Alcohol is a Gateway Drug for Cocaine

A recent study conducted at Columbia University published on the open access journal Science Advances details how alcohol use leads to compulsive cocaine use.

Alcohol to Cocaine

The study, led by Dr. Edmund Griffin Jr., shows that extended alcohol use serves as a primer in rodents to use cocaine but also more frequently and persistently following exposure to alcohol when compared to rodents that have never had alcohol. We have known since we discovered the reward path in 1954 that rats preferred an electrically induced dopamine high more than food or water, even when administered painful negative reinforcement in order to ingest a drug. But the mechanism by which animals exposed to ethanol increased persistent use of cocaine was not known. Griffin et al, (2017).


Griffin and colleagues evaluated cocaine-seeking behaviors of rats that had been given a 10% alcohol solution for 10 days prior to cocaine exposure. The rats were then compared to rats without prior alcohol exposure, as well as rats that were given alcohol and cocaine concurrently.

To test the behavior deficits associated with cocaine, the researchers paired lever-pressing for cocaine delivery with a painful shock from the grid on the floor of the cage. The difference in response was dramatic. The rats with no prior exposure to alcohol, plus those with concurrent alcohol and cocaine exposure, stopped their cocaine-lever-pressing behavior as the intensity of the foot shock was increased. In contrast, rats that were pre-exposed to alcohol were significantly likely to endure the pain from the foot shock in order to get the cocaine reward. In other words, alcohol-primed rats are more likely to seek reward in spite of harmful consequences compared to rats without prior alcohol use.

The epigenetic changes that undergird this finding has to do with degradation of nuclear histone deacetylases HDAC4 and HDAC5 in the nucleus accumbens which is vital to species survival and the rewarding properties of intoxicants, via dopamine release and distribution that leads to increased drug seeking in spite of consequences, as well as the reward-based memory implicated in addiction. Decreased nuclear HDAC activity results in global H3 acetylation, by which, a now cocaine-friendly neurobiological environment induces gene expression. The histone deactylase acts as the molecular brakes in the brain’s reward system. This is a critical mechanism because DNA is wrapped around histones, and DNA expression is regulated by acetylation and de-acetylation.

Why Does This Matter?

These findings offer a model mechanism by which we can understand how the commonly observed gateway hypothesis enhances the behavioral effects of cocaine via HDAC inhibition. Moreover, Denise Kandel and Bob Dupont, pioneers in addiction medicine and addiction psychiatry, have presented compelling arguments that drug use begets drug use. At first glance this seems axiomatic. But is the sequence important? Probably. Even more so in the younger developing brain where permanent neuroadaptation is most likely to occur. In this study, alcohol use like cannabis and cigarettes makes the risk of cocaine use more likely. The brain’s development during and after myflenation is a particularly critical period, making abuse and addiction more likely to occur. Early cigarette use is also associated with lifetime cigarette use, as is early alcohol use and binge drinking.

Marijuana use appears to be related to both vaping and cigarette smoking and we have observed adult cocaine or opioid addicts in the clinical setting, of which, nearly all describe extensive use of marijuana preceding cocaine or opioid use. These findings all point to a shared mechanism of action for alcohol, tobacco smoking or vaping and marijuana use—thus increasing the likelihood of drug seeking to find a better—and higher—high via substances that increase dopamine faster and thus a more robust euphoric experience. The findings also reveal a novel mechanism by which environmental factors may be part of a unique epigenetic process, thereby altering the bio-environment of the reward system that increases vulnerability to cocaine addiction.

Disseminating these data as part of a comprehensive prevention strategy could delay the onset of alcohol or cigarette use, thus preventing drug seeking behavior amongst our youngest most vulnerable citizens.

Ask The Expert

E. A. Griffin, P. A. Melas, R. Zhou, Y. Li, P. Mercado, K. A. Kempadoo, S. Stephenson, L. Colnaghi, K. Taylor, M.-C. Hu, E. R. Kandel, D. B. Kandel, Prior alcohol use enhances vulnerability to compulsive cocaine self-administration by promoting degradation of HDAC4 and HDAC5. Sci. Adv. 3, e1701682 (2017).