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Adolescent THC Exposure Enhances Impulsivity in Adulthood: Insights from a WIN 55,212-2 Self-Administration Mouse Model
E. Martín-García1,2, M. Cajiao-Manrique1, R. Maldonado1
1Universitat Pompeu Fabra, Medicina i Ciències de la Vida, Barcelona, Spain, 2Universitat Autònoma de Barcelona, Psicobiologia i Metodologia de las Ciències de la Salut, Barcelona, Spain

Background: Cannabis addiction is a chronic, relapsing disorder for which effective treatments remain unavailable. Regular cannabis use often begins during adolescence, and early exposure to cannabinoids may heighten the risk of addiction in adulthood.
Aims & Objectives: This study explores the impact of adolescent exposure to Δ9-tetrahydrocannabinol (THC), the primary psychoactive component of cannabis, on addiction-like behaviors in adult mice.
Method: Male mice were exposed to THC (5 mg/kg) daily from postnatal days 37 to 57. In adulthood, mice underwent operant self-administration sessions of WIN 55,212-2 (12.5 μg/kg/infusion) for 10 days and were evaluated for addiction-like criteria, including persistence of response, motivation, and compulsivity. Additionally, two parameters related to craving (resistance to extinction and drug-seeking behavior) and two vulnerability traits for addiction (impulsivity and reward sensitivity) were assessed. Gene expression analysis via qPCR was performed in the medial prefrontal cortex (mPFC), nucleus accumbens (NAc), dorsal striatum, and hippocampus (HPC) to identify differentially expressed genes in addicted versus non-addicted mice.
Results: Adolescent THC exposure did not influence WIN 55,212-2 reinforcement or the development of addiction-like behaviors. However, THC-exposed mice exhibited heightened impulsivity in adulthood, with this trait being more pronounced in mice meeting addiction criteria. Gene expression analysis revealed downregulation of drd2 and adora2a in the NAc and HPC of THC-exposed mice. Additionally, drd2 expression was downregulated in the mPFC of vehicle-treated mice that developed addiction-like behaviors.

FIGURE 1. (A) Complete experimental protocol of our mouse model of operant WIN 55,212–2 intravenous self-administration. (B–D) Mice of vehicle and THC adolescence pre-treatment groups present similar responses in the three addiction-like criteria tests (individual data with median and interquartile range): (B) Persistence to response: Number of responses to the active nose-poke during the 15 min drug-free period. (C) Motivation: The breaking point determined during a four-hour progressive reinforcement schedule represents the maximum number of responses an animal can do to obtain one drug infusion. (D) Compulsivity: Number of shocks received during WIN 55,212-2 self-administration. The dashed horizontal line indicates the 75th percentile of the distribution of the group, used as the threshold to consider a mouse positive for one criterion. Addicted mice are represented in grey- and green-filled circles. (E) Percentage of mice categorized as addicted and non-addicted in the vehicle and THC groups. (F–G) Impulsivity: number of responses to the active nose-poke during the 10 s time-out period (Student’s t-test, *p < 0.05). Addicted and non-addicted mice are shown in the filled circles (F) and the bars (G). (H) Characterization of low-impulsive (LI) and high-impulsive (HI) subgroups. Percentage of mice categorized as LI and HI (nVehicle = 16, nTHC = 14).
Discussion & Conclusions: These findings suggest that adolescent THC exposure increases impulsivity-like behavior in adulthood, potentially through alterations in drd2 and adora2a expression in key brain regions.
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