The Effects of Peripubertal THC Exposure in Neurodevelopmental Rat Models of Psychopathology.
Martina Di BartolomeoTibor StarkSerena Di MartinoFabio Arturo IannottiJana Ruda-KucerovaGiovanni Luca RomanoMartin KucharSamuele LaudaniPetr PalivecFabiana PiscitelliCarsten T WotjakClaudio BucoloFilippo DragoVincenzo Di MarzoClaudio D'AddarioVincenzo MicalePublished in: International journal of molecular sciences (2023)
Adolescent exposure to cannabinoids as a postnatal environmental insult may increase the risk of psychosis in subjects exposed to perinatal insult, as suggested by the two-hit hypothesis of schizophrenia. Here, we hypothesized that peripubertal Δ 9 -tetrahydrocannabinol (aTHC) may affect the impact of prenatal methylazoxymethanol acetate (MAM) or perinatal THC (pTHC) exposure in adult rats. We found that MAM and pTHC-exposed rats, when compared to the control group (CNT), were characterized by adult phenotype relevant to schizophrenia, including social withdrawal and cognitive impairment, as revealed by social interaction test and novel object recognition test, respectively. At the molecular level, we observed an increase in cannabinoid CB1 receptor ( Cnr1 ) and/or dopamine D2/D3 receptor ( Drd2, Drd3 ) gene expression in the prefrontal cortex of adult MAM or pTHC-exposed rats, which we attributed to changes in DNA methylation at key regulatory gene regions. Interestingly, aTHC treatment significantly impaired social behavior, but not cognitive performance in CNT groups. In pTHC rats, aTHC did not exacerbate the altered phenotype nor dopaminergic signaling, while it reversed cognitive deficit in MAM rats by modulating Drd2 and Drd3 gene expression. In conclusion, our results suggest that the effects of peripubertal THC exposure may depend on individual differences related to dopaminergic neurotransmission.