Fear and anxiety disorders and drugs

Question 1

What were the four humors of hippocratic medicine and their personality types?

Answer 1

• Water, black bile (melancholy): introspective
• Fire, yellow bile (choleric): violent
• Air, blood (sanguine, happy): amorous
• Earth, phlegm (phlegmatic, droopy): sluggish

Question 2

What fumes mad hatters mad?

Answer 2

Mercury, used to cure the hats.

Question 3

What is psychosis?

Break down schizophrenia

Answer 3

general lack of contact with reality

Schizein = split
Phren = mind

Question 4

What percent of the population has schizophrenia?

Answer 4

2%, but accounts for half of all admissions to mental hospitals

Rarely emerges after age 45

Question 5

What are the four main types of schizophrenia?

Answer 5

• Disorganized: incoherence, grossly dissorganized behaviour, bizarre thinking, and flat or inappropriate emotions
• Catatonic: marked by stupor, unresponsiveness, posturing and mutism
• Paranoid: Preoccupation with delusions, hallucinations, grandeur or persecuation
• Undifferentiated: Any type of schizophrenia that does not have paranoid, catatonic or disorganized features or symptoms

Question 6

What type of environment stresses are associated with schizophrenia?

Answer 6

Psychological trauma: Often caused by violence, abuse or neglect.

Disturbed family environment: stressful or unhealthy family relationships, communication patterns and emotional atmosphere

Deviant communication patterns: cause guilt, anxiety anger confusion and turmoil

Stress-vulnerability hypothesis: combination of environmental stress and inhered susceptibility cause schizophrenic disorders

Question 7

List three biological bases of schizophrenia

Answer 7

• Genetics
• Neurotransmitters ( excessive dopamine activity)
• Brain damage (enlarged ventricles, especially in males)

Question 8

What is concordance? Discordance?

Answer 8

If two twins suffer from schizophrenia, they are concordant for the disease.

If only one member of the pair suffer from schizophrenia, they are discordant for the disease.

The concordance rate is 50% for identical twins, suggesting a genetic basis.

No single gene causes it or increases susceptibility, but there have been a few identified as abnormal in schizophrenics.

Question 9

Is there a genetic basis to schizophrenia?

Answer 9

Yes

No single gene causes it or increases susceptibility, but there have been a few identified as abnormal in schizophrenics.

Mutated DISC1 transgenic mice develop enlarged lateral ventricles

Question 10

How is parent age associated with susceptibility for schizophrenia?

Answer 10

Paternal age may be a factor, as older fathers are more likely to have a child with schizophrenia

Question 11

How do eye movements of schizophrenics differ from control subjects?

Answer 11

Schizophrenic eye movement is more jerky

Question 12

How does ventricle size affect schizophrenic patients?

Answer 12

More enlarged ventricles predict a poorer response to drug treatment.

Question 13

How do the hippocampus and amygdala of schizophrenics differ from control subjects?

Answer 13

They are smaller

Pyramidal cells of the hippocampus have a disorganized arrangement, this probably occurs during early cell development.

Question 14

How does white/gray matter differ in schizophrenics?

Answer 14

More white matter (thicker corpus callosum)

Loss of gray matter in the frontal lobes and less metabolic activity in this area

Question 15

How does schizophrenia affect the Wisconsin Card Sorting Task: SET SHIFT?

Answer 15

Patients with damage in the lateral prefrontal cortex have difficulty with the WCST.

On each trial, the subjects place the top card on the deck under one of the four target cards.

The experimenter indicates whether the response is correct or incorrect, allowing the subject to learn the sorting rule by trial and error. The sorting rule changes whenever the subject makes ten consecutive correct responses.

Question 16

What are three mechanisms available for presynaptic drug targeting?

Postsynaptic?

Answer 16

Presynaptic

• Transmitter production
• Transmitter release
• Transmitter clearance

Postsynaptic

• Block/activate receptors
• Regulate number of receptors
• Modulate intracellular signalling.

Question 17

Give six categories of medications for mood disorders

Answer 17

• MAO inhibitor
• Tricyclic antidepressants
• SSRIs
• Mood stabilizers (eg. lithium)
• Anticonvulsants
• Antipsychotics

Question 18

What is the efficacy or intrinsic activity of a drug?

Answer 18

The ability of the bound ligand to activate the receptor

Question 19

What is the therapeutic index of a drug?

Answer 19

The separation between the effective dose and a toxic effect.

Question 20

What is amphetamine psychosis?

