EPIGENETIC REGULATION OF COCAINE ADDICTION
EPIGENETIC REGULATION OF COCAINE ADDICTION Arturo Martínez Martínez
Degree in Genetics. Universitat Autònoma de Barcelona. 2014-2015.
Tutor: Antonio Armario García
EPIGENETIC MECHANISMS
NEUROBIOLOGY OF ADDICTION
CONCLUSIONS
Addiction is defined as a chronic, relapsing brain disease that is characterized by compulsive drug seeking and use, despite harmful consequences. The addictive phenotype can persist for the length of an individual’s life, suggesting that drugs of abuse may induce long-lasting changes in the brain.
•The exposition to cocaine triggers mechanisms of epigenetic regulation involved in the modulation of synaptic plasticity and
physiological adaptation in the mesolimbic dopaminergic system. These alterations correlate with escalating cocaine intake.
• Structural plasticity in NAc plays an important role in voluntary decision making towards drug intake.
• Chronic cocaine exposure causes molecular adaptations with contrary consequences, establishing a balance that can contribute more
or less strongly to addiction. This effect may depend on several individual factors, such as genetic predisposition.
• Therapeutic implications: HDAC inhibition allows a faster extinction of drug-seeking behavior, also attenuating the probability of relapse.
Figure 1. Cocaine induces molecular adaptations in the mesolimbic dopaminergic
system. Extracted from Rogge & Wood, 2013.
The activation of the
mesolimbic dopaminergic
system produces a reward
signal, related with learning
mechanisms to beneficial
actions. Drugs of abuse can
activate this circuit far more
intensively than natural
rewards, being able to hijack
these learning mechanisms.
Besides, they can induce
molecular adaptations, that
translate into neuroplastic
changes in the mesolimbic
system.
Histone acetylation
DNA methylation miRNAs
Figure 2. Histone acetylation, mediated by HATs and HDACs, can alter
chromatin conformation. Extracted from Rogge & Wood, 2013.
Figure 4. Schematic representation of cytosine methylation. Extracted from
Zakhari, 2013.
Figure 5. miRNAs form a protein complex (RISC) that can inhibit the
expression of target mRNAs. Adapted from Faraoni et al., 2009.
Histone methylation
Figure 3. Histone methylation. Some modifications are marks of heterochromatin
whereas others produce euchromatin. Adapted from Han & Brunet, 2012.
REFERENCES
Day, J. J. & Sweatt, J. D. Epigenetic Treatments for Cognitive
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Faraoni, I., Antonetti, F. R., Cardone, J. & Bonmassar, E. miR-155
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Han, S. & Brunet, A. Histone methylation makes its mark on longevity.
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Rogge, G. A. & Wood, M. A. The Role of Histone Acetylation in
Cocaine-Induced Neural Plasticity and Behavior.
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Zakhari, S. Alcohol metabolism and epigenetics changes. Alcohol
Res. 35, 6–16 (2013).
Histone acetylation Histone methylation
DNA methylation miRNAs
∆FosB Chronic
cocaine
Acute
cocaine
Fos
Cdk5
BDNF
Chronic
cocaine
G9a
Early behavioral response
to the drug
Overexpression of these
factors is related with
increases in dendritic
spine density in nucleus
accumbens (NAc), altering
synaptic plasticity.
Escalating
cocaine
intake
miR-212
SPRED1
MeCP2 BDNF miR-134 Lim
Kinase 1
Raf1 Adenylyl-
ciclase cAMP
Specific
Kinases
CREB
Pathway that contributes
to addiction
Pathway that protects
against addiction
Synaptic
plasticity
Chronic
cocaine
∆FosB
Cocaine-induced
downregulation of G9a
increases dendritic spine
density in NAc as well as
expression of genes
implicated in synaptic activity. Intergenic
elements
Promoter Gene
TGACGATTCGACCGAG
ACTGCTAAGCTGGCTC
CpG island
M M M
M M M 5’
5’ 3’
3’
DNMT3A
MeCP2
BDNF
miR-134
Lim
Kinase 1
Increases
dendritic
spine density
Methylation
Binding
Chronic
cocaine
Chronic
cocaine +
withdrawal
Figure 6. Methylated CpG island, related with gene
silencing. Adapted from Day & Sweatt, 2012.
