IzBen C. Williams, MD, MPH
Lecturer
Lecture - 3
GENETICS,
ANATOMY, &
BIOCHEMISTRY
OF BEHAVIOR
Genetics of Behavior
 Definition of common terms:
 For fullest appreciation of this presentation students
may wish to refresh their memory on some basic
principles of genetics; particularly on such terms as:
 Genotype and Phenotype,
 Heritability, Penetrance, Expressivity
 Homozygosity and Heterozygosity
 Dominance and Recessivity
Genetics of Behavior -2
 There are basically three methods of studying
behavioral genetics.
A. Family Studies
B. Twin Studies
C. Adoption Studies
Genetics of Behavior -2
 Methods of studying behavioral Genetics.
A. Family Studies:
 These assess the pattern of affliction in the relatives of
an affected individual, who is called the index case,
propositus, or proband
 The family tree showing the occurrence of certain traits
and diseases in different members is called the
pedigree. By studying the pedigree the likely mode of
inheritance may be inferred
Genetics of Behavior -3
 Methods of studying Genetics:
B. Twin Studies:
 These assess the degree to which both members of a
pair of twins manifest a given trait or disease. If both
twins have a certain trait, they are termed concordant
for that trait. If only one twin of the pair has the trait,
the pair is said to be discordant
 Twin studies may be carried out on monozygotic
(identical) or dizygotic (fraternal) twins
Genetics of Behavior -4
 Methods of studying Genetics:
C. Adoption Studies:
 Offer an opportunity to distinguish between genetic
and environmental influences on behavior.
 The prevalence of specific traits or conditions in the
biological versus the adoptive relatives of probands is
compared.
 A genetic condition is characterized by a significantly
higher prevalence of the condition among biological
relatives when compared with adoptive relatives
Specific Disorders
Looking at the genetics of some specific
disorders:
A. Schizophrenia
B. Affective Disorders
C. Other Psychiatric Disorders
Genetics of Psychiatric Disorders
 A. SCHIZOPHRENIA:
 A severe mental illness that is marked by:
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Hallucinations (which are chiefly auditory)
Delusions
Disorganization of thought and speech, and
Emotional blunting
Genetics of Psychiatric Disorders
 Schizophrenia (cont’d)
 1. Family studies: Worldwide lifetime incidence of
Schizophrenia ranges from 0.3% to 3.0% with a mean
incidence of about 0.9%.
 The risk for parents is about 4% to 5%
 The risk for full siblings is 7% to 8%
 Children of a schizophrenic proband, risk of 10% to 12%
 If both parents have schizophrenia, risk is 35% to 46%
Genetics of Psychiatric Disorders
 Schizophrenia (cont’d)
 2. Twin studies: Concordance rate for schiz. is
significantly higher in monozygotic than in dizygotic
twins (35-58% for mono-, 9-26% for di-)
 3. Adoption studies: Prevalence of schiz and related
disorders significantly higher in biological relatives
compared to adoptive relatives
Genetics of Psychiatric Disorders
 Schizophrenia (cont’d)
 4. Inheritance of Schizophrenia:
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
a. The exact mode of transmission of Schiz is unknown
but clearly, in addition to genes, environmental factors
are contributory
It is likely that there are several subtypes of schiz
(schizophrenia spectrum disorders) and that genes are
more important in some than in others
Genetics of Psychiatric Disorders
 Schizophrenia (cont’d)
 4. Inheritance of Schizophrenia:


b. Exactly what is inherited in schiz is not known. Some
investigators have hypothesized that specific biochemical
defects are transmitted.
