Epigenetic regulation of addiction Flashcards
What is drug addiction? (3)
- 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
What are the key transcription factors involved in synaptic plasticity? (3)
- CREB
- Delta FOSB (splice isoform of Cfos)
- NK-kappaB
What are the key chromatin modifiers involved in synaptic plasticity? (4)
- Histone acetyltransferases
- Histone deacetylases
- Histone methyltransferases
- Histone demethylases
How does cocaine work?
Prevents dopamine re-uptake by binding to the dopamine transporter (DAT) which enhances the stimulatory effect of dopamine on target neurones
Which neural circuit is most important in addiction?
Mesolimbic reward circuit
What makes up the mesolimbic reward circuit? (3)
- 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
What is the VTA?
Ventral tegmental area
What is the NAc?
Nucleus accumbens
What is driven by NAc activation?
Reward seeking behaviour
How is reward seeking behaviour usually kept under control?
Negative feedback signals from NAc to VTA to reflect satiety
What is the effect of cocaine on the mesolimbic reward system? (3)
- 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
What are examples of genes that are expressed in response to synaptic signalling? (3)
- Cfos
- Bdnf
- Cdk5
What is the effect of cocaine administration in the NAc on genes that are activated by synaptic activity?
Increased transcription and acetylation
What is the effect of cocaine on methylation in the NAc?
H3K9me2 is inhibited by cocaine exposure
What is the function of H3K9 methylation?
Gene repression
How does cocaine inhibit H3K9me2? (2)
- 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
What is the impact of overexpression of G9a in the NAc? (2)
- Reduces cocaine-induced reward-seeking behaviour in the conditioned place preference (CPP) test
- Attenuates cocaine-induced dendritic spine formation in the NAc
What is the CPP test? (4)
- 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
What are the roles of histone modifications in cocaine-regulated gene transcription? (2)
- Histone acetylation primes and/or activates neuronal gene transcription in the NAc
- H3K9 methylation (G9a) represses neuronal gene transcription in the NAc
What is a potential way to treat addiction?
Stimulate G9a activity
How is alcohol linked to epigenetic mechanisms? (2)
- Ethanol metabolism in the liver produces acetate
- Acetate is converted to acetyl-CoA in the brain by ACSS2
What is ACSS2?
Acetyl-CoA synthetase 2
What is the function of ACSS2? (2)
- 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
What is the effect of alcohol in the brain? (2)
- Causes acetylation of specific neural activity-regulated genes which requires ACSS2
- Results in rewiring of circuits in the hippocampus (learning and memory)
