Mice exposed to the synthetic cannabinoid WIN55,212-2 during adolescence showed reduced cocaine reward (conditioned place preference) in adulthood, accompanied by increased DNMT3a expression in the prefrontal cortex, without changes in anxiety or depression.
Addiction researchers, epigenetics investigators, gateway hypothesis researchers
Adolescent cannabinoid exposure blocked cocaine reward without increasing anxiety or depression
What the researchers found
Adolescent WIN55,212-2 exposure did not alter anxiety or depression in adulthood. However, it blocked cocaine-induced conditioned place preference (a measure of drug reward) without affecting cocaine-induced hyperlocomotion. This was accompanied by increased expression of DNA methyltransferase 3a (DNMT3a) in the prefrontal cortex, suggesting epigenetic changes may modulate cocaine reward sensitivity.
Why it matters
Counter to the gateway hypothesis, this study found adolescent cannabinoid exposure actually reduced cocaine reward sensitivity. The epigenetic mechanism (DNMT3a upregulation) provides a molecular explanation for how early cannabinoid exposure could alter drug reward processing.
The numbers in context
Adolescent WIN55,212-2 exposure; no change in anxiety or depression; blocked cocaine-induced conditioned place preference; no effect on cocaine-induced hyperlocomotion; increased DNMT3a expression in prefrontal cortex
How the study worked
Swiss mice received WIN55,212-2 during adolescence. In adulthood, tested for anxiety (elevated plus maze), depression (forced swim), locomotor activity, and cocaine reward (conditioned place preference). DNMT3a expression measured by real-time PCR in prefrontal cortex.
What this study cannot tell us
Synthetic cannabinoid (WIN55,212-2) may not represent natural cannabis use. Male mice only. Conditioned place preference is one measure of reward; other aspects of addiction (compulsive seeking, relapse) not tested. DNMT3a change is correlational, not proven causal.
How to read the evidence
Novel finding combining behavioral and molecular endpoints, but limited to male mice with a synthetic cannabinoid.
When this study was published
Published in 2021.
The bigger picture
The finding that adolescent cannabinoid exposure increased DNMT3a (a DNA methylation enzyme) and reduced cocaine reward adds complexity to the gateway drug debate. Rather than sensitizing the brain to other drugs, cannabinoid exposure may actually dampen reward responses through epigenetic reprogramming.
Questions still open
- Would natural THC exposure produce the same reduction in cocaine reward? Is the DNMT3a increase protective against cocaine addiction or does it have other behavioral consequences?
Common questions
Does this contradict the gateway drug theory?
What is DNMT3a?
Read the original research
Adolescent cannabinoid exposure modulates the vulnerability to cocaine-induced conditioned place preference and DNMT3a expression in the prefrontal cortex in Swiss mice.
Psychopharmacology, 238(11), 3107-3118
Citation
Gobira, P H; Roncalho, A L; Silva, N R; Silote, G P; Sales, A J; Joca, S R. (2021). Adolescent cannabinoid exposure modulates the vulnerability to cocaine-induced conditioned place preference and DNMT3a expression in the prefrontal cortex in Swiss mice.. Psychopharmacology, 238(11), 3107-3118. https://doi.org/10.1007/s00213-021-05926-4
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