Alternatively, only the predisposition to develop schiz
under certain situations may be transmitted
Genetics of Psychiatric Disorders
 B. AFFECTIVE DISORDERS:
 Conditions marked by pervasive pathologic change in
mood. There are two major forms:
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
Unipolar disorder (pure depressive disorder)
characterized by a single episode of repeated episodes of
depression
Bipolar disorder (manic depressive illness)
characterized by episodes of mania and depression
Genetics of Psychiatric Disorders
 Affective Disorders (cont’d)
 1. Family studies
 a. Unipolar disorder:
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
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Lifetime incidence in the general population is 15% to 20%
40% to 60% have a first-degree relative with an affective
disorder
Morbidity risk for an affective disorder is: 13% for parents; 15%
for siblings, and 21% for children
Relatives of unipolar patients are at much higher risk of
developing unipolar than bipolar illness
Genetics of Psychiatric Disorders
 Affective Disorders (cont’d)
 1. Family studies
 b. Bipolar disorder:


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Lifetime incidence in the general population is 1% to 2%,
however 80% risk for affective disorder in first degree
relative
Morbidity risk: for an affective disorder is: 22% for
parents; 25% for siblings, and 39% for children
Relatives of unipolar patients are at much higher risk of
developing either unipolar or bipolar illness
Genetics of Psychiatric Disorders
 Affective Disorders (cont’d)
 2. Twin studies
 Monozygotic twins reared either apart of together have
a 75% rate of concordance compared to dizygotic twins
who have a 20% concordance rate
 Twins of unipolar probands are likely to be unipolar
 Twins of bipolar probands are likely to be bipolar or
unipolar
Genetics of Psychiatric Disorders
 Affective Disorders (cont’d)
 3. Adoption studies
 There is (as in schiz) a higher prevalence of affective
disorders in biological relatives than in adoptive
relatives of affected individuals
Genetics of Psychiatric Disorders
 4. Inheritance of affective disorders: Studies strongly
suggest that genetic factors contribute to the etiology of
major affective disorders.
 There is (as in schiz) a higher prevalence of affective
disorders in biological relatives than in adoptive relatives of
affected individuals
 An X-linked mode of inheritance suggested
 Depressive spectrum disease proposed on the basis of
high prevalence of sociopathy and alcoholism in male
members of families of probands with major depression
Genetics of Psychiatric Disorders
 C. SOME THER PSYCHIATRIC DISORDERS:
 1. Personality Disorders: Conditions marked by
chronic patterns of maladaptive behavior and the
patients are usually unaware of their own role in the
continuing difficulties that arise.

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Concordance rate several times higher on mono- than in
dizygotic twins
The most conclusive evidence for inherited traits are
antisocial, histrionic, schizoid, schizotypal, and
obsessive compulsive personality disorders
Genetics of Psychiatric Disorders
 C. SOME OTHER PSYCHIATRIC DISORDERS:
 2. OCD & other anxiety disorders: No established
evidence for genetic links
 3. Alcohol and tobacco use: Adoption studies
indicate genetic link for alcoholism.

Little evidence for genetic link in tobacco use
 4. Attention deficit disorder: Twin studied and
adoption studies confirm strong genetic link
Biochemistry & Behavior -1
 This presentation assumes the prior knowledge,
which I am sure you possess, of:
 Neuronal transmission and
 Intra-neuronal transport
 And begins with a brief introduction to aspects of
Inter-neuronal transport
Biochemistry & Behavior -2
 Aspects of Inter-neuronal transport
 Neuroregulators: Chemicals that carry
information between neurons. They include
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Neurotransmitters: transfer of information lasts 1-2
msec
Neuromodulators: effect lasts up to minutes
Neurohormones: released into systemic circulation
Biochemistry & Behavior -3
 Aspects of Inter-neuronal transport
 Types of neurotransmitters
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Excitatory neurotransmitters increase the
likelihood of the firing of the postsynaptic neurons
Inhibitory neurotransmitters decrease the
likelihood of firing of the postsynaptic neuron
Biochemistry & Behavior -4
 Aspects of Inter-neuronal transport
 Some neurotransmitters appear to be solely
excitatory eg glutamate
 Some others appear to be solely inhibitory eg
GABA and glycine
 And others may function either way, eg dopamine
and acetyl choline (ACh)
Biochemistry & Behavior -5
 Neurotransmitter criteria -1
1. The transmitter must be present at nerve
terminals.
