When it comes to preparing for a future situation, our epigenome usually has our back; however, sometimes epigenetic alterations can prime some undesirable responses as a result of environmental exposure. With legalization occurring in many states and nations, research into how cannabis alters our epigenome has entered the spotlight. We have recently seen that cannabis can alter sperm DNA methylation, and now, a fascinating study looking at a later stage of development describes how cannabis exposure in adolescent rats primes an epigenetic gateway to cocaine addiction.
The endocannabinoid system influences neural pathways that regulate reward response as well as learning and memory, and a wealth of studies have led to the hypothesis that interfering with endocannabinoid signaling through, for example, the abuse of psychoactive cannabinoids may remodel or “cross-sensitize” the adolescent brain to enhance responses following exposure to other highly addictive substances. Recently, a team of researchers led by Nobel laureate Eric R. Kandel, Denise B. Kandel, and Philippe A. Melas (Columbia University, New York, NY, USA) sought to describe the molecular underpinnings of this cross-sensitization, and have now linked cannabinoid exposure in adolescent rats to the development of a unique epigenetic profile in the prefrontal cortex following cocaine-induced exposure that prompts enhanced stimulatory effects. Importantly, the mammalian prefrontal cortex continues to mature during adolescence and participates in addiction-related processes.
So what did Scherma and Colleagues discover in their stimulating new study that employed epigenomic, transcriptomic, proteomic, and phosphoproteomic analyses in a previously characterized rat model?
- Chronic exposure of adolescent rats (but not adults) to increasing doses of a synthetic cannabinoid results in cross-sensitization to cocaine administered eight days after the last cannabinoid treatment
- The heightened response to cocaine correlates with pan-histone hyperacetylation, but not histone methylation or phosphorylation, in the prefrontal cortex
- Interestingly, assays of chromatin accessibility via ATAC-seq failed to reveal genome-wide aberrations in the adolescent prefrontal cortex associated with cross-sensitization, as perhaps would be expected given the rise in histone acetylation
- Instead, the study uncovered enhanced chromatin accessibility at specific genes, including the Npas2 (neuronal PAS domain protein 2) gene, which codes for a transcription factor involved in cocaine reward sensitivity and glutamatergic transmission
- Nucleosome repositioning and alternate splicing also correlate with the increase in chromatin accessibility at these specific genes
- While altered HDAC4 splicing events occur in cross-sensitized rats, proteomic analysis suggest that reduced nuclear levels of HDAC6 induce pan-histone hyperacetylation in the prefrontal cortex
- Cross-sensitization also associates with increases in the levels of ERK/MAPK-signaling and global protein hyperphosphorylation, which can influence HDAC6 activity (and vice-versa) and cocaine-induced behavioral sensitization
- These alterations also modulate factors involved in glutamine-mediated synaptic activity, which may mediate some of the neurological effects observed
While these findings have helped to describe the molecular pathways underpinning the neurobehavioral consequences of adolescent drug abuse, the authors also believe that this study has societal and legal relevance given the more permissive view of cannabinoid use seen worldwide. Therefore, they highlight the need for further characterization of the neurobiological consequences of adolescent drug use as an aid to policymakers.
“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 Philippe A. Melas, co-leader of the study.
“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,” said Denise B. Kandel, co-leader of the study.
“These and other experiments are key to understanding the molecular changes to the brain that occur during drug use,” said Eric R. Kandel, co-leader of the study “This knowledge will be crucial for developing effective treatments that curb addiction by targeting the disease’s underlying mechanisms.”
For a deep dive into this highly stimulating read, head over to PNAS, April 2020, now!