TY - JOUR
T1 - Peripubertal cannabidiol treatment rescues behavioral and neurochemical abnormalities in the MAM model of schizophrenia
AU - Stark, Tibor
AU - Ruda-Kucerova, Jana
AU - Iannotti, Fabio Arturo
AU - D'Addario, Claudio
AU - Di Marco, Roberta
AU - Pekarik, Vladimir
AU - Drazanova, Eva
AU - Piscitelli, Fabiana
AU - Bari, Monica
AU - Babinska, Zuzana
AU - Giurdanella, Giovanni
AU - Di Bartolomeo, Martina
AU - Salomone, Salvatore
AU - Sulcova, Alexandra
AU - Maccarrone, Mauro
AU - Wotjak, Carsten T.
AU - Starcuk, Zenon
AU - Drago, Filippo
AU - Mechoulam, Raphael
AU - Di Marzo, Vincenzo
AU - Micale, Vincenzo
PY - 2018
Y1 - 2018
N2 - In agreement with the neurodevelopmental hypothesis of schizophrenia, prenatal exposure of rats to the antimitotic agent methylazoxymethanol acetate (MAM) at gestational day 17 produced long-lasting behavioral alterations such as social withdrawal and cognitive impairment in the social interaction test and in the novel object recognition test, respectively. At the molecular level, an increased cannabinoid receptor type-1 (CB1) mRNA and protein expression, which might be due to reduction in DNA methylation at the gene promoter in the prefrontal cortex (PFC), coincided with deficits in the social interaction test and in the novel object recognition test in MAM rats. Both the schizophrenia-like phenotype and altered transcriptional regulation of CB1 receptors were reversed by peripubertal treatment (from PND 19 to PND 39) with the non-psychotropic phytocannabinoid cannabidiol (30 mg/kg/day), or, in part, by treatment with the cannabinoid CB1 receptor antagonist/inverse agonist AM251 (0.5 mg/kg/day), but not with haloperidol (0.6 mg/kg/day). These results suggest that early treatment with cannabidiol may prevent both the appearance of schizophrenia-like deficits as well as CB1 alterations in the PFC at adulthood, supporting that peripubertal cannabidiol treatment might be protective against MAM insult.
AB - In agreement with the neurodevelopmental hypothesis of schizophrenia, prenatal exposure of rats to the antimitotic agent methylazoxymethanol acetate (MAM) at gestational day 17 produced long-lasting behavioral alterations such as social withdrawal and cognitive impairment in the social interaction test and in the novel object recognition test, respectively. At the molecular level, an increased cannabinoid receptor type-1 (CB1) mRNA and protein expression, which might be due to reduction in DNA methylation at the gene promoter in the prefrontal cortex (PFC), coincided with deficits in the social interaction test and in the novel object recognition test in MAM rats. Both the schizophrenia-like phenotype and altered transcriptional regulation of CB1 receptors were reversed by peripubertal treatment (from PND 19 to PND 39) with the non-psychotropic phytocannabinoid cannabidiol (30 mg/kg/day), or, in part, by treatment with the cannabinoid CB1 receptor antagonist/inverse agonist AM251 (0.5 mg/kg/day), but not with haloperidol (0.6 mg/kg/day). These results suggest that early treatment with cannabidiol may prevent both the appearance of schizophrenia-like deficits as well as CB1 alterations in the PFC at adulthood, supporting that peripubertal cannabidiol treatment might be protective against MAM insult.
KW - Cannabidiol
KW - Cannabinoid CB1 receptor
KW - MAM model
KW - Schizophrenia
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U2 - 10.1016/j.neuropharm.2018.11.035
DO - 10.1016/j.neuropharm.2018.11.035
M3 - Article
C2 - 30496751
AN - SCOPUS:85058120018
VL - 146
SP - 212
EP - 221
JO - Neuropharmacology
JF - Neuropharmacology
SN - 0028-3908
ER -