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

J 2020

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

ŠTARK, Tibor, Martina DI BARTOLOMEO, Roberta DI MARCO, Eva DRAŽANOVÁ, Chiara Bianca Maria PLATANIA et. al.

Basic information

Original name

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

Authors

ŠTARK, Tibor (703 Slovakia, belonging to the institution), Martina DI BARTOLOMEO (380 Italy), Roberta DI MARCO (380 Italy), Eva DRAŽANOVÁ (203 Czech Republic, belonging to the institution), Chiara Bianca Maria PLATANIA (380 Italy), Fabio Arturo IANNOTTI (380 Italy), Jana RUDÁ (203 Czech Republic, belonging to the institution), Claudio D'ADDARIO (380 Italy), Lucie KRATKA (203 Czech Republic), Vladimír PEKAŘÍK (203 Czech Republic, belonging to the institution), Fabiana PISCITELLI (380 Italy), Zuzana BABINSKÁ (703 Slovakia, belonging to the institution), Julia FEDOTOVA (643 Russian Federation), Giovanni GIURDANELLA (380 Italy), Salvatore SALOMONE (380 Italy), Alexandra SULCOVA (203 Czech Republic), Claudio BUCOLO (380 Italy), Carsten T. WOTJAK (276 Germany), Zenon, Jr. STARCUK (203 Czech Republic), Filippo DRAGO (380 Italy), Raphael MECHOULAM (376 Israel), Vincenzo DI MARZO (380 Italy) and Vincenzo MICALE (380 Italy, guarantor)

Edition

Biochemical Pharmacology, OXFORD, PERGAMON-ELSEVIER SCIENCE LTD, 2020, 0006-2952

Other information

Language

English

Type of outcome

Článek v odborném periodiku

Field of Study

30104 Pharmacology and pharmacy

Country of publisher

United Kingdom of Great Britain and Northern Ireland

Confidentiality degree

není předmětem státního či obchodního tajemství

References:

URL

Impact factor

Impact factor: 5.858

RIV identification code

RIV/00216224:14110/20:00116001

Organization unit

Faculty of Medicine

DOI

http://dx.doi.org/10.1016/j.bcp.2020.114004

UT WoS

000541248000065

Keywords in English

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

Abstract

V originále

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 upregulation 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.

Links

EF16_013/0001775, research and development project

Name: Modernizace a podpora výzkumných aktivit národní infrastruktury pro biologické a medicínské zobrazování Czech-BioImaging

LM2015062, research and development project

Name: Národní infrastruktura pro biologické a medicínské zobrazování

Investor: Ministry of Education, Youth and Sports of the CR

MUNI/A/1292/2019, interní kód MU

Name: Preklinický a klinický výzkum studentů v oblasti farmakokinetiky, neuropsychofarmakologie a personalizované farmakoterapie v onkologii

Investor: Masaryk University, Category A

Citovat

ŠTARK, Tibor, Martina DI BARTOLOMEO, Roberta DI MARCO, Eva DRAŽANOVÁ, Chiara Bianca Maria PLATANIA, Fabio Arturo IANNOTTI, Jana RUDÁ, Claudio D'ADDARIO, Lucie KRATKA, Vladimír PEKAŘÍK, Fabiana PISCITELLI, Zuzana BABINSKÁ, Julia FEDOTOVA, Giovanni GIURDANELLA, Salvatore SALOMONE, Alexandra SULCOVA, Claudio BUCOLO, Carsten T. WOTJAK, Zenon, Jr. STARCUK, Filippo DRAGO, Raphael MECHOULAM, Vincenzo DI MARZO and Vincenzo MICALE. Altered dopamine D3 receptor gene expression in MAM model of schizophrenia is reversed by peripubertal cannabidiol treatment. Biochemical Pharmacology. OXFORD: PERGAMON-ELSEVIER SCIENCE LTD, 2020, vol. 177, July 2020, p. 1-12. ISSN 0006-2952. Available from: https://dx.doi.org/10.1016/j.bcp.2020.114004.

