NEW YORK – The use of cannabis makes young brains more sensitive to first exposure to cocaine, according to a new study in mice led by scientists at Columbia University and Cagliari University in Italy. By monitoring the brains of adolescent and adult mice after giving them synthetic psychoactive cannabinoids followed by cocaine, the research team identified key molecular and epigenetic changes that occur in adolescent brains – but not adults. This discovery reveals new interactions between two drugs that have never been directly observed in biological detail.
This finding, reported this week at Proceedings of the National Academy of Sciences, providing a new understanding of how cannabis abuse during adolescence can enhance firsts with cocaine and lead to sustainable use among vulnerable individuals.
“We know from human epidemiological studies that people who abuse cocaine have a history of early cannabis use, and that a person’s initial response to drugs can have a big impact on whether they continue to use it. But many questions remain about how early cannabis. Exposure affects the brain,” said Epidemiologist Denise Kandel, PhD, who is a professor of Sociomedical Sciences in Psychiatry at the College of Physicians and Vagelos Surgeons in Columbia and co-senior author of today’s paper.
“Our study in mice is the first to map detailed molecular and epigenetic mechanisms in which cocaine interacts with the brain that has been exposed to cannabinoids, providing much needed clarity on biological mechanisms that can increase the risk of drug abuse and addiction,” co added. – Nobel Prize Recipient Eric Kandel, MD, codirector of Mortimer B. Zuckerman Mind Behavior Institute, Columbia, and Senior Investigator Howard Hughes Medical Institute.
Previous research has revealed major differences in how cannabis and cocaine affect brain chemistry. “The study of the addictive nature of cocaine has traditionally focused on the mesolimbic dopaminergic pathway, the brain system that underlies our motivation to pursue pleasurable experiences,” said Philippe Melas, PhD, who is a research scientist at Eric Kandel’s laboratory at Zuckerman Institute’s laboratory in Columbia, Zuckerman Institute, Columbia. and is the co-senior author of this paper. “While cannabis increases mesolimbic dopaminergic activity similar to cocaine, it also affects an entirely different neurochemical system that is widespread in the brain called the endocannabinoid system. This system is very important for brain development – a process that is still ongoing in adolescence.”
Apart from the dopaminergic system, marijuana and cocaine seem to have some additional features. Recent studies have shown that the development of cocaine craving depends on the brain’s glutamatergic system. This system uses glutamate, a brain molecule that acts as a synaptic transmitter in the brain, increasing the transmission of signals between brain neurons. According to previous research, as well as the findings presented in new research today, the use of cannabis during adolescence can also influence this glutamatergic signaling process.
To dig deeper into the potential relationship between the two drugs, Dr. Melas and husband and wife team Drs. Eric and Denise Kandel partnered with Paola Fadda, PhD, Maria Scherma, PhD, and Walter Fratta, PhD, researchers in the Department of Biomedical Sciences, at the University of Cagliari in Italy. The group examined the behavioral, molecular and epigenetic changes that occur when juvenile and adult mice first experience WIN, a synthetic cannabinoid with psychoactive properties similar to THC found in cannabis, and then exposed to cocaine.
“We found that adolescent rats that had been previously exposed to WIN had an increased reaction to their initial exposure to cocaine. Specifically, we observed this effect in adult mice but not in adult mice,” Dr. researcher at the Department of Clinical Neuroscience at the Karolinska Institutet in Sweden.
After further examination, the team found that, when preceded by a history of use of psychoactive cannabinoids in adolescence, exposure to cocaine triggered a battery of unique molecular reactions in the rat brain. These reactions include not only the changes in the glutamate receptors mentioned above, but also the key epigenetic modifications. Epigenetic modifications are different, because they affect the way genes are turned on or off but do not affect the order of the genes themselves.
The Columbia team had previously discovered a similar epigenetic mechanism in adult animals in response to nicotine and alcohol in the brain’s appreciation center, known as nucleus accumbens. However, in this study, the epigenetic effects of canabinoids were found to be specific for adolescents and target the brain’s prefrontal cortex. The prefrontal cortex, which plays a role in a variety of executive functions, including long-term planning and self-control, is one of the last areas of the brain to reach maturity, a fact that has long been linked to teenagers’ propensity for risky behavior. .
In addition, deviant prefrontal cortex activity is often observed in patients suffering from addictions. Efforts to improve the function of the prefrontal cortex are currently being evaluated in the treatment of addictions through the use of brain stimulation and other methodologies.
“Our findings show that exposure to psychoactive cannabinoids during adolescence primed the prefrontal cortex of animals, so that the response to cocaine was different from animals that had been given cocaine without previously having experienced cannabis,” Dr. Weld.
These results in mice offer important clues to biological mechanisms that might underlie the way various classes of drugs can mutually reinforce in humans. These results also support the idea that cannabis abuse during adolescence can enhance a person’s initial positive experience with different drugs, such as cocaine, which in turn can have an effect on whether that person chooses to continue, or expand, their initial use of cocaine. .
“This study shows that adolescents who use marijuana may have favorable initial reactions to cocaine, which will increase the likelihood of them being involved in repeated use so that they eventually become addicted, especially if they carry additional environmental or genetic vulnerability,” Dr. Denise Kandel.
Most research involving mice and addictions has traditionally focused on adult animals. It is also largely limited to studying one substance of abuse at a time, without considering the history of drug exposure in adolescence.
“These and other experiments are the key to understanding the molecular changes to the brain that occur during drug use,” Dr. Eric Kandel, who is also a University Professor and Kavli Professor of Brain Sciences at Columbia. “This knowledge will be very important for developing effective treatments that reduce addiction by targeting the mechanisms underlying this disease.”
This paper is entitled “Exposure to Cannabinoids in adolescent rats reprogramming initial behavioral, molecular and epigenetic responses to cocaine.” Additional contributors include Johanna S. Qvist, Arun Asok, PhD, Shao-shan C. Huang, PhD, Paolo Masia, PhD, Matteo Deidda, PhD, Ya B. Wei, PhD and Rajesh K. Soni, PhD.
This research was supported by the Howard Hughes Medical Institute, Cohen Veterans Bioscience, Swedish Research Council (DN 350-2012-6535), Royal Physiographic Society in Lund (Sweden), Swedish-American Foundation, American National Institute of Mental Health (F32MH114306) and Project Department Biomedical Sciences in Italy (RICDIP_2012_Fratta_01).
The author states there is no conflict of interests.
Mortimer B. Zuckerman’s Mind Brain Behavior Institute from Columbia University brings together a group of world-class scientists and scholars to pursue the most pressing and interesting challenge of our time: understanding the brain and mind. A deeper understanding of the brain promises to change the health of humans and society. From effective treatments for disorders such as Alzheimer’s, Parkinson’s, depression and autism to advances in areas as fundamental to computer science, economics, law, the arts and social policy, the potential for humanity is staggering. To learn more, visit: zuckermaninstitute.columbia.edu.