The Effects of Peripubertal THC Exposure in Neurodevelopmental Rat Models of Psychopathology
Martina di Bartolomeo, Tibor Stark, Serena di Martino, Fabio Arturo Iannotti, Jana Kučerová, Giovanni Luca Romano, Martin Kuchař, Samuele Laudani, Petr Palivec, Fabiana Piscitelli, Carsten T. Wotjak, Claudio Bucolo, Filippo Drago, Vincenzo di Marzo, Claudio D’addario, Vincenzo Micale
International Journal of Molecular Sciences February 15, 2023 DOI: 10.3390/ijms24043907 via OpenAlex
Summary
Rats exposed to the toxin methylazoxymethanol acetate (MAM) before birth or to THC shortly after birth showed adult behaviors resembling schizophrenia, such as social withdrawal and memory problems, along with increased expression of cannabinoid and dopamine receptor genes in the prefrontal cortex linked to DNA methylation changes. Giving THC during adolescence impaired social behavior in otherwise healthy rats but did not worsen the schizophrenia-like traits in rats already exposed to THC after birth. In rats exposed to MAM before birth, adolescent THC paradoxically reversed their memory deficit by altering dopamine receptor gene expression. The effects of adolescent THC exposure appear to depend on individual differences in dopamine signaling.
Study at a glance
| Characteristics | Experimental animal study Peer reviewed |
|---|---|
| Population | Adult rats |
| Interventions | prenatal methylazoxymethanol acetate (MAM) perinatal THC peripubertal Δ9-tetrahydrocannabinol (aTHC) |
| Keywords | Dopaminergic Schizophrenia object-oriented programming Prefrontal cortex Cannabinoid Psychosis |
| Citations | 23 |
| Key finding | Peripubertal THC exposure reversed cognitive deficits in rats prenatally exposed to MAM by modulating dopamine receptor gene expression, but did not exacerbate the altered phenotype in rats perinatally exposed to THC. |
Abstract
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 Δ9-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.