@article{1670462,
   author = {Štark, Tibor and Di Bartolomeo, Martina and Di Marco, Roberta and Dražanová, Eva and Platania, Chiara Bianca Maria and Iannotti, Fabio Arturo and Rudá, Jana and D'Addario, Claudio and Kratka, Lucie and Pekařík, Vladimír and Piscitelli, Fabiana and Babinská, Zuzana and Fedotova, Julia and Giurdanella, Giovanni and Salomone, Salvatore and Sulcova, Alexandra and Bucolo, Claudio and Wotjak, Carsten T. and Starcuk, Zenon, Jr. and Drago, Filippo and Mechoulam, Raphael and Di Marzo, Vincenzo and Micale, Vincenzo},
   article_location = {OXFORD},
   article_number = {July 2020},
   doi = {http://dx.doi.org/10.1016/j.bcp.2020.114004},
   keywords = {Cannabidiol; Dopamine D3 receptor; Molecular Dynamics; Arterial Spine Labelling; MAM model; Schizophrenia},
   language = {eng},
   issn = {0006-2952},
   journal = {Biochemical Pharmacology},
   title = {Altered dopamine D3 receptor gene expression in MAM model of schizophrenia is reversed by peripubertal cannabidiol treatment},
   url = {https://www.sciencedirect.com/science/article/pii/S000629522030232X?via%3Dihub},
   volume = {177},
   year = {2020}
}

TY  - JOUR
ID  - 1670462
AU  - Štark, Tibor - Di Bartolomeo, Martina - Di Marco, Roberta - Dražanová, Eva - Platania, Chiara Bianca Maria - Iannotti, Fabio Arturo - Rudá, Jana - D'Addario, Claudio - Kratka, Lucie - Pekařík, Vladimír - Piscitelli, Fabiana - Babinská, Zuzana - Fedotova, Julia - Giurdanella, Giovanni - Salomone, Salvatore - Sulcova, Alexandra - Bucolo, Claudio - Wotjak, Carsten T. - Starcuk, Zenon, Jr. - Drago, Filippo - Mechoulam, Raphael - Di Marzo, Vincenzo - Micale, Vincenzo
PY  - 2020
TI  - Altered dopamine D3 receptor gene expression in MAM model of schizophrenia is reversed by peripubertal cannabidiol treatment
JF  - Biochemical Pharmacology
VL  - 177
IS  - July 2020
SP  - 1-12
EP  - 1-12
PB  - PERGAMON-ELSEVIER SCIENCE LTD
SN  - 00062952
KW  - Cannabidiol
KW  - Dopamine D3 receptor
KW  - Molecular Dynamics
KW  - Arterial Spine Labelling
KW  - MAM model
KW  - Schizophrenia
UR  - https://www.sciencedirect.com/science/article/pii/S000629522030232X?via%3Dihub
L2  - https://www.sciencedirect.com/science/article/pii/S000629522030232X?via%3Dihub
N2  - 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 upregulation 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.
ER  -

ŠTARK, Tibor, Martina DI BARTOLOMEO, Roberta DI MARCO, Eva DRAŽANOVÁ, Chiara Bianca Maria PLATANIA, Fabio Arturo IANNOTTI, Jana RUDÁ, Claudio D'ADDARIO, Lucie KRATKA, Vladimír PEKAŘÍK, Fabiana PISCITELLI, Zuzana BABINSKÁ, Julia FEDOTOVA, Giovanni GIURDANELLA, Salvatore SALOMONE, Alexandra SULCOVA, Claudio BUCOLO, Carsten T. WOTJAK, Zenon, Jr. STARCUK, Filippo DRAGO, Raphael MECHOULAM, Vincenzo DI MARZO and Vincenzo MICALE. Altered dopamine D3 receptor gene expression in MAM model of schizophrenia is reversed by peripubertal cannabidiol treatment. \textit{Biochemical Pharmacology}. OXFORD: PERGAMON-ELSEVIER SCIENCE LTD, 2020, vol.~177, July 2020, p.~1-12. ISSN~0006-2952. Available from: https://dx.doi.org/10.1016/j.bcp.2020.114004.

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