Altered dopamine D3 receptor gene expression in MAM model of schizophrenia is reversed by peripubertal cannabidiol treatment.

Animals Antipsychotic Agents / pharmacology Brain / diagnostic imaging Cannabidiol / chemistry Cerebrovascular Circulation Disease Models, Animal Female Gene Expression Regulation Haloperidol / chemistry Magnetic Resonance Imaging Male Methylazoxymethanol Acetate / toxicity Models, Molecular Molecular Dynamics Simulation Pregnancy Prenatal Exposure Delayed Effects Puberty Rats, Sprague-Dawley Receptors, Dopamine D2 / chemistry Receptors, Dopamine D3 / chemistry Schizophrenia / chemically induced

Arterial Spine Labelling Cannabidiol Dopamine D3 receptor MAM model Molecular Dynamics Schizophrenia

Journal

Biochemical pharmacology

ISSN: 1873-2968

Titre abrégé: Biochem Pharmacol

Pays: England

ID NLM: 0101032

Informations de publication

Date de publication:
07 2020

Historique:

received: 28 01 2020

accepted: 24 04 2020

pubmed: 4 5 2020

medline: 15 12 2020

entrez: 4 5 2020

Statut: ppublish

Résumé

Gestational methylazoxymethanol acetate (MAM) treatment produces offspring with adult phenotype relevant to schizophrenia, including positive- and negative-like symptoms, cognitive deficits, dopaminergic dysfunction, structural and functional abnormalities. Here we show that adult rats prenatally treated with MAM at gestational day 17 display significant increase in dopamine D3 receptor (D3) mRNA expression in prefrontal cortex (PFC), hippocampus and nucleus accumbens, accompanied by increased expression of dopamine D2 receptor (D2) mRNA exclusively in the PFC. Furthermore, a significant change in the blood perfusion at the level of the circle of Willis and hippocampus, paralleled by the enlargement of lateral ventricles, was also detected by magnetic resonance imaging (MRI) techniques. Peripubertal treatment with the non-euphoric phytocannabinoid cannabidiol (30 mg/kg) from postnatal day (PND) 19 to PND 39 was able to reverse in MAM exposed rats: i) the up-regulation of the dopamine D3 receptor mRNA (only partially prevented by haloperidol 0.6 mg/kg/day); and ii) the regional blood flow changes in MAM exposed rats. Molecular modelling predicted that cannabidiol could bind preferentially to dopamine D3 receptor, where it may act as a partial agonist according to conformation of ionic-lock, which is highly conserved in GPCRs. In summary, our results demonstrate that the mRNA expression of both dopamine D2 and D3 receptors is altered in the MAM model; however only the transcript levels of D3 are affected by cannabidiol treatment, likely suggesting that this gene might not only contribute to the schizophrenia symptoms but also represent an unexplored target for the antipsychotic activity of cannabidiol.

Identifiants

DOI: 10.1016/j.bcp.2020.114004 PMID: 32360362

pubmed: 32360362

pii: S0006-2952(20)30232-X

doi: 10.1016/j.bcp.2020.114004

pii:

doi:

Substances chimiques

Antipsychotic Agents 0

DRD2 protein, mouse 0

Receptors, Dopamine D2 0

Receptors, Dopamine D3 0

Cannabidiol 19GBJ60SN5

Methylazoxymethanol Acetate 592-62-1

Haloperidol J6292F8L3D

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

Pagination

114004

Informations de copyright

Déclaration de conflit d'intérêts

Declaration of Competing Interest VD is a consultant for GW Pharmaceuticals, UK, and FAI, FP and VD receive funding from GW Pharmaceuticals, UK. CTW is employed by Boehringer Ingelheime Pharma & Co KG which did not influence design, analysis and interpretation of the study.