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

Int J Mol Sci. 2023 Feb 15;24(4):3907. doi: 10.3390/ijms24043907.

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.

Keywords: dopamine D2/D3 receptors; methylazoxymethanol acetate; psychopathology; Δ9-tetrahydrocannabinol.

MeSH terms

  • Animals
  • Disease Models, Animal
  • Dopamine / metabolism
  • Dronabinol* / toxicity
  • Female
  • Humans
  • Prefrontal Cortex / drug effects
  • Prefrontal Cortex / metabolism
  • Pregnancy
  • Prenatal Exposure Delayed Effects* / metabolism
  • Rats
  • Receptors, Dopamine D3 / metabolism
  • Schizophrenia* / chemically induced

Substances

  • Dopamine
  • Dronabinol
  • Receptors, Dopamine D3

Grants and funding

This work was supported by the project “Preclinical and clinical research in pharmacokinetics, neuropsychopharmacology and personalized pharmacotherapy in oncology” (MUNI/A/1342/2022) with the support of the Specific University Research at Masaryk University provided by the Ministry of Education, Youth and Sports of the Czech Republic (MEYS CR) in the year 2022 and by SoMoPro II Programme (project No. 3SGA5789). This work was also supported by the Italian Minister of the University and Research (FIRS2019-00202; to C.D. and V.M.), by the Ministry of the Interior of the Czech Republic (project VK01010212; to M.K. and P.P.), and by Long-term conceptual development of research organization (RVO 00023752; to M.K.).