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A BMS 381 - Developmental neurobiology > Drug addiction > Flashcards

Drug addiction Flashcards

1
Q

What is the worst drug of addiction in western society?

A

Alcohol

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2
Q

Where do drugs exert their effects?

A

On different receptors of the brain

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3
Q 
What R do:
- Opiates 
- Nicotine
- Cannabis
- Alcohol
Effect??
A

Opiates - opiate R

Nicotine - ACh R

Cannabis - Cannaboid

Alcohol:

  • SEVERAL different receptors
  • Main ones being: GABA and NDMA
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4
Q

What do drugs of abuse act secondarily through?

A

Dopamine release from the mesolimbic ‘reward’ system

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5
Q

Where is DA released from in the MLR pathway?

A

FROM: Ventral Tegmental Area neurons

INTO: Frontal cortex and the nucleus accumbens

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6
Q

What is the nucleus accumbens involved in?

A

The REWARD circuit

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7
Q

What are natural rewards?

A

Food
Sex
Social interaction

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8
Q

What are learned rewards?

A

Positive reinforcement to drug addiction

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9
Q

Why are some people more likely to develop an addiction?

A

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

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10
Q

How does genetics influence drug addiction?

A

Determines sensitivity and development of tolerance

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11
Q

What is SENSITIVITY?

A

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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12
Q

What is the DEVELOPMENT of TOLERANCE?

A

Reduction in sensitivity when a drug is REPEATEDLY used over time

(higher amount to achieve the same response)

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13
Q

How can SENSITIVITY and TOLERANCE be studied?

A

Model organisms - drosophila

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14
Q

Why are flies a good model?

A

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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15
Q

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

A
  • Neurological diseases
  • Cancer
  • Developmental disorders
  • Metabolic disorders
  • Cardiovascular disease
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16
Q

Are flies a good model for drug addiction?

A
  • Genes associated with alcohol addiction in humans (GABA, NMDA, dopamine)
  • BUT, no OPIOD/CANNABINOID R in drosophila
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17
Q

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

A

‘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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18
Q

Describe the locomotor velocity profile of flies with ethanol

What is important about this experiment?

A

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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19
Q

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

A

Because BEHAVIOUR is not good for HIGH-THROUGHPUT screening

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20
Q

Describe a second study of flies with ethanol (inebriometer)

A
  • 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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21
Q

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

A

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
22
Q

What can the inebriometer test?

How?

A

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
23
Q

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

A

Can:
- Genetics

Can’t

  • Environment
  • Personality
24
Q

What does ethanol sensitivity have to do with alcoholism?

Why?

A

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
25
Q

What mutant was identified using the inebriometer technique?

Was is the result of this mutant?

A

CHEAPDATE mutant:

Flies with this mutant elute FASTER at every dose of ethanol

26
Q

What gene is mutated in the cheapdate mutant?

A

The amnesiac gene

27
Q

What is the function of amnesiac?

A

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

28
Q

Describe the cAMP pathway

A

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

29
Q

What is CREB?

A

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

30
Q

What does the activity of the cAMP pathway cause?

What happens if there is a mutation in this pathway?

A

A DECREASE in ALCHOL SENSITIVITY

Mutations in different parts of the pathway –> increase in sensitivity

31
Q

What is the cheapdate mutant?

What does it cause

A

Mutant in the neuropeptide of cAMP pathway

INCREASE sensitivity (MET decrease)

32
Q

What rutabaga?

What happens when mutated?

A

Gene that encodes adenylyl cyclase

Mutated –> INCREASE sensitivity (MET decrease)

33
Q

What is DCO?

What happens when mutant?

A

PKA catalytic subunit

Mutated –> INCREASE sensitivity (MET decrease)

34
Q

What is DUNCE?

What happens when mutant?

A

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)

35
Q

How to test the development of tolerance?

What happens in NORMAL flies?

A

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
36
Q

What mutants have a REDUCED tolerance to alcohol?

A

Hangover mutants:

- Tolerance still increases but at a MUCH LESSER extent than WT

37
Q

How were the mutants in the hangover gene created?

Describe this technique

What does this show?

A

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

38
Q

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

What does this suggest?

A

A Zn-finger protein

Suggests the hangover protein to bind to DNA or RNA

39
Q

Where are Zn-finger domains usually found

Function?

A

In TF and other proteins

Bind to nucleic acids (DNA, RNA)

40
Q

What is seen in the mutant using western blotting?

WT?

A

Hangover is ABSENT

WT - Hangover is widely expressed in the BRAIN

41
Q

How does Hangover gene regulate tolerance?

A
  • Encodes an RNA binding protein that binds DUNCE RNA (has nothing to do with sensitivity)
42
Q

How does Hng affect Dunce?

A

INCREASES the amount of transcript when bound to RNA

43
Q

What happens when there is Hng mutant?

A

Less Hng = less dunce = SLOWER cAMP inactivation

44
Q

What does FASTER DEACTIVATION of the cAMP pathway mean?

A

Promotes the development of TOLERANCE

45
Q

What pathway is responsible for sensitivity?

A

Activation of the cAMP/PKA pathway

46
Q

What pathway is responsible for tolerance?

A

Inactivation of the cAMP/PKA pathway

47
Q

What is important about the cAMP pathway?

A

REUSED differently for:

  • Development of the NS
  • Homeostasis
  • Maintaining adult organism
48
Q

How can Hang reveal new mechanisms for potential drug targets?

A
  • Know that Hang is required for tolerance development
  • Know that tolerance leads to addiction
  • Can target pathway –> prevent alcoholism??
49
Q

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

A

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

50
Q

How does the clock impact on alcoholism?

A

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

A BMS 381 - Developmental neurobiology (17 decks)

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