2. Stimulation of the nerve must cause the release
of the transmitter in sufficient amounts to exert
its action at the post synaptic terminal
3. Effects of the transmitter on the post synaptic
membrane must be similar to those of
transmitter stimulation of presynaptic nerve
Biochemistry & Behavior -6
 Neurotransmitter criteria -2
4. Pharmacologic agents should alter the doseresponse curve of the applied transmitter in the same
magnitude and direction that they alter the naturally
occurring synaptic potential
5. A mechanism of inactivation or metabolism of the
transmitter must exist in the vicinity of the synapse
Biochemistry & Behavior -7
 Neurotransmitter criteria -3
 Proven or definite neurotransmitters meet all
the criteria (ACh, dopamine, Epi & NEpi, GABA,
Serotonin and glycine)
 Putative neurotransmitters meet a few of the
criteria (glutamate, aspartate, substance P)
 Neurotransmitter candidates meet one or two
criteria (adenosine, cAMP, prostaglandins, and most
peptides)
Neurotransmitters -1
THREE CLASSES OF NEUROTRANSMITTER
SUBSTANCES:
1. BIOGENIC AMINES
2. AMINO ACIDS
3. NEUROPEPTIDES
4. Other Non-Peptide Neurotransmitter
Candidates
Neurotransmitters -3
1. BIOGENIC AMINES
a) Dopamine
b) Norepinephrine
c) Epinephrine
d) Serotonin (5-HT)
e) Histamine
f) Acetylcholine
Neurotransmitters
Biogenic Amines
1. DOPAMINE
• Synthesis: tyrosine hydroxylation is the ratelimiting step in the synthesis of all of the major
catecholamines (ie, dopamine, Nor Epi, and Epi)
• Metabolism: Two enzymes are important for the
inactivation of catecholamines (MAO and COMT)
• Receptors: Action may be excitatory or inhibitory
but inhibition appears to be the more common.
There are at least two, and possibly four types of
Dopamine receptors (D1-4)
Neurotransmitters
Biogenic Amines
DOPAMINE: Important brain tracts in the CNS
 1. Nigrostriatal tract (movement)
 2. Mesolimbic and mesocortical tracts (affect,
cognition and motivation in man)
 3. Tuberohypophyseal (pituitary, prolactin release)
 4. Medullary periventricular tract (?function)
 5. Incertohypothalamic tract (? function)
In addition dopaminergic neurons are located in the
retina and in the olfactory bulb
Neurotransmitters
Biogenic Amines
DOPAMINE: Behavioral functions 1
From a behavioral perspective the three most
important tracts are the nigrostriatal, mesolimbic
and mesocortical
 The nigrostriatal pathway degenerates in
Parkinson’s disease
 Neuroleptic drugs, because they block post
synaptic dopamine receptors, and reserpine
because it depletes dopamine, also cause
parkinsonism
Neurotransmitters
Biogenic Amines
Neurotransmitters
Biogenic Amines
DOPAMINE: Behavioral functions
 XS of dopamine transmission is thought to be
important in some disorders of XSive
movement (hyperkinetic disorders) eg tardive
dyskinesia
 Dopamine also important for the organization of
thought and feeling (the dopamine hypothesis of
schizophrenia)
Neurotransmitters
Biogenic Amines
DOPAMINE: Behavioral functions
 The psychotic symptoms of schiz are believed to
result from a hyperdopaminergic state
 Neuroleptic drugs block dopamine receptors. This
correlates with their anti psychotic effect
 Dopamine agonist drugs such as amphetamine and
L-dopa make schiz symptoms worse

Dopamine & Serotonin Tracts
Neurotransmitters
Biogenic Amines
 SEROTONIN: synthesis
Neurotransmitters
Biogenic Amines
SEROTONIN (5-HT):
 Receptors: Two types of serotonergic receptors
 S1 bind serotonin, are affected by guanine
 S2 bind spiperone and are less affected by guanine
nucleotides than S1
 The predominant action of serotonin on
receptors is inhibition
 LSD acts as a receptor blocker and partial agonist
Neurotransmitters
Biogenic Amines
SEROTONIN (5-HT):
 Important brain tracts: The most important
serotonergic neurons in the brain are located in
clusters in or around the midline (or raphe) of the
pons and mesencephalon, including the median
and dorsal raphe nuclei
 Median raphe neurons innervate limbic structures
 Dorsal raphe innervates striatum, cerebral cortex,
thalamus and cerebellum
Neurotransmitters
Biogenic Amines
SEROTONIN (5-HT):
 Behavioral functions:
 Important in many central processes
 Involved in the pathophysiology of both
affective disorders and schizophrenia
 Affective disorders: permissive serotonin
hypothesis (low in depression, high in mania)
 Transmethylation hypothesis of schizophrenia
Neurotransmitters
Biogenic Amines
2. NOREPINEPHRINE
• Synthesis: tyrosine hydroxylation is the ratelimiting step in the synthesis of all of the major
catecholamines (ie, dopamine, Nor Epi, and Epi)
• Metabolism: Two metabolites of nor-epi are
commonly measured in plasma or urine: 3-methyl4-hydroxyphenylglycol and Vanillymandelic acid
(HMPG and VMA)
Neurotransmitters
Biogenic Amines
2. NOREPINEPHRINE
Receptors: four types α1, α2, β1 and β2
• α1 post synaptic receptors, blocked by prazocin
• α2 presynaptic receptors, decrease the synthesis of
NEpi when stimulated
• β1 post synaptic, linked to atenolol, albutalol etc
are selective antagonists
• β2 post synaptic, linked to adenylate cyclase.
