psychosis
DOPAMINE &
POSITIVE SYMPTOMS
PROJECTIONS
 Major CNS dopaminergic
systems include:
 Nigrostriatal System
(role in movement)
POSITIVE SYMPTOMS
 Mesolimbic Dopamine
 VTA-amygdala
in reinforcement/reward)
 Drugs that agonize DA
 Mesolimbic System (role
 Mesocortical System
(role in short-term
memory, planning, and
problem solving)
release (cocaine, etc.)
can also cause positive
symptoms of
schizophrenia
Dopamine Theory of Schizophrenia
 Intravenous injection of
amphetamine in control
and patients with
schizophrenia
DA Release
 Laruelle et al (1996)
 Amphetamine caused
more release of DA in
striatum of schizophrenics
 See Figure 16.2
Dopamine Theory of Schizophrenia
 Greater amount of DA
release was also
correlated with positive
symptoms
 See Figure 16.2
Dopamine Receptors
Potency of Binding to DA Rs
Results
Snyder & colleagues demonstrated:
► Potency of a particular drug in binding to DA Rs in vitro
was positively correlated with its clinical effectiveness
DA Receptors
D1-Like
D2-Like
D1 & D5
D2, D3, D4
•All DA receptors are metabotropic
•This division is based on whether or not receptor
activation stimulates formation of the 2nd messenger,
cyclic AMP.
• Activation of D1-like Rs stimulates cAMP
• Activation of D2-like Rs inhibits cAMP
Anti-Schizophrenic Drugs
2 Classes
Butyrophenones
Phenothiazines
Chlorpromazine
Binds to D1 & D2
Receptors
Haloperidol
(Haldol)
Spiroperidol
Bind to D2
Receptors only
Revised DA Theory of Schizophrenia
►Schizophrenia is caused by hyperactivity
at D2 Rs, rather than DA Rs in general
► Based on 2 findings:
 Selective binding of butyrophenones to D2 Rs
 Butyrophenones greater potency in the clinic
Brain Imaging
► Measure DA Rs in brains of recently diagnosed
schizophrenics not previously exposed to
neuroleptics
 Radioactive ligand of the D2 R was injected iv & its
concentration measured in the corpus striatum
 Two Results
► Brains of schizophrenics have an abnormally high #
of D2 Rs
► Higher level of occupancy of those Rs by DA
► Suggest both pre & postsynaptic abnormalities
 Too much release & too many receptors
(modest)
Side-Effects of Long-Term AntiSchizophrenic Drugs
 Similarly to long-term use of Parkinson’s drug treatments, there
can be side-effects with long-term use of anti-psychotic drugs.
 Tardive Dyskinesia
 Tardus – slow
 Dyskinesia- faulty movement
 Late-developing
 TD: unable to stop moving
 Supersensitivity: possible that DA receptors become
hypersensitive if they are blocked for long periods of time
 D2 receptors in caudate and putamen
Problems with the D2 Theory
 Schizophrenia associated with brain damage
 Little damage to dopamine circuitry
 Damage not explained by dopamine theory
 It takes several weeks of neuroleptic therapy to
alleviate schizophrenic symptoms
 Conventional neuroleptics (D2 blockers) mainly
effective for positive symptoms
 Negative and cognitive symptoms might be caused
by brain damage
 May be best to think of schizophrenia as multiple
disorders with multiple causes
Schizophrenia as a Neurological
Disorder
 Predisposing factors (genetic, environmental, or both)
give rise to:
1. Abnormalities in both DA transmission and PFC
2. Abnormalities in DA transmission that cause
abnormalities in PFC
3. Abnormalities in PFC cause abnormalities in DA
transmission
Schizophrenia: Brain Abnormalities
 Evidence of brain
damage
 Negative and
cognitive
symptoms
 Loss of brain
tissue
 Lateral ventricles
more than twice
as large in
schizophrenic
patients than
control subjects
Possible Causes of Brain
Abnormalities
 Epidemiological Studies
 Season of birth
 Viral epidemics
 Population density
 Prenatal malnutrition
 Maternal stress
Possible Causes of Brain
Abnormalities
 Season of birth (seasonality)
 Late winter and early spring (northern hemisphere)
 Reverse in southern hemisphere
 Possible link: viruses
 Effect seen in cities, not in countryside
See Figure 16.5
Possible Causes of Brain
Abnormalities
 Vitamin D deficiency
 Dealberto (2007)
 Northern Europe: 3-fold increase in schizophrenia in immigrants
(equatorial regions)
 Thiamine deficiency
 Two-fold increase in incidence of schizophrenia in offspring of
women pregnant during severe food shortage in WWII (Germany and
Netherlands)
 Maternal/paternal substance abuse – smoking
 Complications during childbirth
 Mother: Diabetes of mother, bleeding, preclampsia (high blood
pressure, protein in urine)
 Other: oxygen or blood flow deprivation
Evidence for Abnormal Brain
Development
 Home movies from families with schizophrenic child
 Compared to normal siblings, schizophrenic child displayed
more negative affect and more abnormal movements
 265 Danish children (11-13 years) were videotaped eating
lunch
 Children who later developed schizophrenia displayed less
sociability and deficient psychomotor functioning
 Hypothesis – although schizophrenia is not seen in
childhood, the early brain development of children who
become schizophrenic is not normal
Age of Onset
 See Figure 16.8
 Symptoms rarely begin before late adolescence or early adulthood
 Progression:
 Negative symptoms  cognitive symptoms  positive symptoms
Abnormal Brain Development
 Brain damage is sudden (during
young adulthood)
 Thompson et al. (2001)
 Adolescence with early onset
schizophrenia
 MRI
 Normals:
 Loss of 0.5-1.0%
 Schizophrenic patients:
 2-3%
 Loss:
 See Figure 16.9
 Parietal to temporal lobe
 Somatosensory and motor
 Prefrontal cortex
Abnormal Brain Development
 See Figure 16.10
 Hypofrontality and Negative and Cognitive Symptoms
 Decreased activity of the prefrontal cortex (dlPFC); believed to
be responsible for the negative symptoms of schizophrenia.
 Above fig: Task required increased concentration and attention
 Possibly caused by decreased DA activity in prefrontal regions
NMDA , Dopamine
and Hypofrontality
 PCP and ketamine can cause
positive, negative and cognitivelike symptoms
 NMDA receptor antagonists;
decrease DA and metabolic activity
in frontal cortex
Role of D2 Receptors in
Development of Schizophrenia
 Abnormalities in the striatal DA system may be the cause
of schizophrenia
 Virus inserted into striatum that increased D2 recpetors
 Caused the development of behavioral deficits characteristic
of schizophrenia
 Abnormal activity of dlPFC
Treatment with Partial DA
Receptor Agonists
 Atypical drugs are able to
reduce ALL symptoms
 Increase DA activity in PFC
 Reduce DA activity in the NA
 Aripoprazole: Atypical
 Partial DA agonist
 High affinity for receptor but
less than ligand
 Can act like an antagonist
 Nucleus accumbens
 Can act like an agonist
 Prefrontal cortex
 http://www.youtube.com/watch?v=USxHsSWCaJA