Cocaine Cues

Researchers have found there are enzymes in the brain that decide which genes become active when a user first starts taking drugs. Those enzymes determine how strong those early experiences are when a user later tries to quit, according to research at the Medical University of South Carolina published online on September 27, 2017 in the journal Neuron.

Why do some drug users keep seeking drugs despite the danger of losing family, friends, jobs or health? When drug use first begins, users recall certain things about their surroundings or their emotions that can last. They are called cues, and they can later push someone who is trying to quit to use drugs again.

A major challenge in addiction research is to understand how such brief moments can cause relapse, according to MUSC professor Christopher 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 are addicted are quite different from those of early or casual users. Lasting links form between the early use of a drug and different cues in the early drug-using environment, such as the location in which a drug was first taken or the emotions a user was feeling at the time. This can cause addicted users who have quit to have cravings when in a similar setting. Understanding these links could lead to better treatments for addiction.

Cowan’s challenge was to figure out which genes became active when users were in the same places or emotional state as when they first used drugs. Cowan and his fellow researchers had already found that an enzyme called HDAC5 slowed down the rodent brain from forming links between cocaine and simple cues such as light and sound. HDAC5 is found in high amounts in the reward center of the brain that reacts strongly to cocaine, opioids and alcohol in rodents and humans. HDACs can block the ability of certain genes to be turned on, as long as those HDACs are inside the cell nucleus where DNA is. They are called epigenetic enzymes because they can turn genes off without changing the structure of the genes.

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 or a brief sound went off. These served as simple cues for drug use. Next, some rodents were given a form of HDAC5 that stayed in the nucleus of cells, right next to DNA where it could keep certain genes turned off. Those rodents still pressed the lever just as many times to receive the drug, meaning that HDAC5, on its own, was likely not blocking genes that pushed them to seek the drug early on. 

Yet the next experiment proved that HDAC5 reduced drug-seeking later when rodents were taken off the drug. To mimic how humans might try to quit taking cocaine, rodents were given rest without cocaine for one week, followed by a time during which they were allowed to press the lever again. To mimic relapse, the rodents were shown the cues of light or sound again, this time without needing to press the lever. When the light or sound went off, the rodents began pressing the lever many times, proving that the links between the drug and the cues present when they first took the drug still lasted in their brains. In contrast, animals who had the form of HDAC5 that kept genes turned off in the cell nucleus did not press the lever nearly as often, not even when given a very small dose of cocaine to help remind them to seek the drug. 

All together, these results mean that HDAC5 did keep genes turned off, but those genes were likely only involved in rodents looking for cocaine later on and not early on.

The researchers next used an experiment to find all the possible genes that HDAC5 could block. They found that HDAC5 was blocking a gene that is usually active very early on in drug use, just what Cowan and his team were looking for. Rodents with less of that early gene took much longer to form links between cocaine and the cues of light or sound. Later on, they still looked for drug just as often, though. Apparently, that was the gene that caused animals to look for drug early on but not later on after their cocaine habits had formed. This meant that HDAC5 was also blocking a gene in the later stages of addiction, but it was not that early gene. They are still searching for that later gene. Cowan thinks finding more genes in this way could untangle how the brain changes from early drug use to addiction, and how new treatments might prevent relapse in people with substance use disorders. 

Rodents in experiments may not exactly mimic human addiction. But former drug users report feeling drug cravings when they are given reminders of that early drug-using setting, such as pictures of the drug they used. Also, animals and humans both have HDAC5 and both have similar brain areas. Perhaps most exciting for addiction research is that this finding may extend to cocaine, alcohol or opioid addiction. “We might have tapped into a [finding] with relevance to multiple substance use disorders,” says Cowan.