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The interaction of environmental cues and triggers that promote drug relapse have a genetic and epigenetic basis that can be modified in the experiment below. Epigenetics is the modification of DNA expression as a result of environmental triggers. It would be great to induce modification of an addicts DNA to decrease cravings from triggers and cues as shown in the experiment below with mice and cocaine addiciton. The articles are scavenged per the sources:
Epigenetics of addiction: Epigenetic study untangles addiction and relapse in the brain
September 27, 2017
Medical University of South Carolina
New research uncovers an epigenetic reason why drug users who attempt to quit are prone to relapse despite negative consequences to their health and livelihood. The findings help to explain how casual drug use can produce long-lasting brain changes that increase vulnerability to relapse in individuals suffering from substance use disorders.
Why do some drug users continue to seek out drugs despite the prospect of losing family, friends, health or livelihood?
There are notable features — cues — of the early drug-using environment that often develop into persistent and powerful triggers for relapse. Epigenetic factors — enzymes in the brain that alter the packaging and accessibility of genes without changing the genes themselves — influence this process, according to research at the Medical University of South Carolina (MUSC) appearing online on September 27, 2017 in Neuron.
A major challenge in addiction science is to understand how transient experiences lead to long-lasting risk for relapse in users who try to quit, according to MUSC professor Christopher W. Cowan, Ph.D., William E. Murray SmartState® Endowed Chair in Neuroscience, and senior researcher on the project. “Our goal was to discover the brain mechanisms responsible for the rewarding effects of the drug and the motivation to seek it even after long periods of abstinence,” says Cowan.
The brains of drug users who have progressed to addiction differ markedly from those of early or casual users. Long-lasting associations form between the early use of a drug and different aspects of the early drug-using environment, such as the location in which a drug was first taken or the emotions a user was experiencing at the time. This can cause addicted users who have quit to experience cravings when in a similar setting. Understanding these connections could lead to better treatments for addiction.
Cowan’s challenge was to determine which genes were activated in the early drug-using environment. Cowan and his fellow researchers had previously found that the epigenetic enzyme histone deacetylase 5 (HDAC5) slows the rodent brain from forming associations between cocaine and simple cues in the environment, such as light and sound. HDAC5 is found in high amounts in neurons in the nucleus accumbens, part of the reward center of the brain that reacts strongly to cocaine, opioids and alcohol — both in rodents and humans. When HDACs are in the nucleus of neurons, they change the way genomic DNA is packaged in the cell nucleus and often block the ability of certain genes to be turned on.
In the new study, rodents were trained to press a lever to receive a dose of cocaine. Each time they received a dose, a lamp went on above the lever and a brief sound was generated. These served as simple environmental cues for drug use. Next, some rodents were given a form of HDAC5 that traveled straight to the nuclei of neurons. Those rodents still pressed the lever just as many times to receive drug, meaning that HDAC5, on its own, was likely not blocking genes that promoted early drug-seeking behavior.
Yet the next experiment proved that HDAC5 reduced drug-seeking behavior during abstinence. To simulate withdrawal and abstinence, rodents were given rest without cocaine for one week, followed by a period during which they had access to the lever again. To simulate relapse, the rodents were shown the environmental cues again, this time without having pressed the lever. The presentation of the cues triggered robust lever pressing, indicating drug seeking, in control animals, proving that the associations between drug and environment persisted in their brains. In contrast, animals who had the nuclear form of HDAC5 did not press the lever nearly as often, even after the experimenters gave the animals a small priming dose of cocaine, which often produces strong drug-seeking behaviors.
HDAC5, the gene suppressor, did not prevent addiction-like behaviors from forming, but it did prevent later drug seeking and relapse during abstinence — at least in rodents.
The researchers next used a cutting-edge technique that encourages epigenetic enzymes to bind to DNA, allowing them to identify all the genes inhibited by HDAC5. The gene for NPAS4 was a top hit, and significant for an important reason: it is an early-onset gene, meaning that its effects could be exerted on the brain rapidly unless HDAC5 was there to inhibit it — just the molecular event Cowan and his team were seeking.
In similar experiments, animals with less NPAS4 in the nucleus accumbens took more time to form those early connections between environmental cues and cocaine, but they still sought the drug just as often during later simulated relapse. Apparently, NPAS4 accounts for some addiction-related learning and memory processes in the brain, but not all of them, meaning that HDAC5 must be regulating additional genes that reduce relapse events. Cowan thinks uncovering additional downstream genes could help researchers untangle the details of how the brain transitions from early drug use to addiction, and how new treatments might be developed to reduce relapse in individuals suffering from substance use disorders.
Animals in the research setting may not mimic the full complexity of human addiction. However, abstinent patients report cravings when given reminders of their drug-associated environment or cues, and animals and humans share similar enzyme pathways and brain structures. Perhaps most exciting for addiction research is that these processes may be similar in the transition to cocaine, alcohol and opioid addictions. “We might have tapped into a mechanism with relevance to multiple substance use disorders,” says Cowan.
Nuclear HDAC5 in the NAc attenuates relapse-like drug-seeking behaviors
ChIP-seq revealed numerous HDAC5-associated target genes including Npas4
NPAS4 in NAc (Nucleus accumbens) is induced in subset of FOS+ neurons during cocaine-context learning
HDAC5 and NPAS4 in NAc are involved in cocaine-conditioned behaviors
Individuals suffering from substance-use disorders develop strong associations between the drug’s rewarding effects and environmental cues, creating powerful, enduring triggers for relapse. We found that dephosphorylated, nuclear histone deacetylase 5 (HDAC5) in the nucleus accumbens (NAc) reduced cocaine reward-context associations and relapse-like behaviors in a cocaine self-administration model. We also discovered that HDAC5 associates with an activity-sensitive enhancer of the Npas4 gene and negatively regulates NPAS4 expression. Exposure to cocaine and the test chamber induced rapid and transient NPAS4 expression in a small subpopulation of FOS-positive neurons in the NAc. Conditional deletion of Npas4 in the NAc significantly reduced cocaine conditioned place preference and delayed learning of the drug-reinforced action during cocaine self-administration, without affecting cue-induced reinstatement of drug seeking. These data suggest that HDAC5 and NPAS4 in the NAc are critically involved in reward-relevant learning and memory processes and that nuclear HDAC5 limits reinstatement of drug seeking independent of NPAS4.
The molecular mechanisms underlying the association between environmental cues and drug reward are of great interest. Furthermore, the contribution of specific enzymes that participate in chromatin remodeling in response to drugs of abuse is an active area of research.
Taniguchi et al. report that the dephosphorylated, nucleus localized HDAC5 in the nucleus accumbens (Nac) acts as a protective molecule that reduces the association between context cues and cocaine reward. Using Chip-seq, the authors identified the IEG Npas4 as one of the gens that associate with nuclear HDAC5. The authors further show that HDAC5 negatively regulates Npas4 expression and that both drug and environmental cues produce a rapid and transient increase in Npas4 expression in a small subpopulation of cFos-positive Nac neurons. Finally, the authors show that Npas4 contributes to learning and memory processes associated with cocaine reward.
This is a very elegant study that identified a novel signaling pathway in which the key participants contribute in opposite directions to cocaine reward seeking behaviors. Specifically, nuclear HDAC5 gates behaviors associated with cocaine reward whereas Npas4 promotes them. Also of note is the finding that Npas4’s expression is induced by cocaine only in a subpopulation of Nac neurons. The consequences of the manipulation of both genes in these specific neurons would be an interesting future direction.