cocaine and marijuana
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Studies in rodents by scientists at Columbia University and the University of Cagliari in Italy have shown how cannabis use during adolescence can make the brain more sensitive to subsequent first exposure to cocaine. By monitoring changes in the brains of both adolescent and adult rats after the administration of synthetic psychoactive cannabinoids followed by cocaine, the research team identified molecular and epigenetic changes that occurred in the brains of the adolescent, but not the adult animals.

The findings reveal an interplay between the two drugs that had never previously been observed directly at molecular level detail, giving scientists new neurobiological insights into how the abuse of cannabis during teenage years may enhance the first experience with cocaine and lead to addiction among vulnerable individuals.

“Our study in rats is the first to map the detailed molecular and epigenetic mechanisms by which cocaine interacts with brains already exposed to cannabinoids, providing much-needed clarity to the biological mechanisms that may increase the risk for drug abuse and addiction,” stated Nobel laureate Eric Kandel, MD, co-director of Columbia’s Mortimer B. Zuckerman Mind Brain Behavior Institute and senior investigator of the Howard Hughes Medical Institute. Kandel is co-author of the researchers’ published paper in the Proceedings of the National Academy of Sciences (PNAS), which is titled, “Cannabinoid exposure in rat adolescence reprograms the initial behavioral, molecular, and epigenetic response to cocaine.”

It’s already known that humans and animals vary in how they respond to the first use of drugs, and this can predict future drug use. “Positive first experiences with cocaine, for example, are associated with future cocaine use, shorter latency to second use, and the development of cocaine dependence,” the authors noted. Increasing evidence also suggests that psychoactive cannabinoid use in adolescence is associated with an increased risk for later use of cocaine, and enhances the behavioral effects of cocaine. Studies in animals have similarly shown that cannabinoids can “cross-sensitize” to cocaine, enhance cocaine self-administration, and modify cocaine-related withdrawal symptoms.

“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,” said epidemiologist Denise Kandel, PhD, who is a professor of sociomedical sciences in psychiatry at Columbia’s Vagelos College of Physicians and Surgeons and co-senior author of the paper. “But many questions remain on how early cannabis exposure affects the brain.” As the authors noted, “Despite these behavioral data, there is still no neurobiological evidence demonstrating that cannabinoids can change the brain’s initial response to cocaine.”

Previous research had revealed key differences in how cannabis and cocaine affect brain chemistry. “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,” said senior co-author Philippe Melas, PhD, who was an associate research scientist in Eric Kandel’s lab at Columbia’s Zuckerman Institute. “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.”

Besides the dopaminergic system, cannabis and cocaine also appear to share some features. Recent studies have suggested that the development of cocaine craving is dependent on the brain’s glutamatergic system, and previous research—which is now supported by the newly reported results—indicate that using cannabis during adolescence may affect glutamatergic signaling.

To investigate in greater detail a potential link between the two drugs, Melas, together with the husband-and-wife team of 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 occurred when both adolescent and adult rats were first exposed to the synthetic cannabinoid, WIN, and then were subsequently exposed to cocaine. WIN has psychoactive properties similar to those of THC found in cannabis. “… we utilized a multiomics approach (epigenomics, transcriptomics, proteomics, and phosphoproteomics) to characterize how the rat brain responds to its first encounter with cocaine, with or without preexposure to the synthetic cannabinoid WIN 55,212-2 (WIN),” the team wrote.

They found that adolescent rats that had been pre-exposed to WIN demonstrated an enhanced reaction to their initial exposure to cocaine. “Notably, we observed this effect in adolescent but not in adult rats,” stressed Melas, who is currently at the department of clinical neuroscience at the Karolinska Institutet in Sweden. Further studies indicated that, when preceded by a history of psychoactive cannabinoid use during adolescence, exposure to cocaine was associated with key molecular changes in the rat brain. These included alteration to glutamate receptors, but also key epigenetic modifications.

The Columbia team had previously identified epigenetic mechanisms in adult animals in response to nicotine and alcohol in the brain’s reward center, known as the nucleus accumbens. “Our previous studies on other “gateway” drugs, such as nicotine and alcohol, suggested that drug-priming properties are mediated by epigenetic mechanisms (e.g., HDACs and histone acetylation) in line with the epigenetic-priming hypothesis in addiction,” they wrote. In their newly reported study, however, the epigenetic effects of cannabinoids were found to be specific to adolescents and to target the brain’s prefrontal cortex (PFC). This region of the brain plays a role in various executive functions, including long-term planning and self control, and is one of the last regions of the brain to reach maturity, a fact that has long been linked to adolescents’ propensity for risky behavior.

The team’s experimental results suggested that WIN pre-exposure resulted in cocaine-induced histone hyperacetylation in the adolescent PFC. Given that histone acetylation is known to increase chromatin accessibility, the team next asked whether the acetylation changes observed in the adolescent PFC translated into widespread changes in open chromatin regions. Their findings showed that histone hyperacetylation wasn’t associated with changes to chromatin accessibility on a genome-wide scale, but rather, WIN pre-exposure-linked cocaine-induced histone hyperacetylation was associated with “enhanced chromatin accessibility and alternative splicing events in a limited number of genes.”

The combined results of the investigators’ experiments indicated that cannabinoid exposure during adolescence led to alterations in subsequent cocaine-induced gene expression patterns, alternative splicing events in genes related to neurotransmitter receptor membrane localization, and enhanced effects of cocaine on protein phosphorylation. “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 results in rats offer up clues to the biological mechanisms that may underlie the way that different classes of drugs can reinforce each other in humans.

The reported findings also support the notion that cannabis abuse during adolescence might enhance an initial positive experience with cocaine, which in turn can have an effect on whether that person chooses to continue, or expand, their use of the drug. “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,” Denise Kandel added.

Interestingly, aberrant prefrontal cortex activity is often observed in patients suffering from addiction. Efforts to enhance the function of the prefrontal cortex are currently being evaluated in the treatment of addiction through the use of brain stimulation and other methodologies.

The authors acknowledged that while there were some limitations to their study, the findings could also have implications for future drug-related health policies. “Given the current increase in permissive societal and legal attitudes toward cannabis use, our study also highlights the need to further characterize the neurobiological consequences of cannabis exposure in adolescence in order to guide future legislature and public policies,” they concluded.

Most research involving rodents and addiction has traditionally focused on adult animals. It has also largely been limited to studying one substance of abuse at a time, without taking into consideration a history of drug exposure in adolescence. “These and other experiments are key to understanding the molecular changes to the brain that occur during drug use,” added Eric Kandel, who is also university professor and Kavli professor of brain science at Columbia. “This knowledge will be crucial for developing effective treatments that curb addiction by targeting the disease’s underlying mechanisms.”

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