GENETICS, AND BIOCHEMISTRY

OF BEHAVIOR

NATIA BADRIDZE,MD
 THE GENETICS OF BEHAVIOR-Studies for
examining the genetics of behavior
1. Family risk studies compare how frequently a behavioral disorder
or trait occurs in the relatives of the affected individual (proband)
with how frequently it occurs in the general population.
2. Twin studies
a. Adoption studies using monozygotic twins or dizygotic twins reared
in the same or in different homes are used to differentiate the effects
of genetic factors from environmental factors in the occurrence of
psychiatric, substance abuse (e.g., alcoholism), and neuropsychiatric
disorders.
b. If there is a genetic component to the etiology, a disorder may be
expected to have a higher concordance rate in monozygotic twins
than in dizygotic twins (i.e., if concordant, the disorder occurs in both
twins).
 THE GENETICS OF BEHAVIOR-Studies for
examining the genetics of behavior
It has been difficult to link particular chromosomes with psychiatric
illnesses. However, in a number of studies over years, such
associations have been made.

a. Schizophrenia has been associated with markers on

chromosomes 1, 6, 7, 8, 13, 21, and 22.
b. Bipolar disorder and major depressive disorder recently have
been associated with markers on chromosomes 3, 5 and 6.
 NEUROTRANSMISSION
• Synapses and neurotransmitters
1. Information in the nervous system is transferred across
the synaptic cleft (i.e., the space between the axon
terminal of the presynaptic neuron and the dendrite of
the postsynaptic neuron).

2. When the presynaptic neuron is stimulated, a

neurotransmitter is released, travels across
the synaptic cleft, and acts on receptors on the
postsynaptic neuron.

Neurotransmitters are excitatory if they increase the

chances that a neuron will fire and inhibitory if they
decrease these chances.
 NEUROTRANSMISSION
• Presynaptic and postsynaptic receptors are
proteins present in the membrane of the
neuron that can recognize specific
neurotransmitters.

The changeability of number or affinity of

receptors or specific neurotransmitters
(neuronal plasticity) can regulate the
responsiveness of neurons.
Classification of neurotransmitters
• Biogenic amines (monoamines);
• Amino acids;
• Peptides
Are the three major classes of neurotransmitters.
Regulation of neurotransmitter activity
1. The concentration of neurotransmitters in the
synaptic cleft is closely related to mood and
behavior. A number of mechanisms affect this
concentration.

2. After release by the presynaptic neuron,

neurotransmitters are removed from the synaptic
cleft by mechanisms including:
a. Reuptake by the presynaptic neuron .
b. Degradation by enzymes such as monoamine oxidase
(MAO).
 Psychiatric Conditions and Associated Neurotransmitter Activity
Neuropsychiatric Condition Neurotransmitter Activity
Increased (↑) or Decreased (↓)

Depression Norepinephrine (↓), serotonin (↓),

dopamine (↓)

Mania Dopamine (↑), g-aminobutyric

acid (GABA) (↓), serotonin (↑)

Schizophrenia Dopamine (↑), serotonin (↑),

glutamate (↑ or ↓)

Anxiety GABA (↓), serotonin (↓),

norepinephrine (↑)

Alzheimer’s disease Acetylcholine (↓), glutamate (↑)

 BIOGENIC AMINES
1. The biogenic amines, or monoamines, include
catecholamines, indolamines, ethylamines,and quaternary
amines.

2. The monoamine theory of mood disorder hypothesizes that

lowered monoamine activity results in depression and
elevated levels in mania.

3. Metabolites of the monoamines are often measured in

psychiatric research and diagnosis because they are more
easily measured in body fluids than the actual monoamines.
 Dopamine
1. Dopamine, a catecholamine, is involved in the
pathophysiology of schizophrenia and other psychotic
disorders, Parkinson’s disease, mood disorders, the
conditioned fear response , and the “rewarding” nature of
certain drugs.

2. Synthesis. The amino acid tyrosine is converted to the

precursor or dopamine by the enzyme tyrosine hydroxylase.

3. Receptor subtypes. At least five dopamine receptor subtypes

(D1–D5) have been identified; the major site of action of
traditional antipsychotic agents is D2 and D1 and D4 as well
as D2 for the newer “atypical” antipsychotic agents.
 Norepinephrine
Norepinephrine, a catecholamine, plays a role in
mood, anxiety, arousal, learning, and memory.
1. Synthesis
a. Like dopaminergic neurons, noradrenergic
neuron synthesize dopamine.
b. Dopamine β-hydroxylase, present in
noradrenergic neurons, converts this dopamine
to norepinephrine.
 Serotonin
Serotonin, an indolamine, plays a role in mood, sleep, sexuality,
and impulse control.
Elevation of serotonin is associated with improved mood and
sleep but decreased sexual function (particularly
delayed orgasm). Very high levels are associated with psychotic
symptoms.
Decreased serotonin is associated with poor impulse control,
depression, and poor sleep.
1. Synthesis. The amino acid tryptophan is converted to
serotonin (also known as 5-hydroxytryptamine[5-HT]) by the
enzyme tryptophan hydroxylase as well as by an amino acid
decarboxylase.
 Antidepressants and serotonin.
Heterocyclic antidepressants (HCAs), selective serotonin
and serotonin and norepinephrine reuptake inhibitors (SSRIs and
SNRIs), and monoamine oxidase inhibitors (MAOIs) ultimately
increase the presence of serotonin and norepinephrine in the
synaptic cleft.

