The Effects of Peripubertal THC Exposure in Neurodevelopmental Rat Models of Psychopathology


DI BARTOLOMEO Martina ŠTARK Tibor DI MARTINO Serena IANNOTTI Fabio Arturo RUDÁ Jana ROMANO Giovanni Luca KUCHAR Martin LAUDANI Samuele PALIVEC Petr PISCITELLI Fabiana WOTJAK Carsten T BUCOLO Claudio DRAGO Filippo DI MARZO Vincenzo D'ADDARIO Claudio MICALE Vincenzo

Year of publication 2023
Type Article in Periodical
Magazine / Source International Journal of Molecular Sciences
MU Faculty or unit

Faculty of Medicine

Keywords tetra(9)-tetrahydrocannabinol; methylazoxymethanol acetate; dopamine; D2/D3 receptors; psychopathology
Description 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 ?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.
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