Cocaine’s Effects Are Most Potent when Estrogen Levels are High

Eric J. Nestler, M.D. - Brain & Behavior Research Expert on Addiction
Eric J. Nestler, M.D.

Changes in hormone levels alter the way the female brain responds to cocaine during different phases of the estrous cycle in mice (equivalent to the menstrual cycle in humans), according to new research reported January 10 in Nature Communications. The findings could help explain why women who are addicted to cocaine tend to have more trouble than men abstaining from the drug.

Researchers have noted significant gender differences with respect to cocaine use and dependence: Women are more likely than men to use cocaine at an early age, take larger quantities of the drug, and are more susceptible to relapse during recovery. Similar gender distinctions have been observed in animal studies, suggesting they are caused by biological differences between males and females.  

The new study was designed to investigate how female sex hormones might affect the brain’s response to cocaine. It was led by Eric J. Nestler, M.D., a NARSAD 1996 Distinguished Investigator, BBRF Scientific Council member, and winner of the 2008 Goldman-Rakic Prize and 2009 Falcone Prize; and Ming-Hu Han, Ph.D., a 2007 Young Investigator and 2015 Independent Investigator. Both are at the Icahn School of Medicine at Mount Sinai. Other team members included 2016 Young Investigator Erin S. Calipari, Ph.D., and 2015 Young Investigator Michael E. Cahill, Ph.D., also at the Icahn School of Medicine, and 2005 and 2008 Young Investigator, BBRF Scientific Council member, and 2013 Goldman-Rakic Prizewinner Karl Deisseroth, M.D., Ph.D., at Stanford University.

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Cocaine blocks the transporter that removes the neurotransmitter dopamine from junctions between neurons, causing it to accumulate and activate reward pathways. By studying neuronal activity in the brains of awake, behaving mice, the researchers discovered that estrogen makes the dopamine transporter more vulnerable to inhibition by cocaine, thus enhancing the drug’s pleasurable effects.

Due to activation of the brain’s reward system, mice in the study learned to associate pleasurable feelings with the environment where they consumed cocaine. Even after the drug was removed, they would favor this location in their cage. This preference for the environment previously paired with the drug was strongest in female mice that had consumed the cocaine when their estrogen levels were high, indicating they had experienced greater reward activation than males, or female mice that consumed the drug while their estrogen levels were low.  

Though the current study focused on the brain’s response to cocaine, the researchers say estrogen may have similar effects on other forms of substance abuse. The findings emphasize the importance of recognizing and studying gender differences in drug addiction.

TAKEAWAY: Takeaway: Researchers uncover hormonal effects on the brain’s reward system that influence how females respond to cocaine.