•HCAs and SNRIs block reuptake of serotonin and

norepinephrine, and SSRIs such as fluoxetine (Prozac) selectively
block reuptake of serotonin by the presynaptic neuron.

b. MAOIs prevent the degradation of serotonin and

norepinephrine by MAO.
 Histamine
1. Histamine, an ethylamine, is affected by
psychoactive drugs.

2. Histamine receptor blockade with drugs such

as antipsychotics and tricyclic
antidepressants
is associated with common side effects of these
drugs such as sedation.
 Acetylcholine (Ach)
Acetylcholine (Ach), a quaternary amine, is the transmitter used
by nerve–skeleton–muscle junctions.
1.Degeneration of cholinergic neurons is associated with
Alzheimer’s disease, Down’s syndrome, and movement and
sleep disorders.

2. Cholinergic neurons synthesize Ach from acetyl coenzyme A

and choline using the enzyme choline acetyltransferase.

3. Acetylcholinesterase (AchE) breaks Ach down into choline and

acetate.
 Acetylcholine (Ach)
Blocking the action of AchE with drugs such as Donepezil (Aricept),
Rivastigmine (Exelon), and Galantamine (Reminyl) may delay the
progression of Alzheimer’s disease but cannot reverse the function
already lost.

4. Blockade of muscarinic Ach receptors with drugs such as

antipsychotics and tricyclic antidepressants results in the classic
“anticholinergic” adverse effects seen with the use of these drugs,
including dry mouth, blurred vision, urinary hesitancy, and
constipation.
Use of these agents can also result in central anticholinergic effects
such as confusion and memory problems.
5. Anticholinergic agents are commonly used to treat the Parkinson
-like symptoms caused by antipsychotic agents
 AMINO ACID
NEUROTRANSMITTERS
These neurotransmitters are involved in
most synapses in the brain and include:
• Glutamate,
•Y-aminobutyric acid (GABA),
•Glycine.
 Glutamate
Glutamate is an excitatory neurotransmitter that contributes to
the pathophysiology of neurodegenerative illnesses such as
Alzheimer’s disease and schizophrenia.

a.The mechanism of this association involves activation of the

glutamate receptor N-methyl-d-aspartate (NMDA) by sustained
elevation of glutamate.

b. Such activation results in calcium ions entering neurons

leading to nerve cell degeneration and death through
excitotoxicity.

c. Memantine (Namenda), an NMDA receptor antagonist,

ultimately blocks this influx of calcium and is indicated to
patients with moderate to severe Alzheimer’s disease.
 GABA
• GABA is the principal inhibitory neurotransmitter in the CNS. It is
synthesized from glutamate by the enzyme glutamic acid
decarboxylase, which needs vitamin B6 (pyridoxin e) as a co factor.

• GABA is closely involved in the action of antianxiety agents such as

benzodiazepines (e.g.,diazepam [Valium]) and barbiturates (e.g.,
secobarbital [Seconal]).

• Benzodiazepines and barbiturates increase the affinity of GABA or

its GABA A-binding site, allowing more chloride to enter the
neuron.

• The chloride-laden neurons become hyperpolarized and inhibited,

decreasing neuronal firing and ultimately decreasing anxiety.

• Anticonvulsants also potentiate the activity of GABA.

 Glycine
• Glycine is an inhibitory neurotransmitter
found primarily in the spinal cord.

• Glycine works on its own and as a regulator of

glutamate activity.
 NEUROPEPTIDES
• Endogenous opioids such as enkephalins,
endorphins, dynorphins, and endomorphins
are produced by the brain itself .

• They act to decrease pain and anxiety and

have a role in addiction and mood.
Aging, Death, and Bereavement
 AGING
• Gerontology, the study of aging, and geriatrics, the care of aging
people, have become important medical field.

• Geriatricians typically manage rather than cure the chronic

illness of aging such as hypertension, cancer, and diabetes.
• A major aim of geriatrics is to keep elderly patients mobile and
active.

