-
[show abstract]
[hide abstract]
ABSTRACT: Drug addiction is considered a disorder of neuroplasticity in brain reward and cognition systems resulting from aberrant activation of gene expression programs in response to prolonged drug consumption. Non-coding RNAs (ncRNAs) are key regulators of almost all aspects of cellular physiology. MicroRNAs (miRNAs) are small (∼21-23 nucleotides) ncRNAs transcripts that regulate gene expression at the post-transcriptional level. Recently, miRNAs were shown to play key roles in the drug-induced remodeling of brain reward systems that likely drives the emergence of addiction. Here, we review evidence suggesting that one particular miRNA, miR-212, plays a particularly prominent role in vulnerability to cocaine addiction. We review evidence showing that miR-212 expression is increased in the dorsal striatum of rats that show compulsive-like cocaine-taking behaviors. Increases in miR-212 expression appear to protect against cocaine addiction, as virus-mediated striatal miR-212 overexpression decreases cocaine consumption in rats. Conversely, disruption of striatal miR-212 signaling using an antisense oligonucleotide increases cocaine intake. We also review data that identify two mechanisms by which miR-212 may regulate cocaine intake. First, miR-212 has been shown to amplify striatal cAMP response element binding protein (CREB) signaling through a mechanism involving activation of Raf1 kinase. Second, miR-212 was also shown to regulate cocaine intake by repressing striatal expression of methyl CpG binding protein 2 (MeCP2), consequently decreasing protein levels of brain-derived neurotrophic factor (BDNF). The concerted actions of miR-212 on striatal CREB and MeCP2/BDNF activity greatly attenuate the motivational effects of cocaine. These findings highlight the unique role for miRNAs in simultaneously controlling multiple signaling cascades implicated in addiction.
Frontiers in genetics. 01/2013; 4:43.
-
[show abstract]
[hide abstract]
ABSTRACT: Dynamic chromatin remodeling is at the heart of most biological processes including gene transcription, DNA replication and repair, cell differentiation and apoptosis. Chromatin remodeling as a result of covalent histone modifications, including histone acetylation, methylation or SUMOylation, play important roles in these processes. Similarly, direct chemical modification of DNA, most notably DNA methylation, also plays a key role in controlling gene expression and basic aspects of cell biology. Memory, one of the most fundamental of all brain functions, is a complex process involving diverse cellular signaling cascades and coordinated regulation of entire networks of genes. Synaptic plasticity, which is defined as activity-dependent changes in synaptic strength between neurons, provides the cellular basis of memory. The role for covalent histone modifications in synaptic plasticity and in learning and memory has been now been firmly established. In contrast, much less had been known concerning DNA methylation in memory formation and storage. Emerging evidence now suggests that DNA methylation plays a central role in these processes, likely by directly influencing the expression of genes involved in synaptic plasticity.
Epigenetics: official journal of the DNA Methylation Society 06/2011; 6(6):671-4. · 4.58 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The X-linked transcriptional repressor methyl CpG binding protein 2 (MeCP2), known for its role in the neurodevelopmental disorder Rett syndrome, is emerging as an important regulator of neuroplasticity in postmitotic neurons. Cocaine addiction is commonly viewed as a disorder of neuroplasticity, but the potential involvement of MeCP2 has not been explored. Here we identify a key role for MeCP2 in the dorsal striatum in the escalating cocaine intake seen in rats with extended access to the drug, a process that mimics the increasingly uncontrolled cocaine use seen in addicted humans. MeCP2 regulates cocaine intake through homeostatic interactions with microRNA-212 (miR-212) to control the effects of cocaine on striatal brain-derived neurotrophic factor (BDNF) levels. These data suggest that homeostatic interactions between MeCP2 and miR-212 in dorsal striatum may be important in regulating vulnerability to cocaine addiction.
Nature Neuroscience 09/2010; 13(9):1120-7. · 15.53 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Cocaine addiction is characterized by a gradual loss of control over drug use, but the molecular mechanisms regulating vulnerability to this process remain unclear. Here we report that microRNA-212 (miR-212) is upregulated in the dorsal striatum of rats with a history of extended access to cocaine. Striatal miR-212 decreases responsiveness to the motivational properties of cocaine by markedly amplifying the stimulatory effects of the drug on cAMP response element binding protein (CREB) signalling. This action occurs through miR-212-enhanced Raf1 activity, resulting in adenylyl cyclase sensitization and increased expression of the essential CREB co-activator TORC (transducer of regulated CREB; also known as CRTC). Our findings indicate that striatal miR-212 signalling has a key role in determining vulnerability to cocaine addiction, reveal new molecular regulators that control the complex actions of cocaine in brain reward circuitries and provide an entirely new direction for the development of anti-addiction therapeutics based on the modulation of noncoding RNAs.
Nature 07/2010; 466(7303):197-202. · 36.28 Impact Factor
