TY - JOUR
T1 - Crosstalk between the transcriptional regulation of dopamine D2 and cannabinoid CB1 receptors in schizophrenia
T2 - Analyses in patients and in perinatal Δ9-tetrahydrocannabinol-exposed rats
AU - Di Bartolomeo, Martina
AU - Stark, Tibor
AU - Maurel, Oriana Maria
AU - Iannotti, Fabio Arturo
AU - Kuchar, Martin
AU - Ruda-Kucerova, Jana
AU - Piscitelli, Fabiana
AU - Laudani, Samuele
AU - Pekarik, Vladimir
AU - Salomone, Salvatore
AU - Arosio, Beatrice
AU - Mechoulam, Raphael
AU - Maccarrone, Mauro
AU - Drago, Filippo
AU - Wotjak, Carsten T.
AU - Di Marzo, Vincenzo
AU - Vismara, Matteo
AU - Dell'Osso, Bernardo
AU - D'Addario, Claudio
AU - Micale, Vincenzo
N1 - Publisher Copyright:
© 2020 Elsevier Ltd
Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2020/12
Y1 - 2020/12
N2 - Perinatal exposure to Δ9-tetrahydrocannabinol (THC) affects brain development and might increase the incidence of psychopathology later in life, which seems to be related to a dysregulation of endocannabinoid and/or dopaminergic systems. We here evaluated the transcriptional regulation of the genes encoding for the cannabinoid CB1 receptor (Cnr1) and the dopamine D2 receptor (Drd2) in perinatal THC-(pTHC) exposed male rats, focusing on the role of DNA methylation analyzed by pyrosequencing. Simultaneously, the molecular and behavioral abnormalities at two different time points (i.e., neonatal age and adulthood) and the potential preventive effect of peripubertal treatment with cannabidiol, a non-euphoric component of Cannabis, were assessed. The DRD2 methylation was also evaluated in a cohort of subjects with schizophrenia. We observed an increase in both Cnr1 and Drd2 mRNA levels selectively in the prefrontal cortex of adult pTHC-exposed rats with a consistent reduction in DNA methylation at the Drd2 regulatory region, paralleled by social withdrawal and cognitive impairment which were reversed by cannabidiol treatment. These adult abnormalities were preceded at neonatal age by delayed appearance of neonatal reflexes, higher Drd2 mRNA and lower 2-arachidonoylglycerol (2-AG) brain levels, which persisted till adulthood. Alterations of the epigenetic mark for DRD2 were also found in subjects with schizophrenia. Overall, reported data add further evidence to the dopamine-cannabinoid interaction in terms of DRD2 and CNR1 dysregulation which could be implicated in the pathogenesis of schizophrenia spectrum disorders, suggesting that cannabidiol treatment may normalize pTHC-induced psychopathology by modulating the altered dopaminergic activity.
AB - Perinatal exposure to Δ9-tetrahydrocannabinol (THC) affects brain development and might increase the incidence of psychopathology later in life, which seems to be related to a dysregulation of endocannabinoid and/or dopaminergic systems. We here evaluated the transcriptional regulation of the genes encoding for the cannabinoid CB1 receptor (Cnr1) and the dopamine D2 receptor (Drd2) in perinatal THC-(pTHC) exposed male rats, focusing on the role of DNA methylation analyzed by pyrosequencing. Simultaneously, the molecular and behavioral abnormalities at two different time points (i.e., neonatal age and adulthood) and the potential preventive effect of peripubertal treatment with cannabidiol, a non-euphoric component of Cannabis, were assessed. The DRD2 methylation was also evaluated in a cohort of subjects with schizophrenia. We observed an increase in both Cnr1 and Drd2 mRNA levels selectively in the prefrontal cortex of adult pTHC-exposed rats with a consistent reduction in DNA methylation at the Drd2 regulatory region, paralleled by social withdrawal and cognitive impairment which were reversed by cannabidiol treatment. These adult abnormalities were preceded at neonatal age by delayed appearance of neonatal reflexes, higher Drd2 mRNA and lower 2-arachidonoylglycerol (2-AG) brain levels, which persisted till adulthood. Alterations of the epigenetic mark for DRD2 were also found in subjects with schizophrenia. Overall, reported data add further evidence to the dopamine-cannabinoid interaction in terms of DRD2 and CNR1 dysregulation which could be implicated in the pathogenesis of schizophrenia spectrum disorders, suggesting that cannabidiol treatment may normalize pTHC-induced psychopathology by modulating the altered dopaminergic activity.
KW - Cannabidiol
KW - Cannabinoid CB1 receptor
KW - DNA methylation
KW - Dopamine D2 receptor
KW - Epigenetics
KW - Schizophrenia
KW - THC
UR - http://www.scopus.com/inward/record.url?scp=85099693901&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85099693901&partnerID=8YFLogxK
U2 - 10.1016/j.phrs.2020.105357
DO - 10.1016/j.phrs.2020.105357
M3 - Article
C2 - 33285233
AN - SCOPUS:85099693901
JO - Pharmacological Research
JF - Pharmacological Research
SN - 1043-6618
M1 - 105357
ER -