Answer 20

Repeated use of amphetamines leads to delusions, auditory hallucinations, paranoia and other symptoms that resemble schizophrenia.

Presumably through upregulation of dopamine

Question 21

Abnormalities in what part of the dopaminergic system are associated with schizophrenia?

Answer 21

The VTA and its projections to limbic areas and the cortex

Question 22

Describe antipsychotic drugs

Answer 22

• Neuroleptics block Dopamine D2 receptors and can treat amphetamine psychosis and schizophrenia

Question 23

Give 5 problems with the dopamine hypothesis

Answer 23

• Schizophrenics have normal DA metabolite levels
• Drugs block D2 receptors much faster (immediately) than symptoms are reduced (takes 2-3 weeks)
• Some patients show no change
• Atypical neuroleptics, like clozapine, block 5-HT2 receptors as well as D2 receptors
• Other effective neuroleptics don’t support the dopamine hypothesis, some actually increase dopamine levels in the frontal cortex

Question 24

What is nutrigenomics?

Answer 24

The science of nutrigenomics seeks to provide a molecular understanding for how common dietary chemicals (ie. nutrients) affect health by altering the expression and/or conformational structures of an individuals genetic makeup

Question 25

What is the most compelling evidence for the interaction of nutrients and DNA methylation?

Answer 25

Dietary factors involved in one-carbon metabolism because they influence the supply of methyl groups, and therefore the biochemical pathways of methylation processes.

Question 26

List some nutrients that might affect DNA methylation

Answer 26

• B-vitamins
• Dietary methyl donor nutrients (eg. methionine, choline, betaine, serine)
• Micronutrients (retinoic acid, zinc, selenium)
• Bioactive food compounds (genistein, tea, polyphenols)

Question 27

What is the mismatch hypothesis of disease?

Answer 27

A high degree of individual adaptive plasticity is mediated by environmental influences throughout lifespan on the epigenetic signature. In turn, epigenetic modulations (predominantly) early in life may permanently alter gene expression and can therefore program the individual to be well-adapted to the expected environment.

In other words, epigenetic modulation decreases as we age, but environment continuously adapts us for optimal fitness and survival.

However, adaptive mechanisms can also have an inherent risk of maladaption if the prediction about the environment turns out not to be correct

Question 28

Describe nutritional control of reproductive status in honeybees via DNA methylation

Answer 28

• Honeybees grow to be either queens or workers, depending on whether they are fed royal jelly or beebread
• All bees are genetically identical, but honeybees fed pure royal jelly are markedly different from workers
• Royal jelly silences Dnmt3, specific genes are activated supporting fertil queen morphology
• When Dnmt3 is active in bee larvae, the queen genes are epigeneticaly silenced and the larvae develop into the default ‘sterile worker’ variety

Question 29

How does maternal diet effect epigenetic gene regulation of tail kinking in mice?

Answer 29

• Supplementing diet with methyl donors before and during pregnancy:
• Increased methylation at axin fused (Axin-Fu)
• Silenced cryptic promoter expression
• Decreased the incidence of tail kinking in Axin-Ful+ offspring

The hypermethylation is tail-specific, suggesting a mid-gestation effect

Therefore influences are not limited to early embryonic development

Question 30

Describe control of phenotype and health in agouti mice by maternal diet and DNA methylation

Answer 30

Genetically identical mice were given a methyl donor depleted diet: cofactors folic acid, vitamin B12, choline chloride and anhydrous betaine, also BPA

The altered (methyl donor depleted) diet led to agouti gene (A-vy) activation in some offspring, leading to obesity, diabetes and an increased risk of cancer.

A-vy contains IAP insertion (retrovirus-like mobile element) that contains a promoter expressed in all cells, and promotes yellow pigmentation on black hair shafts.

Question 31

What percent of the human chromosomal DNA is transposable?

What is the consequence of this?

How does the body deal with this?

Answer 31

42-45%

Middle repetitive DNA - eg. short or long interspersed sequence element (LINE and SINE) repeats

These contribute to spontaneous mutation, genetic rearrangements, horizontal transfer of genetic material and aid speciation and genomic change (in bacteria, transposons are often associated with antibiotic resistance genes)

Most transposable elements in the mammalian genome are normally silenced by CpG methylation

Question 32

How are mobile genetic elements transposed?

Answer 32

Use of an RNA intermediate

• Element is transcribed
• Reverse transcriptase produces a double-stranged DNA copy from mRNA transcript
• Intergrase mediates insertion at another site.

