Drug addiction Flashcards by Karla Littleford

What is the worst drug of addiction in western society?

Alcohol

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Where do drugs exert their effects?

On different receptors of the brain

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What R do:
- Opiates 
- Nicotine
- Cannabis
- Alcohol
Effect??

Opiates - opiate R

Nicotine - ACh R

Cannabis - Cannaboid

Alcohol:

SEVERAL different receptors
Main ones being: GABA and NDMA

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What do drugs of abuse act secondarily through?

Dopamine release from the mesolimbic ‘reward’ system

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Where is DA released from in the MLR pathway?

FROM: Ventral Tegmental Area neurons

INTO: Frontal cortex and the nucleus accumbens

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What is the nucleus accumbens involved in?

The REWARD circuit

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What are natural rewards?

Food
Sex
Social interaction

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What are learned rewards?

Positive reinforcement to drug addiction

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Why are some people more likely to develop an addiction?

1) GENETICS
2) SOCIAL ENVIRONMENT
3) PERSONALITY/PERSONAL HISTORY

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How does genetics influence drug addiction?

Determines sensitivity and development of tolerance

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What is SENSITIVITY?

The INABILITY to tolerate the adverse effects of a drug (how much of a drug can be consumed before has an effect)

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What is the DEVELOPMENT of TOLERANCE?

Reduction in sensitivity when a drug is REPEATEDLY used over time

(higher amount to achieve the same response)

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How can SENSITIVITY and TOLERANCE be studied?

Model organisms - drosophila

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Why are flies a good model?

FAST generation time

~50% of drosophila genes in humans

~75% of genes implicated in disease are present in drosophila

Simple but exhibit COMPLEX behaviours that can be used to IDENTIFY GENES on a whole genome level

There are mutant and transgenic flies for almost EVERY gene in the drosophila genome

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What categories of genes are well suited to drosophila analysis? (5)

Neurological diseases
Cancer
Developmental disorders
Metabolic disorders
Cardiovascular disease

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Are flies a good model for drug addiction?

Genes associated with alcohol addiction in humans (GABA, NMDA, dopamine)
BUT, no OPIOD/CANNABINOID R in drosophila

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Describe the study of flies with ethanol (booz-o-mat)

‘booz-o-mat’:

Flies in chamber
Humidified air (control) OR air with ethanol
Record the behaviour of flies over time

Results:

Flies move more ACTIVELY when ethanol is applied
Over time - ethanol treatment causes the flies to fall over

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Describe the locomotor velocity profile of flies with ethanol

What is important about this experiment?

BEHAVIOUR over time:
- Startle response (sharp increase and decrease again)

Increase in locomotion
Sedation

SAME effects at the same concentrations as in HUMANS

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Why must different technique be used to determine the effects of ethanol on drosophila?

Because BEHAVIOUR is not good for HIGH-THROUGHPUT screening

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Describe a second study of flies with ethanol (inebriometer)

Tube with series of steps

Flies into chamber from the top:
- If sober/active –> crawl up the steps and stay in the chamber

If drunk to a state of unconsciousness –> flies fall over and fall out of the tube
Measure ELUTION time for flies

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What is the elution time for flies and what does it measure?

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How quickly/slowly the ethanol acts on the flies to cause them to become unconscious

Measures the SENSITIVITY to ethanol:

Sensitive - elute faster
Resistant - elute slower

What can the inebriometer test?

How?

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GENETICS
Test different flies with different genetic variations and COMPARE sensitivity to ethanol (known genes??)

OR IDENTIFY GENES responsible for SENSITIVITY DIFFERENCES (find genes??)

Irradiate flies –> induce spontaneous mutations in the genome
Screen mutants (pick flies that elute first and last/high and low sensitivity)
IDENTIFY the gene mutated

What can/cant be studied using flies in relation to addiction?

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Can:
- Genetics

Can’t

Environment
Personality

What does ethanol sensitivity have to do with alcoholism?

Why?

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Low sensitivity (high resistance) to modest doses are associated with a SIGNIFICANT increase in the risk of alcoholism

Doses of alcohol are higher in order to get the SAME effect
Increases the chances a person will drink more heavily and often

What mutant was identified using the inebriometer technique? Was is the result of this mutant?

