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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1792, 497–505 (2009).

Han, S. & Brunet, A. Histone methylation makes its mark on longevity.

Trends Cell Biol. 22, 42–49 (2012).

Rogge, G. A. & Wood, M. A. The Role of Histone Acetylation in

Cocaine-Induced Neural Plasticity and Behavior.

Neuropsychopharmacology 38, 94–110 (2012).

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.