Sex-dependent effects of in utero cannabinoid exposure on cortical function

Anissa Bara; Antonia Manduca; Axel Bernabeu; Milene Borsoi; Michela Serviado; Olivier Lassalle; Michelle Murphy; Jim Wager-Miller; Ken Mackie; Anne-Laure Pelissier-Alicot; Viviana Trezza; Olivier J Manzoni

doi:10.7554/eLife.36234

Sex-dependent effects of in utero cannabinoid exposure on cortical function

Elife. 2018 Sep 11:7:e36234. doi: 10.7554/eLife.36234.

Authors

Anissa Bara^#^{1

2}, Antonia Manduca^#^{1

2

3}, Axel Bernabeu^{1

2

4}, Milene Borsoi^{1

2}, Michela Serviado³, Olivier Lassalle^{1

2}, Michelle Murphy^{2

5

6}, Jim Wager-Miller^{2

5

6}, Ken Mackie^{2

5

6}, Anne-Laure Pelissier-Alicot^{1

2

4

7}, Viviana Trezza³, Olivier J Manzoni^{1

2}

Affiliations

¹ Aix Marseille University, INSERM, INMED, Marseille, France.
² Cannalab, Cannabinoids Neuroscience Research International Associated Laboratory, Indiana University, Indiana, United States.
³ Section of Biomedical Sciences and Technologies, Department of Science, University Roma Tre, Rome, Italy.
⁴ APHM, CHU Conception, Service de Psychiatrie, Marseille, France.
⁵ Department of Psychological and Brain Sciences, Indiana University, Bloomington, United States.
⁶ Gill Centre, Indiana University, Bloomington, United States.
⁷ APHM, CHU Timone Adultes, Service de Médecine Légale, Marseille, France.

^# Contributed equally.

Abstract

Cannabinoids can cross the placenta, thus may interfere with fetal endocannabinoid signaling during neurodevelopment, causing long-lasting deficits. Despite increasing reports of cannabis consumption during pregnancy, the protracted consequences of prenatal cannabinoid exposure (PCE) remain incompletely understood. Here, we report sex-specific differences in behavioral and neuronal deficits in the adult progeny of rat dams exposed to low doses of cannabinoids during gestation. In males, PCE reduced social interaction, ablated endocannabinoid long-term depression (LTD) and heightened excitability of prefrontal cortex pyramidal neurons, while females were spared. Group 1 mGluR and endocannabinoid signaling regulate emotional behavior and synaptic plasticity. Notably, sex-differences following PCE included levels of mGluR1/5 and TRPV1R mRNA. Finally, positive allosteric modulation of mGlu5 and enhancement of anandamide levels restored LTD and social interaction in PCE adult males. Together, these results highlight marked sexual differences in the effects of PCE and introduce strategies for reversing detrimental effects of PCE.

Keywords: cannabis; in-utero; neuroscience; rat; sex difference; social behavior.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Allosteric Regulation / drug effects
Animals
Anxiety / pathology
Arachidonic Acids / metabolism
Behavior, Animal
Cannabinoids / pharmacology*
Endocannabinoids / metabolism
Female
Gene Expression Regulation, Developmental / drug effects
Long-Term Potentiation / drug effects
Male
Neuronal Plasticity / drug effects
Nucleus Accumbens / drug effects
Nucleus Accumbens / pathology
Polyunsaturated Alkamides / metabolism
Prefrontal Cortex / drug effects
Prefrontal Cortex / pathology
Prefrontal Cortex / physiopathology*
Pregnancy
Prenatal Exposure Delayed Effects / pathology*
Prenatal Exposure Delayed Effects / physiopathology*
Pyramidal Cells / drug effects
Pyramidal Cells / metabolism
RNA, Messenger / genetics
RNA, Messenger / metabolism
Rats, Wistar
Receptor, Cannabinoid, CB1 / metabolism
Receptor, Metabotropic Glutamate 5 / metabolism
Sex Characteristics*
Social Behavior
Social Isolation
TRPV Cation Channels / metabolism

Substances

Arachidonic Acids
Cannabinoids
Endocannabinoids
Polyunsaturated Alkamides
RNA, Messenger
Receptor, Cannabinoid, CB1
Receptor, Metabotropic Glutamate 5
TRPV Cation Channels
Trpv1 protein, rat
anandamide

Abstract

Publication types

MeSH terms

Substances

Grants and funding