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L3 Epigenetics > Epigenetic regulation of addiction > Flashcards

Epigenetic regulation of addiction Flashcards

1
Q

What is drug addiction? (3)

A
  • A form of maladaptive neural plasticity in vulnerable individuals produced as a response to exposure to a drug of abuse which creates craving and a compulsion to consume the drug
  • Vulnerability is determined by genetic and non-genetic factors
  • Once established, addiction can drive long-term behavioural abnormalities with risks to health and wellbeing
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2
Q

What are the key transcription factors involved in synaptic plasticity? (3)

A
  • CREB
  • Delta FOSB (splice isoform of Cfos)
  • NK-kappaB
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3
Q

What are the key chromatin modifiers involved in synaptic plasticity? (4)

A
  • Histone acetyltransferases
  • Histone deacetylases
  • Histone methyltransferases
  • Histone demethylases
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4
Q

How does cocaine work?

A

Prevents dopamine re-uptake by binding to the dopamine transporter (DAT) which enhances the stimulatory effect of dopamine on target neurones

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5
Q

Which neural circuit is most important in addiction?

A

Mesolimbic reward circuit

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6
Q

What makes up the mesolimbic reward circuit? (3)

A
  • Dopaminergic neurones from the VTA stimulate limbic targets and the NAc
  • Glutamatergic neurons from limbic targets stimulate the NAc
  • I.e. dopamine and glutamate signals converge on the NAc
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7
Q

What is the VTA?

A

Ventral tegmental area

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8
Q

What is the NAc?

A

Nucleus accumbens

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9
Q

What is driven by NAc activation?

A

Reward seeking behaviour

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10
Q

How is reward seeking behaviour usually kept under control?

A

Negative feedback signals from NAc to VTA to reflect satiety

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11
Q

What is the effect of cocaine on the mesolimbic reward system? (3)

A
  • Blocks dopamine reuptake so potentiates the dopaminergic signals from the VTA to the NAc which causes increased reward seeking
  • Negative feedback system from the NAc becomes overwhelmed and stops working properly
  • Results in deleterious positive feedback going through the mesolimbic reward system with continued cocaine administration
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12
Q

What are examples of genes that are expressed in response to synaptic signalling? (3)

A
  • Cfos
  • Bdnf
  • Cdk5
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13
Q

What is the effect of cocaine administration in the NAc on genes that are activated by synaptic activity?

A

Increased transcription and acetylation

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14
Q

What is the effect of cocaine on methylation in the NAc?

A

H3K9me2 is inhibited by cocaine exposure

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15
Q

What is the function of H3K9 methylation?

A

Gene repression

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16
Q

How does cocaine inhibit H3K9me2? (2)

A
  • Specifically suppresses transcription of H3K9me2 methyltransferases G9a and GLP
  • Potentiation of dopaminergic signalling in the NAc by inhibiting methylation of target genes which allows their acetylation and transcription
17
Q

What is the impact of overexpression of G9a in the NAc? (2)

A
  • Reduces cocaine-induced reward-seeking behaviour in the conditioned place preference (CPP) test
  • Attenuates cocaine-induced dendritic spine formation in the NAc
18
Q

What is the CPP test? (4)

A
  • Put a mouse in a 2 chambered enclosure
  • On odd days put it in 1 chamber with drug in the water, on even days put it in the other chamber with saline in the water
  • After conditioning period give the mouse the choice of chamber
  • Reward-seeking behaviour indicated by preference for the chamber with the drug
19
Q

What are the roles of histone modifications in cocaine-regulated gene transcription? (2)

A
  • Histone acetylation primes and/or activates neuronal gene transcription in the NAc
  • H3K9 methylation (G9a) represses neuronal gene transcription in the NAc
20
Q

What is a potential way to treat addiction?

A

Stimulate G9a activity

21
Q

How is alcohol linked to epigenetic mechanisms? (2)

A
  • Ethanol metabolism in the liver produces acetate
  • Acetate is converted to acetyl-CoA in the brain by ACSS2
22
Q

What is ACSS2?

A

Acetyl-CoA synthetase 2

23
Q

What is the function of ACSS2? (2)

A
  • Localised to chromatin with acetylated core histones
  • Provides a localised source of acetyl-CoA (substrate) to histone acetyltransferases such as CBP to promote immediate-early gene transcription in synapses
24
Q

What is the effect of alcohol in the brain? (2)

A
  • Causes acetylation of specific neural activity-regulated genes which requires ACSS2
  • Results in rewiring of circuits in the hippocampus (learning and memory)
25
Q

What is the impact of ACSS2 knockdown on alcohol-induced reward seeking in the CPP test? (2)

A
  • WT animals show preference for alcohol compartment
  • Knockdowns show no preference

L3 Epigenetics (15 decks)

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