Adolescent female mice carrying a human FAAH gene variant associated with problematic drug use showed enhanced dopamine circuitry and stronger THC preference that persisted into adulthood.
Genetics researchers, addiction scientists, people interested in sex differences in cannabis effects
Effects were specific to adolescent females; males showed no enhanced THC vulnerability
What the researchers found
Adolescent female FAAHC/A mice (but not males) showed enhanced mesolimbic dopamine circuitry from VTA to nucleus accumbens, altered CB1 receptor levels at inhibitory and excitatory terminals in the VTA, and increased THC conditioned place preference that persisted into adulthood.
Why it matters
This identifies a specific genetic mechanism that could explain sex differences in cannabis vulnerability during adolescence, with relevance to a human gene variant already linked to substance use problems.
The numbers in context
The FAAH polymorphism enhanced VTA-to-NAc dopamine circuitry and altered CB1R at both inhibitory and excitatory VTA terminals specifically in adolescent females. THC preference persisted into adulthood.
How the study worked
Genetic knock-in mouse model (FAAHC/A) recapitulating a human FAAH polymorphism associated with problematic drug use. Researchers examined mesolimbic dopamine circuitry, CB1R levels, and THC conditioned place preference in adolescent and adult mice of both sexes.
What this study cannot tell us
Mouse model; THC conditioned place preference is a proxy for reward, not direct addiction; the FAAH variant studied is one of many genetic factors that could influence cannabis vulnerability.
How to read the evidence
Single animal study using a genetic knock-in model, examining one polymorphism in one species.
When this study was published
Published in 2020.
The bigger picture
Sex-specific genetic vulnerability to cannabis during adolescence could help explain why some young people develop cannabis dependence while others do not, and why rates may differ between males and females.
Questions still open
- Do human adolescent females carrying this FAAH variant show higher rates of cannabis dependence? Could this finding inform targeted prevention strategies?
Common questions
Why were only females affected?
How common is this FAAH gene variant in humans?
Read the original research
Endocannabinoid genetic variation enhances vulnerability to THC reward in adolescent female mice.
Science advances, 6(7), eaay1502
Citation
Burgdorf, Caitlin E; Jing, Deqiang; Yang, Ruirong; Huang, Chienchun; Hill, Matthew N; Mackie, Ken; Milner, Teresa A; Pickel, Virginia M; Lee, Francis S; Rajadhyaksha, Anjali M. (2020). Endocannabinoid genetic variation enhances vulnerability to THC reward in adolescent female mice.. Science advances, 6(7), eaay1502. https://doi.org/10.1126/sciadv.aay1502
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