CHEAPDATE mutant: Flies with this mutant elute FASTER at every dose of ethanol

What gene is mutated in the cheapdate mutant?

The amnesiac gene

What is the function of amnesiac?

NEUROPEPTIDE that ACTIVATES the cAMP pathway to change the transcription of a range of genes to result in a DECREASE in ALCHOL SENSITIVITY

Describe the cAMP pathway

1) Peptide binds to a G protein receptor 2) Alpha subunit activates ADENYLYL CYCLASE --> converts ATP into cAMP 3) cAMP ACTIVATES PKA 4) Activated PKA translocates into the nucleus and binds CREB

What is CREB?

cAMP response element binding protein (a TF) that regulates the transcription (increase/decrease) of a range of genes

What does the activity of the cAMP pathway cause? What happens if there is a mutation in this pathway?

A DECREASE in ALCHOL SENSITIVITY Mutations in different parts of the pathway --> increase in sensitivity

What is the cheapdate mutant? What does it cause

Mutant in the neuropeptide of cAMP pathway INCREASE sensitivity (MET decrease)

What rutabaga? What happens when mutated?

Gene that encodes adenylyl cyclase Mutated --> INCREASE sensitivity (MET decrease)

What is DCO? What happens when mutant?

PKA catalytic subunit Mutated --> INCREASE sensitivity (MET decrease)

What is DUNCE? What happens when mutant?

cAMP phosphodiesterase (inactivates cAMP by converting it to ATP) Mutant - DOESN'T decrease sensitivity INSTEAD - INACTIVATES the pathway (doesn't matter if mutant- activity of the pathway is what matters)

How to test the development of tolerance? What happens in NORMAL flies?

Using the inebriometer but with REPEATED experiments on the SAME FLIES: - Apply ethanol to the flies several times to determine if ALTERS when the flies elute - Screened for mutants In NORMAL flies: - Less sensitive to alcohol on second exposure - Elute later (need higher dose) - Mean elution time increases - -> First step to addiction

What mutants have a REDUCED tolerance to alcohol?

Hangover mutants: | - Tolerance still increases but at a MUCH LESSER extent than WT

How were the mutants in the hangover gene created? Describe this technique What does this show?

Using MOBILE ELEMENTS: - Insert mobile element into gene --> interferes with transcription of the gene - Can REMOVE the mobile element from the genome--> normal function of the gene is experimentally restored Shows: - Normal development of tolerance when the tolerance when the gene is removed --> mutant phenotype is due to a miss-function of this particular gene

What does the hangover gene encode as part of their DNA sequence What does this suggest?

A Zn-finger protein Suggests the hangover protein to bind to DNA or RNA

Where are Zn-finger domains usually found Function?

In TF and other proteins Bind to nucleic acids (DNA, RNA)

What is seen in the mutant using western blotting? WT?

Hangover is ABSENT WT - Hangover is widely expressed in the BRAIN

How does Hangover gene regulate tolerance?

- Encodes an RNA binding protein that binds DUNCE RNA (has nothing to do with sensitivity)

How does Hng affect Dunce?

INCREASES the amount of transcript when bound to RNA

What happens when there is Hng mutant?

Less Hng = less dunce = SLOWER cAMP inactivation

What does FASTER DEACTIVATION of the cAMP pathway mean?

Promotes the development of TOLERANCE

What pathway is responsible for sensitivity?

Activation of the cAMP/PKA pathway

What pathway is responsible for tolerance?

Inactivation of the cAMP/PKA pathway

What is important about the cAMP pathway?

REUSED differently for: - Development of the NS - Homeostasis - Maintaining adult organism

How can Hang reveal new mechanisms for potential drug targets?

- Know that Hang is required for tolerance development - Know that tolerance leads to addiction - Can target pathway --> prevent alcoholism??

As well as the mesolimbic pathway, what can alcohol exposure impact on?

Chronic exposure --> overall increase of HPA (hypothalamic-pituitary-adrenal axis) activity (increases glucocorticoids throughout the day)

How does the clock impact on alcoholism?

1) Allelic variation in clock genes --> association with high vs low alcohol intake BUT correlation doesn't mean causation 2) Chronic mild stress - affects expression of clock genes - -> Linked to chances of high alcohol intake

Drug addiction Flashcards

(50 cards)