Chronic exposure to cannabinoids during adolescence causes long‐lasting behavioral deficits in adult mice

Abstract

Regular use of marijuana during adolescence enhances the risk of long‐lasting neurobiological changes in adulthood. The present study was aimed at assessing the effect of long‐term administration of the synthetic cannabinoid WIN55212.2 during adolescence in young adult mice. Adolescent mice aged 5 weeks were subjected daily to the pharmacological action of WIN55212.2 for 3 weeks and were then left undisturbed in their home cage for a 5‐week period and finally evaluated by behavioral testing. Mice that received the drug during adolescence showed memory impairment in the Morris water maze, as well as a dose‐dependent memory impairment in fear conditioning. In addition, the administration of 3 mg/kg WIN55212.2 in adolescence increased adult hippocampal AEA levels and promoted DNA hypermethylation at the intragenic region of the intracellular signaling modulator Rgs7, which was accompanied by a lower rate of mRNA transcription of this gene, suggesting a potential causal relation. Although the concrete mechanisms underlying the behavioral observations remain to be elucidated, we demonstrate that long‐term administration of 3 mg/kg of WIN during adolescence leads to increased endocannabinoid levels and altered Rgs7 expression in adulthood and establish a potential link to epigenetic changes.

Concomitant THC and stress adolescent exposure induces impaired fear extinction and related neurobiological changes in adulthood

“…In agreement with our data, no lasting effects by adolescent THC exposure were previously observed in aversive memory as revealed by the lack of deficits in passive avoidance task (Rubino et al, 2009a;Rubino et al, 2009b) or cued and contextual fear conditioning (Ballinger et al, 2015). However, a long-lasting impairment of fear conditioning has been described after chronic administration of the synthetic cannabinoid WIN 55,212-2 during adolescence (Gleason et al, 2012;Tomas-Roig et al, 2017), which has a higher intrinsic activity on cannabinoid receptors than THC (Kuster et al, 1993). On the other hand, repeated adolescent CB1R antagonism induced greater contextual fear memory recall in adult female, but not male, rats in comparison with control animals (Simone et al, 2018b).…”

The Effects of Cannabinoids on Executive Functions: Evidence from Cannabis and Synthetic Cannabinoids—A Systematic Review

“…In addition, further preclinical research is needed to examine the degree of persistence of deficiencies induced by chronic treatments with cannabinoid agonists [ 31 ]. Yet, a growing number of publications indicate that exposures to cannabinoids in early age are associated with greater and persistent WM deficits, suggesting that the age of onset may be a mediating factor in the association between cannabinoids and WM performance [ 32 , 106 , 111 , 112 , 113 ].…”

The Developmental Neuroepigenetics of Substance Abuse

“…Similar effects are noted in adult populations, with chronic exposure to exogenous cannabinoids producing unique impairments in emotionality, serotoninergic and GABAergic transmission [313,314,315]. Given these behavioral effects and alterations in multiple neural systems, investigations of the epigenetic mechanisms underlying the effects of cannabinoids have been reported and discussed at length (for review, see [316]).…”