Question 33

How are transposable elements susceptible to nutritional influences during early development?

Answer 33

Epigenetic metastability of transposable elements regions

Question 34

What is a pseudo-agouti mouse?

Answer 34

Silenced agouti gene in agouti mouse due to methylation. Mouse is healthy and almost all brown.

Question 35

Feeding a pregnant Avy/a mouse with methyl-rich supplements does what? What type of offspring does she have?

Answer 35

Represses the ectopic Avy promoter.

Offspring of diet supplemented mice have brown coat colour and methylated IA (healthy!)

When the LTR is suppressed in Avy mice, expression of the agouti gene is regulated by its normal promoters, is cyclic and occurs only in the hair
follicles.

Question 36

What is the methyl donor diet?

Answer 36

• Cofactors folic acid
• Vitamin B12
• Choline chloride
• Anhydrous betaine

Question 37

What happened to agouti mice when they were given BPA and genistein (methy promotion) supplementation?

Answer 37

Distribution of 50/50 agouti phenotype, same as control diet.

Question 38

Describe the Hertfordshire Cohort Study (HSC) that linked early growth and death from heart disease.

What did Barker propose was the roots of the effects he found?

Answer 38

Relation between low birth weight (poor growth while in the womb) and poor growth in early childhood and risk for coronary heart disease later in life.

The deprived population had high rates of infant mortality and cardiovascular disease.

Mother who had a high intake of carbohydrates in early pregnancy and a low intake of dairy protein in late pregnancy tended to have infants that were thin at birth
- Mothers who themselves had a low birth weight also tended to have thin infants, each 100 g increase in maternal birth weight was associated with 24-27 g increase in infant birth weight

These associations may reflect constraints on placental development imposed by a woman’s nutrition in pregnancy and during her own intrauterine life
- Barker proposed the roots of cardiovascular disease lay in the effects of poverty on the mother resulting in undernutrition in fetal life and early infancy.

Question 39

Give the four main developmental origins for the Barker Hypothesis (Hertfordshire cohort study)

Answer 39

• Impaired intrauterine growth and development is associated with several of the major disesases of later life (inc. CV disease and major psychiatric disorders)
• These diseases are consequences of programming, early event at sensitive period had permanent effects of structure, physiology and metabolism
• Strong indicators that fetal adaptations invoked when maternal-placental nutrient supply fails to match the fetal nutrient demand
• Early epidemiologic studies pointed to long-term effects of an adverse intrauterine environment based on strategy of following up men and women in middle and late life whose body measurements at birth had been recorded

In a nutshell, adverse intrauterine events permanently programmed postnatal structure, function and homeostasis for fetal survival with increased risk of adult disease.

Question 40

Give further evidence for Barkers theory from the Hertfordshire study.

Answer 40

Dutch famine

• Fertility decreased and maternal weight fell during pregnancy
• High infant mortality
• Offspring had low birth weight, their offspring also had low birth weight
• Decreased intracranial volume
• Increaed risk of neural tube defects, CV disease, cancer, diabetes, depression (women) and schizophrenia (men)
• Babies that had been breast fed had less diabetes than bottle fed babies

Question 41

Why could mothers not breastfeed during the Dutch famine?

Answer 41

Insufficient glandular tissue (IGT)

This caused diabetes in babies

Question 42

Give epigenetic evidence from the Dutch famine for increased risk of chronic disease in adulthood

Answer 42

60 years later

• Differential methylation in several genes for: immunity, food intake, cancer, fat metabolism,
• Hypomethylation of the IGF2 DMR, a maternally imprinted gene implicated in growth and developent, in offspring exposed during the peri-conceptional period, relative to unexposed siblings.

Imprinting results in parent-of-origin dependent monoallelic expression

Question 43

Describe the imprinted brain theory derived from Barker’s findings, the Dutch famine and the Great Chinese Famine

Answer 43

• Imprinted genes are highly expressed, not only in placenta, but also in the brain, suggesting that the expression of these genes play an important role in brain development and behaviour.

When is out of balance you get disease, such as schizophrenia (undergrowth) or autism (overgrowth)

We need to identify the genes imprinted in humans and their epigenetically modified regulatory elements (the imprintome)

Question 44

Paternally expressed genes function mainly in the ___ parts of the brain

Maternally expressed genes are found principally in the ___

Answer 44

Paternally expressed genes function mainly in the limbic (ancient) parts of the brain

Maternally expressed genes are found principally in the neocortex