Because fractures (e.g., of the hip) are more likely than chronic
illness to cause loss of mobility leading to disability and death in
the elderly, preventing falls and prevention and management of
osteoporosis are important foci in management.
 Somatic and neurologic changes during aging
• Strength and physical health gradually decline.
• This decline shows great variability but commonly includes
not only osteoporosis but also:
• Impaired vision,
• Hearing,
• Immune responses;
• Decreased muscle mass and strength;
• Decreased renal, pulmonary, and gastrointestinal function;
• Reduced bladder control;
• Decreased responsiveness to changes in ambient
temperature.
 Changes in the brain occur with aging.
• These changes include decreased brain weight, enlarged ventricles
and decreased cerebral blood flow.

• Amyloid (senile) plaques and neurofibrillary tangles are present in

the normally aging brain but to a lesser extent than in
neurocognitive disorder due to Alzheimer’s disease.

• Neurochemical changes that occur in aging include decreased

availability of neurotransmitters such as norepinephrine,
dopamine, γ-aminobutyric acid, and acetylcholine; increased
availability of monoamine oxidase; and decreased responsiveness
of neurotransmitter receptors.

These changes can be associated with psychiatric symptoms such as

depression and anxiety.
 Cognitive changes
1. Although learning speed may decrease, in the
absence of brain disease, intelligence remains
approximately the same throughout life.

2. Some memory problems may occur in normal aging

(e.g., the patient may forget the name of a new
acquaintance).

However, these problems do not interfere with the

patient’s functioning or ability to live independently.
 Psychopathology and related
problems
Depression is the most common psychiatric disorder in the elderly.
Suicide is more common in the elderly than in the general
population .
•Factors associated with depression in the elderly include loss of
spouse, other family members, and friends; decreased social
status; and decline of health.
•Depression may mimic and thus be misdiagnosed as Alzheimer’s
disease.
•This misdiagnosed disorder is referred to as pseudodementia
because it often is associated with memory loss and cognitive
problems.
•Depression can be managed successfully using supportive
psychotherapy in conjunction with pharmacotherapy or
electroconvulsive therapy.
•Sleep patterns change, resulting in loss of sleep, poor sleep
quality, or both.
 Psychopathology and related problems cont’
• Anxiety and fearfulness may be associated with realistic fear-
inducing situations (e.g.,worries about developing a physical
illness or falling and breaking a bone).

• Alcohol-related disorders are often unidentified but are present

in 10%–15% of the geriatric population.

• Psychoactive agents may produce different effects in the elderly

than in younger patients. For example, using antihistamines
such as diphenhydramine as sleep agents should be avoided
because they may cause delirium in elderly patients.

• For a realistic picture of the functioning level of elderly patients,

the physician should ideally evaluate patients in familiar
surroundings, such as their own homes..
 STAGES OF DYING AND DEATH
• According to Dr. Elizabeth Kübler-Ross, the
process of dying involves five stages: denial,
anger, bargaining, depression, and
acceptance.
• The stages usually occur in the following order
but also may be present simultaneously or in
another order.
 STAGES OF DYING AND DEATH
Denial. The patient refuses to believe that he or she is dying. (“The
laboratory made an error.”)
Anger. The patient may become angry at the physician and hospital
staff. (“It is your fault that I am dying. You should have checked on
me weekly.”) Physicians must learn not to take such comments
personally.
Bargaining. The patient may try to strike a bargain with God or
some higher being. (“I will give half of my money to charity if I can
get rid of this disease.”)
Depression. The patient becomes preoccupied with death and may
become emotionally detached. (“I feel so distant from others and
so hopeless.”) Some people become “stuck” in this stage and may
be diagnosed with a complicated grief reaction.
Acceptance. The patient is calm and accepts his or her fate. (“I am
ready to go now.”)
 BEREAVEMENT (NORMAL GRIEF) VERSUS COMPLICATED
BEREAVEMENT (DEPRESSION)

• After the loss of a loved one, there is a normal

grief reaction.
• This reaction also occurs with other losses,
such as loss of a body part, or, or younger
people, with a miscarriage or abortion.
• A normal grief reaction must be distinguished
from a complicated grief reaction , which is
often pathologic.
 Characteristics of normal grief (bereavement)
1. Grief is characterized initially by shock and denial.

2. In normal grief , the bereaved may experience an illusion that

the deceased person is physically present.

3. Normal grief generally subsides after 1–2 years, although

some features may continue longer.

Even after they have subsided, symptoms may return on

holidays or special occasions (the “anniversary reaction”).

4. The mortality rate is high in the first year of bereavement.

 Physician’s response to death
• The major responsibility of the physician is to give support to the
dying patient and the patient’s family.

• Generally, physicians make the patient completely aware of the

diagnosis and prognosis.

• However, a physician should follow the patient’s lead as to how

much he or she wants to know about the condition. With the
patient’s permission, the physician may tell the family the diagnosis
and other details of the illness.

• Physicians often feel a sense of failure at not preventing the death

of a patient. They may deal with this sense by becoming
emotionally detached from the patient. Such detachment can
preclude helping the patient and family through this important
transition.
• Thank you