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Cannabis Use Makes Young Brains More Sensitive to Cocaine, Finds Rodent Study

By Alexander Beadle

Published: Apr 22, 2020   
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Cannabis use during adolescence can make the brain more sensitive to subsequent first exposure to cocaine, say scientists at the Columbia University and the University of Cagliari in Italy, following the completion of a new rodent study.

By monitoring the brains of adolescent and adult rats before and after administering a synthetic psychotropic cannabinoid followed by cocaine, the researchers say they identified key molecular and epigenetic changes in the brains of the adolescent rats that didn’t occur in the adult group.

These findings, published in the Proceedings of the National Academy of Sciences, reveal new interplay between the two drugs that has never previously been observed directly in biological detail, say the scientists.

The results shed light on how early cannabis use during teenage years may lead to continued drug use among vulnerable individuals.

Investigating cannabis’ effects on the brain

The research group set out to examine the behavioral, molecular, and epigenetic changes that occur after exposing both adolescent and adult rats to WIN55212-2, a synthetic cannabinoid with similar effects to the naturally occurring tetrahydrocannabinol (THC). After exposure to WIN, both the adolescent and adult rats were given doses of cocaine, and the results compared against a control group.

“We found that adolescent rats that had been pre-exposed to WIN had an enhanced reaction to their initial exposure to cocaine. Notably, we observed this effect in adolescent but not in adult rats,” said Philippe Melas, PhD, the paper's co-senior author, in a press statement.

The researchers observed that when proceeded by cannabis use in adolescence, exposure to cocaine set off a battery of unique molecular reactions inside the rats’ brains. These reactions included changes in brain’s glutamatergic system, which has been previously linked to the development of cocaine craving, and also some key epigenetic modifications. Epigenetic modifications are distinct, in that they affect the way genes are switched on or off but don’t affect the sequences of the genes themselves.

“Studies on the addictive properties of cocaine have traditionally focused on the mesolimbic dopaminergic pathway, a brain system that underlies our motivation to pursue pleasurable experiences,” Melas explained. “While cannabis enhances mesolimbic dopaminergic activity similarly to cocaine, it also affects an entirely different neurochemical system that is widespread in the brain called the endocannabinoid system. This system is essential for brain development – a process that is still ongoing in adolescence.”

The epigenetic effects of the cannabinoids seen in this study were found to be specific to adolescents and targeted the brain’s prefrontal cortex. This part of the brain plays a role in actions like long-term planning and self-control, and is one of the last regions of the brain to reach maturity, a fact that has been associated with teenagers’ propensity for risky behavior. But aberrant prefrontal cortex activity has also been observed in patients suffering from addiction.

“Our findings suggest that exposure to psychoactive cannabinoids during adolescence primes the animals' prefrontal cortex, so that it responds differently to cocaine compared to animals who had been given cocaine without having previously experienced cannabis,” said Melas.

The implications for future addiction studies

As the researchers say, this new study in rats offers important clues as to the biological mechanisms that may underpin how different drugs interact and may even reinforce each other in humans. It also supports the hypothesis that cannabis abuse during teenage years can enhance later experiences with other drugs, which can have a meaningful influence on whether that person continues to use it.

“We know from human epidemiological studies that individuals who abuse cocaine have a history of early cannabis use, and that a person's initial response to a drug can have a large impact on whether they continue to use it. But many questions remain on how early cannabis exposure affects the brain,” said epidemiologist Denise Kandel, PhD, co-senior author of the new paper.

“This study suggests that teenagers who use cannabis may have a favorable initial reaction to cocaine, which will increase their likelihood of engaging in its repeated use so that they eventually become addicted, especially if they carry additional environmental or genetic vulnerabilities.”

To date, most research involving rodent models of addiction have used adult animals. Additionally, these studies have largely been limited to studying the effects of one substance at a time, without taking into the account the effects that a history of other drug exposure in adolescence may have.

“These and other experiments are key to understanding the molecular changes to the brain that occur during drug use,” said Eric Kandel, MD, co-author of the study and a Nobel laureate. “This knowledge will be crucial for developing effective treatments that curb addiction by targeting the disease's underlying mechanisms.”


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