Experiments in rodents suggest that epigenetic control of gene expression in the brains of people with substance abuse disorders may influence how environmental cues become strong triggers that increase the likelihood of relapse after they quit. The research, led by Christopher W. Cowan, Ph.D., at the Medical University of South Carolina (MUSC), and colleagues in the U.S., Japan, and the Republic of Panamá, found that the epigenetic enzyme histone deacetylase 5 (HDAC5) controls genes in the nucleus accumbens (NAc) reward center of the brain that impacts on the development of reward-relevant, drug-reinforcing activities and relapse-like behaviors in the experimental animals. 

The research by Prof. Cowan’s team is published in Neuron, in a paper entitled “HDAC5 and Its Target Gene, Npas4, Function in the Nucleus Accumbens to Regulate Cocaine-Conditioned Behaviors.”

The brains of people with drug abuse disorders develop strong associations between the rewarding effects of the drug and environmental cues, such as location, or even emotions. These associations can create powerful cravings that lead to relapse in individuals who have previously quit. Understanding mechanisms in the brain that underpin such connections could potentially offer new opportunities for treatment. The new research by Prof. Cowan’s team was designed to identify genes that are activated early on in drug use. “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,” explained Cowan, who is the Murray SmartState® Endowed Chair in Neuroscience at MUSC.

Green fluorescent protein expressed in neurons of the nucleus accumbens, a critical brain region involved in drug addiction. [Dr. Christopher Cowan/Medical University of South Carolina]
Green fluorescent protein expressed in neurons of the nucleus accumbens, a critical brain region involved in drug addiction. [Dr. Christopher Cowan/Medical University of South Carolina]

The team built on their previous work, which had shown that nuclear HDAC5 slows rodents’ brains from forming associations between cocaine and environmental cues such as light and sound. For their latest studies, the team used rodents that had learned to press a lever to receive a cocaine dose. Every time they self-medicated with a dose of the drug, a lamp went on above the lever and a sound was generated to represent simple environmental cues.

As a first experiment, the team gave animals  a form of HDAC5 that directly enters the nuclei of neurons. These rodents pressed the level to receive cocaine as often as did the control animals, which indicated that HDAC5 wasn’t blocking genes that promoted early drug-seeking behavior.

The rodents then had their access to cocaine withdrawn for a week, to mirror abstinence. Some animals were then presented with the light and sound environmental cues, which prompted them to press the lever repeatedly, indicating drug-seeking behavior as a direct response to those cues. This demonstrated that their brains had retained the association between the drug and the environmental cues.

In contrast, rodents that had been given nuclear HDAC5 pressed the lever far less often, even after they’d been given a small, priming dose of cocaine to kick-start drug-seeking behavior. In effect, while HDAC5 didn’t stop drug-seeking behaviors from developing initially in the rodents, it did prevent them from subsequent relapse and drug-seeking behavior.

When the team analyzed which genes HDAC5 binds to in neurons, they identified NPAS4 as a key early-onset gene. They also found that exposing animals to cocaine and to the test chamber caused rapid, transient expression of NPAS4 in a subpopulation of neurons in the NAc. The NAc is part of the brain’s reward center that reacts to cocaine and substances such as opioids and alcohol in rodents and in humans.

In contrast, deleting NPAS4 in this region of the brain led to animals taking much longer to develop the initial connections between the environmental cues and cocaine, indicating that it was involved in developing those early connections. However, deleting NPAS4 didn’t affect relapse after abstinence. In other words, HDAC5 must also be regulating other genes that lessen the strength of relapse seen in the earlier studies.

“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 authors conclude in their published paper.

If scientists can uncover which other genes are involved in how the brain switches between early drug use and full addiction, it may be possible to develop new treatments that can help to reduce relapse in patients with drug abuse disorders, Dr. Cowan believes. It’s also possible that similar mechanisms may underly addiction to other substances such as alcohol and opioid drugs. As he concludes, “we might have tapped into a mechanisms with relevance to multiple substance abuse disorders.”

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