Addiction has become an epidemic that is sweeping not only the nation, but the whole world. Returning substance abusers develop an emotional connection to a situation, environment or people that are present at the time of first usage, which generally means that when they encounter a similar experience, they look to use again. Kicking an addiction and all its symptoms may be one of the hardest things that a human has to endure. Half the battle is stopping use of the substance, and the other half is spent on fighting withdrawal symptoms, and the desire to use again. Previously, it had been studied that an epigenetic drug could alter DNA methylation in the brain during drug withdrawal with hopes in halting addiction. Thanks to a recent epigenetic research study, the quitting process could become a little less painful with help from a key epigenetic enzyme.
Dr. Christopher W. Cowan and his research team at the Medical University of South Carolina (MUSC) wanted to dive into the epigenetic mechanisms in the brain that were related to the euphoric effects of substance abuse, why users often continue usage when exposed to similar environmental cues, and the transitional process between early drug use and addiction development: “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”.
The main obstacle that the researchers had to overcome was determining which genes were activated when forming an addiction. Previously, the team had experimented with histone deacetylases, which are epigenetic enzymes that remove the acetyl group from core histones, allowing a regulation of gene expression, and discovered some success with histone deacetylase 5 (HDAC5).
They found that HDAC5 has the ability to hinder the rodent brain from forming connections between environmental cues and cocaine use. HDAC5 is found in high abundance in the neurons of the reward center of the brain called the nucleus accumbens or NAc. The NAc operates on two essential “feel good” neurotransmitters called serotonin and dopamine, which is why this area of the brain responds strongly to alcohol, opioids, cocaine and other drugs. When HDAC5 is present in the nucleus of these neurons, it alters the DNA packaging in the cells and can prevent certain genes from activating.
In the study conducted at MUSC, rats were trained to press a lever and receive a fixed dose of cocaine. To establish an environmental cue, a sound and a light were produced every time the lever was pressed. Some rats were then treated with a type of HDAC5 that traveled directly to the nuclei of the neurons in the brain. These rats still pressed the lever to receive cocaine just as often as the untreated rats, meaning that HDAC5 alone is ineffective at preventing drug-seeking behavior.
To induce symptoms of withdrawal, the rats were then given a week without cocaine, followed by a duration of time with access to the lever. The rats were again shown the environmental cues, but this time the cues were given without the rodents having pressed the lever. The sound and light cues were immediately followed by frequent lever pressing, indicating a relapse for the drug-seeking rats, proving the connection in their brains between environment and drug use. Contrastingly, the rats treated with HDAC5 received the same experience and did not press the lever nearly as frequently, even after receiving an initial small dose of cocaine, indicating that, overall, HDAC5 did not prevent the formation of addiction, but did suppress later drug-seeking and relapse behaviors.
Cowan and his team then used an epigenetic technique called ChIP-Seq to determine all genes inhibited by HDAC5. The results determined that NPAS4 (a gene connected to the memory process and addiction-related learning) plays a role in forming early connections between environmental cues and cocaine use. Previous studies have shown that animals with less NPAS4 in the NAc took a longer time to develop these connections, but would still seek the drug during periods of relapse, leading Cowan to believe that there are other genes that HDAC5 regulates to prevent relapse.
Though this study was conducted on rats, HDAC5 treatment shows promise against human addiction as animals and humans share a similar brain structure and enzymatic pathways. Cowan hopes that the discoveries made in this study can apply to not only cocaine addiction, but alcohol and opioid dependence as well.
Moving forward, Cowan looks to determine the additional downstream genes that are responsible for how the brain evolves early drug use into addiction, and how to further advance HDAC5 treatment to hopefully put an end to drug relapse and dependence.
Source: Cowan,Taniguchi, Makoto et al. (2017). HDAC5 and Its Target Gene, Npas4, Function in the Nucleus Accumbens to Regulate Cocaine-Conditioned Behaviors. Neuron, 96(1): 130 – 144.e6 DOI: 10.1016/j.neuron.2017.09.015
Reference: Medical University of South Carolina. “Epigenetics of addiction: Epigenetic study untangles addiction and relapse in the brain.” ScienceDaily. 27 Sep 2017. Web.