THC exposure during adolescence increases impulsivity-like behavior in adulthood in a WIN 55,212-2 self-administration mouse model

Front Psychiatry. 2023 May 25:14:1148993. doi: 10.3389/fpsyt.2023.1148993. eCollection 2023.

Abstract

Background: Cannabis addiction is a chronically relapsing disorder lacking effective treatment. Regular cannabis consumption typically begins during adolescence, and this early cannabinoid exposure may increase the risk for drug addiction in adulthood.

Objective: This study investigates the development of cannabis addiction-like behavior in adult mice after adolescent exposure to the main psychoactive component of cannabis, Δ9-tetrahydrocannabinol (THC).

Methods: Adolescent male mice were exposed to 5 mg/kg of THC from postnatal days 37 to 57. Operant self-administration sessions of WIN 55,212-2 (12.5 μg/kg/infusion) were conducted for 10 days. Mice were tested for three addiction-like criteria (persistence of response, motivation, and compulsivity), two parameters related to craving (resistance to extinction and drug-seeking behavior), and two phenotypic vulnerability traits related to substance use disorders (impulsivity and reward sensitivity). Additionally, qPCR assays were performed to detect differentially expressed genes in medial prefrontal cortex (mPFC), nucleus accumbens (NAc), dorsal striatum, and hippocampus (HPC) of "addicted" and "non-addicted" mice.

Results: Adolescent THC exposure did not modify WIN 55,212-2 reinforcement nor the development of cannabis addiction-like behavior. Inversely, THC pre-exposed mice displayed impulsive-like behavior in adulthood, which was more pronounced in mice that developed the addiction-like criteria. Moreover, downregulated drd2 and adora2a gene expression in NAc and HPC was revealed in THC pre-exposed mice, as well as a downregulation of drd2 expression in mPFC of vehicle pre-treated mice that developed addiction-like behaviors.

Discussion: These findings suggest that adolescent THC exposure may promote impulsivity-like behavior in adulthood, associated with downregulated drd2 and adora2a expression in NAc and HPC.

Keywords: THC; WIN 55,212-2 self-administration mouse model; adolescence; adora2a; cannabis addiction; drd2; impulsivity.

Grants and funding

This work was supported by the Spanish “Ministerio de Ciencia e Innovación (MICIN), Agencia Estatal de Investigación (AEI)” (PID2020-120029GB-I00/MICIN/AEI/10.13039/501100011033, R D21/0009/0019) to RM, the “Generalitat de Catalunya, AGAUR” (2017 SGR-669) to RM, the “ICREA-Acadèmia” (2020) to RM, the “European Commission-DG Research” (PainFact, H2020-SC1-2019-2-RTD-848099 and QSPain Relief, H2020-SC1-2019-2-RTD-848068) to RM, the Spanish “La Caixa” Foundation under the project code LCF/PR/HR22/52420017 to RM, the Spanish “Instituto de Salud Carlos III, RETICS-RTA” (RD16/0017/0020) to RM, the Spanish “Ministerio de Sanidad, Servicios Sociales e Igualdad, Plan Nacional Sobre Drogas” (PNSD-2021I076 to RM and PNSD-2019I006 to EM-G), and Ministerio de Ciencia e Innovación (ERA-NET NEURON) PCI2021-122073-2A to EM-G. MC-M acknowledged the Generalitat de Catalunya and the AGAUR for a “FI-SDUR” scholarship (EMC/3345/2020). AG-B acknowledged the Generalitat de Catalunya and the AGAUR for the “FI” scholarship (FI_B00337_2020). VC-A acknowledged the Spanish MCIN/AEI/10.13039/501100011033 for a “Juan de la Cierva” fellowship (FJC2019-041020-I).