Rats exposed to THC before birth showed increased dopamine D1 and D2 receptor expression in the prefrontal cortex during adolescence, with male offspring showing reduced D2 DNA methylation, altered neuron excitability, and disrupted neural guidance cues.
Researchers studying prenatal cannabis effects and readers concerned about long-term impacts of THC exposure during pregnancy.
Male offspring showed reduced D2 receptor DNA methylation and altered prefrontal neuron excitability
What the researchers found
Prenatal cannabis exposure increased mRNA levels of dopamine D1 and D2 receptors in the prefrontal cortex, with a particularly strong effect on D2 in males. Male rats showed reduced Drd2 DNA methylation (potentially explaining increased expression), changes in selective miRNAs regulating both receptors, altered excitability of prefrontal pyramidal neurons, and disrupted Netrin-1/DCC guidance cue system. Endocannabinoid system gene expression remained stable.
Why it matters
The prefrontal cortex is critical for decision-making, impulse control, and emotional regulation, and it undergoes major development during adolescence. Finding that prenatal THC exposure reprograms dopamine signaling in this region through epigenetic mechanisms provides a biological pathway that could explain behavioral and psychiatric risks associated with prenatal cannabis exposure.
The numbers in context
Increased Drd1 and Drd2 mRNA in PFC. Male-specific: notable Drd2 increase, consistent reduction in Drd2 DNA methylation, altered PFC pyramidal neuron excitability, changes in Netrin-1/DCC system. Both receptors regulated by selective miRNAs. Endocannabinoid system genes showed stable expression.
How the study worked
An animal model of prenatal cannabis exposure was used, with offspring studied during adolescence. Researchers analyzed gene expression and DNA methylation of dopamine and endocannabinoid system genes in the prefrontal cortex, measured miRNA regulators, performed electrophysiological recordings of pyramidal neurons, and assessed the Netrin-1/DCC guidance cue system.
What this study cannot tell us
Animal model using controlled THC exposure that may not reflect human prenatal exposure patterns. Only adolescent timepoint was assessed; effects may differ at other ages. The specific THC dose and timing were not detailed in the abstract. Translation from rodent prefrontal cortex to human is imperfect.
How to read the evidence
Animal study with multi-level analysis (epigenetic, transcriptional, electrophysiological) but limited to one timepoint and species.
When this study was published
Published in 2025.
The bigger picture
The sex-specific nature of these findings is consistent with human epidemiological data showing that males may be more vulnerable to some neurodevelopmental effects of prenatal cannabis exposure. The epigenetic mechanism (DNA methylation changes) suggests these are not transient effects but persistent reprogramming of gene regulation that manifests during the critical adolescent period.
Questions still open
- Do these dopamine receptor changes persist into adulthood? Could they increase vulnerability to psychosis or addiction during adolescence? Would the effects be different with full-spectrum cannabis versus pure THC? Are similar sex-dependent epigenetic changes detectable in human offspring?
Common questions
Why does this matter for human pregnancies?
Why were males more affected?
Read the original research
Prenatal Delta-9-Tetrahydrocannabinol Exposure Induces Transcriptional Alterations in Dopaminergic System with Associated Electrophysiological Dysregulation in the Prefrontal Cortex of Adolescent Rats.
Cells, 14(12)
Citation
Di Bartolomeo, Martina; Aroni, Sonia; Serra, Marcello; Serra, Valeria; Martella, Francesca; Gilardini, Federica; Melis, Miriam; D'Addario, Claudio. (2025). Prenatal Delta-9-Tetrahydrocannabinol Exposure Induces Transcriptional Alterations in Dopaminergic System with Associated Electrophysiological Dysregulation in the Prefrontal Cortex of Adolescent Rats.. Cells, 14(12). https://doi.org/10.3390/cells14120904
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