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Alcohol is Gateway Drug to Compulsive Cocaine Use

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A recent study from Columbia University published today in the open access journal Science Advances details how prolonged alcohol use in rats leads to compulsive cocaine use. 

The study, led by Dr. Edmund Griffin Jr. shows that long-term alcohol intake primes rats to become addicted to cocaine, suggesting alcohol is a gateway drug to cocaine addiction.

In the video below, the researchers explain their findings that rats given alcohol for 10 days prior to cocaine exhibited enhanced cocaine-addiction behavior, including continuing to seek cocaine despite receiving a brief electric shock when they did so.

In this video the authors of the study, Dr. Edmund Griffin Jr., Prof. Eric Kandel and Prof. Denise Kandel explain their findings and the importance of this work. Columbia Medical Centre.

The rats were given alcohol in their water bottles for 2 hours daily at a concentration of 10%. Edmund Griffin Jr. and colleagues evaluated cocaine-seeking behaviors of rats that had been given alcohol in this manner for 10 days prior to cocaine administration compared to rats without prior alcohol exposure, as well as rats given alcohol and cocaine concurrently.

In a test where they paired lever-pressing for cocaine delivery with a painful foot shock the rats that with no prior exposure to alcohol and those with alcohol and cocaine concurrent exposure stopped their cocaine-seeking lever-pressing behavior at similar levels as the intensity of the foot shock was increased. However, the rats that had been pre-exposed to alcohol were significantly more resistant to the punishment of the foot shock and more determined to press the lever to get the cocaine reward.

Furthermore, the group identified the epigenetic changes that underlie this increase in compulsive cocaine use. They identify that prolonged alcohol consumption leads to a degradation of nuclear histone deacetylases HDAC4 and 5 in the nucleus accumbens, an area of the brain important for reward-based memory implicated in addiction.

As Edmund Griffin Jr. explains, "The histone deactylase acts as a molecular brake-pad in the reward system of the brain." 

Removing or degrading the HDAC activity in this area of the brain makes for a more permissive environment for the development of addiction to cocaine.

This was confirmed when they gave rats an HDAC inhibitor, MC1568, in the nucleus accumbens and this led to compulsivity for cocaine self-administration.  

The results of the study suggest alcohol increases compulsive cocaine use by promoting the breakdown of important proteins in the nucleus accumbens, a brain region critical for reward-based memory. While addiction to cocaine is commonly preceded by use of other substances such as alcohol, nicotine and marijuana, the biological mechanisms by which these “gateway drugs” contribute to cocaine addiction are only beginning to be understood. Since only a fraction (about 21%) of cocaine users progress to compulsive use, it is thought that both genetic and environmental factors are involved in vulnerability to cocaine addiction.


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).