Chronic cocaine use changes gene expression in the hippocampus, according to research in mice recently published in Journal of Neuroscience.
Chronic drug users learn to associate the drug-taking environment with the drug itself, reinforcing memories that contribute to addiction.
These memories are thought to be created by changes in gene expression in the hippocampus and potentially involve the gene FosB, but the exact mechanism is unknown.
A.J. Robinson and colleagues at Michigan State University examined how cocaine exposure affected expression of the FosB gene in the hippocampus.
Mice that were administered cocaine daily showed increased expression of FosB compared to mice that received saline.
Chronic cocaine use caused epigenetic modification of the gene, leading it to becoming more active.
Additionally, when the scientists blocked the changes made to FosB, the mice were unable to form associations between cocaine and the environment where they received it, implicating epigenetic regulation of the gene in drug memory formation.
Hippocampal neurons (green) expressing the FosB gene (red) after cocaine exposure. The image is credited to credited to Gajewski et al., JNeurosci 2019.
These results offer new insights in the molecular changes that take place in the hippocampus during chronic cocaine use.
Further research in this area could lead to the development of addiction therapies.
Substance use disorders (formerly drug dependence), including cocaine use disorders, are characterized by complex behavioural symptoms, the development of physiological tolerance, and painful withdrawal symptoms .
Pharmacologically, cocaine is a psychostimulant that increases synaptic dopamine ; however, the behavioral complexity that accompanies the transition from casual drug use to cocaine dependence points to numerous, long lasting changes in cellular functioning.
Researchers in this field have described an “addiction cycle” which consists of three behavioral/psychological states: binge or intoxication, withdrawal and a negative effect, and preoccupation/drug craving .
The development of chronic drug dependence involves the progression through the addiction cycle; alongside neuroadaptive changes to important components of the mesocorticolimbic dopamine system (Figure 1).
The striatum receives direct midbrain dopaminergic input from the ventral tegmental area (VTA), and is one of the most studied brain regions in relation to cocaine neurobiology. For example, in the nucleus accumbens (NAc), which is highly implicated in the motivational aspects of drug-seeking, repeated cocaine injections leads to increases in dendritic branching and dendritic spine formation [4,5].
The specificity of these changes, with distinct networks of genes being up- or down-regulated, suggests that epigenetic mechanisms, which can be defined as covalent modifications to chromatin, may be involved.
Although epigenetic mechanisms are a prominent aspect of research in developmental biology, oncology, and plant biology, the intersection between epigenetics and psychiatry is a relatively new idea.
Post-translational modifications of histone tails aid in the transition between active and repressed chromatin states, and are the most well-studied epigenetic mechanisms in the context of cocaine use disorders (for review, see ).
Cytosine modifications represent another mechanism of transcriptional regulation that have begun to gain attention in the cocaine literature. The most highly studied cytosine modification in mammals is 5′ methylated cytosine (5mC), which occurs primarily, although not exclusively, at cytosine-guanine dinucleotides (CpGs).
In gene promoters, 5mC is linked to transcriptional repression, often through the recruitment of methyl-binding proteins such as MeCP2 and chromatin remodelling enzymes including histone deacetylases (HDACs) [15,16] (Figure 2a).
It has also been shown that the presence of cytosine methylation within promoter sites directly represses transcription through preventing transcription factor binding, a mechanism that is particularly important in cocaine dependence [17,18] (Figure 2b).
Conversely, cytosine methylation within gene bodies may promote gene expression [19,20] and recent evidence suggests that DNA methylation dynamics can negatively regulate CTCF-mediated exon translation, and alternative splicing [21,22].
In addition, 5′ hydroxymethylation (5hmC), an oxidative product of active DNA demethylation, may represent a stable epigenetic mark separate from 5mC and warrants investigation in relation to cocaine use disorders (Figure 2b) [23,24,25].
In the dentate gyrus of the hippocampus, stimulation is accompanied by widespread increases in chromatin accessibility, especially around enhancer and transcription factor binding sites .
These changes may be a permissive, first step for active methylation changes that have been observed after stimulation [27
Although the mechanisms through which changes in neuronal activity lead to epigenomic change are unclear, they may be mediated by intracellular calcium signalling, extracellular signal-related kinase (ERK) activity, and extracoding RNA (ecRNA) [29,30,31].
These phenomena lend further support to the notion that long term synaptic changes in the mesocorticolimbic system during cocaine dependence may be mediated by altered DNA methylation.
Indeed, the last decade saw an increase in the number of studies investigating DNA methylation and cocaine exposure, and the purpose of this review is to summarize the findings in this field. These findings can be divided into two general categories; those related to methylation machinery, the readers and writers of cytosine modifications, and those that identify differences in the presence or absence of the marks themselves.
Calli McMurray – SfN
The image is credited to Gajewski et al., JNeurosci 2019.
Original Research: Closed access
“Epigenetic Regulation of Hippocampal FosB Expression Controls Behavioral Responses to Cocaine”.Paula A. Gajewski, Andrew L. Eagle, Elizabeth S. Williams, Claire E. Manning, Haley Lynch, Colin McCornack, Ian Maze, Elizabeth A. Heller and A.J. Robison.