(Feb. 4th, 2010) So far, there is no proven effective pharmacological treatment of cocaine addiction. US neuroscientists now provide evidence that chromatin modifications and chromatin modifying enzymes might be useful potential drug targets to deal with cocaine dependence.
In a recent edition of Science (vol. 327: 213-16) Ian Maze et al. showed that the histone methylating enzyme G9a had an important role in cocaine-induced alterations of behaviour and neuronal morphology in mice. Knockdown or inhibition of the enzyme increased the preference for cocaine. Modulation of G9a expression altered the density of dendritic spines of neurons after repeated cocaine treatment in a brain region involved in motivation, reward and the establishment of addicted behaviour. Increased spine density of medium spiny neurons in this brain region, named Nucleus Accumbens, has been associated with sensitization to the psychomotor activating and rewarding effects of drugs. Additionally, cocaine abuse reduced the expression of lysine dimethyltransferase G9a in Nucleus Accumbens neurons. Decreased G9a expression resulted in a reduction of histone 3 lysine 9 dimethylation and altered gene expression.
Several modifications associated with addiction
Besides methylation, other post-translational modifications like acetylation and posphorylation were linked to drug addiction. Histones at promoters of genes known to contribute to addicted behaviour were hyperacetylated for days to weeks after the last drug exposure, resulting in increased gene expression. Chronic cocaine administration also led to increased phosphorylation and nuclear export of histone deacetylase 5 (HDAC5), allowing hyperacetylation of histones at target genes for HDAC5 and up-regulation of genes involved in addiction. Additionally, HDAC5 deficient mice were hypersensitive to chronic cocaine exposure, indicating a regulatory role of HDAC5 in behavioural responses to the drug. All types of chromatin modifications identified to date are potentially reversible, making drug-induced chromatin modifications a potential target for therapeutic interventions to improve drug rehabilitation. Malvaez and co-authors, for example, suggested that approved histone deacetylase inhibitors might be used in combination with behavioural extinction therapy to overcome drug-seeking behaviour.
Cocaine is the second most used illicit drug in Europe, after cannabis. It is estimated that 3.9 % of Europeans aged 15 to 64 have used the drug once in their lifetime. Cocaine use is concentrated in a few European countries, notably Denmark, Spain, Italy, Ireland and the UK. Discontinuation rates among cocaine users are high. However, regular cocaine use can lead to cardiovascular, neurological and psychiatric problems.
New therapies tested in clinical trials
Several clinical trials in the UK and the Netherlands are investigating novel approaches including pharmaceutical agents, reinforcement and punishment strategies and cognitive behavioural therapy. A joint Spanish and Italian study is analysing the efficacy of the cocaine vaccine TA-CD. The vaccine stimulates the production of antibodies, which bind to cocaine in the bloodstream and thus prevent the drug from crossing the blood-brain barrier and from causing euphoria.
So far, there is no pharmacological treatment of proven efficacy for cocaine dependence. The recent findings that alterations of chromatin modifications underlie cocaine-induced behavioural changes provide an additional avenue for the development of therapeutics. New drugs could target the chromatin itself or chromatin modifying enzymes to block or reverse addiction.
Bettina Dupont
Sources:
- Maze I. et al., Science 327: 213-16
- Crepaldi L. and Riccio A. 2009. Chromatin learns to behave. Epigenetics 4: 23-26.
- European Monitoring Centre for Drugs and Drug Addiction. 2009. Annual report 2009: the state of the drugs problem in Europe. Luxembourg: Publications Office of the European Union.
- Kuehn B.M. 2009. Scientists target cocaine addiction. JAMA 302: 2641-2642.
- Malvaez M. et al. 2009. Epigenetic mechanisms underlying extinction of memory and drug-seeking behavior. Mamm. Genome 20:612–623.
- Renthal W. and Nestler E.J. 2009. Chromatin regulation in drug addiction and depression. Dialogues Clin Neurosci. 11: 257-268.
- The Cochrane Library, Issue 1, 2010. Chichester: Wiley.