Terbutaline and albutalol are selective agonists
Neurotransmitters
Biogenic Amines
2. NOREPINEPHRINE
Important brain tracts. Two major groups
I. The first group arises from the locus ceruleus
with projections going to the cerebellum and
spinal cord, and to the hippocampus ventral
striatum and entire cerebral cortex
II. The second group originates from the ventral
tegmental area and projects to basal forebrain
areas such as the septum and amygdala
Norepinephrine tracts
Neurotransmitters
Biogenic Amines
2. NOREPINEPHRINE
Behavioral functions
 Projects to most areas of the brain and is an
important neuromodulator (eg, sleep-wake, pain,
arousal, orientation)
 Genesis of mood and anxiety disorders
(catecholamine theory of mood disorders)
 Implicated in some movement disorders, eg
Tourette’s, Parkinson’s, torsion dystonia, tardive
dyskinesia
Neurotransmitters
Biogenic Amines
ACETYLCHOLINE (ACh):
 Synthesis:
 Choline cannot be synthesized in neurons hence
high and low affinity transport processes transports
it into the brain.
 The high affinity process is the regulating factor
Neurotransmitters
Biogenic Amines
Neurotransmitters
Biogenic Amines
ACETYLCHOLINE (ACh):
 Metabolism:
 ACh is inactivated by cholinesterases (including
both acetylcholinesterase and
pseudocholinesterase)
 It is reversibly inhibited by physostigmine and
almost irreversibly inhibited by
organophosphorus compounds (found in
insecticides)
Neurotransmitters
Biogenic Amines
ACETYLCHOLINE (ACh):
 Receptors:
 Nicotinic receptors: are excitatory
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
In the PNS their cell bodies lie in the spinal cord or
brainstem. They innervate skeletal muscle
Nicotine receptor agonists include nicotine and
antagonists include curare drugs, gallamine,
decamethonium
Neurotransmitters
Biogenic Amines
ACETYLCHOLINE (ACh):
 Receptors:
 Muscarinic receptors: are excitatory or inhibitory
 Their cell bodies lie primarily outside the CNS.
 They innervate smooth muscle and glands
 Agonists include muscarine, pilocarpine
 Antagonists include atropine
Acetylcholine brain tracts
Neurotransmitters
Biogenic Amines
ACETYLCHOLINE (ACh):
 Behavioral functions: in humans, the most
important known effects involve movement and
memory
 ACh involved in movement peripherally (skeletal
muscles) and centrally (balancing the
extrapyramidal motor system.
 Ach important in memory and cognition.
Associated with dementing illness
AMINO ACIDS
 GABA
 Glycine
 Glutamate and Aspartate
Amino Acids
Amino Acids
 GABA:
 Receptors: GABA was the first amino acid
demonstrated to be a receptor
 GABA, unlike most other transmitters, is dedicated
to the CNS
 It is purely inhibitory
 It is the most abundant neurotransmitter X plenty
Amino Acids
GABA:
 Two kinds of GABAergic receptors in the CNS
 GABA-A receptors, muscinol is a selective agonist
 GABA-B receptors, bacolfen is a selective agonist
 Some GAGA receptors are coupled to a third
recognition site for benzodiazepines which
potentiate the inhibitory action of GABA
GABA Brain Tract
 GABA is the neurotransmitter for Purkinje
cells, the only efferent neurons for the entire
cerebral cortex
 Inhibitory interneurons in all areas of the brain
contain GABA
