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

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.

Sex‐specific behavioural deficits induced at early life by prenatal exposure to the cannabinoid receptor agonist WIN55, 212‐2 depend on mGlu5 receptor signalling

“…Therefore, we surmise that the sex‐specific behavioural deficits we here observed at early life stages after prenatal WIN exposure could be similar to those obtained by administering THC during the prenatal period. In support of this hypothesis, we recently demonstrated that prenatal THC administration (from GD 5 to GD 20) induced similar sex‐specific synaptic deficits in the prefrontal cortex of adult rats, without any sign of toxicity and/or gross malformations in the rat offspring as WIN did (Bara et al, ). However, in a recent inhalation mouse study, a dose of ~0.5 mg·kg −1 ·day −1 THC smoke from GD 5.5 to GD 17.5 produced deficits in fetal growth and reduced birth weights in cannabis‐exposed male offspring suggesting that low‐dose exposure to THC via inhalation can compromise fetal development (Benevenuto et al, ).…”

“…Our previous works demonstrated the ability of mGlu 5 positive allosteric modulation to correct synaptic and behavioural deficits induced by prenatal WIN exposure at adulthood (Bara et al, ). Along this line, we found that systemic treatment with the positive allosteric modulator of mGlu 5 receptors CDPPB (1.5 mg, i.p.)…”

“…Indeed, the developmentally dependent increase in endocannabinoid mobilization (that occurs between the neonatal and juvenile stages) correlates with increases in the levels of protein expression of mGlu 5 R (Liang et al, ). Based on this evidence and our recent findings on the interaction between cannabinoids and mGlu 5 R in modulating behavioural and synaptic states in the context of nutrition (Manduca et al, ) and social interaction in male offspring after in utero cannabinoid exposure (Bara et al, ), we here investigated whether the positive allosteric modulator of mGlu 5 R CDPPB normalized the behavioural deficits induced by in utero cannabinoid exposure.…”

“…Maternal exposure to cannabinoid drugs during pregnancy and/or lactation might particularly affect the ontogeny of motor behaviours: an age‐dependent hyperlocomotion has been reported in the lactating offspring of mothers receiving THC (during GD 6–12; Borgen, Lott, & Davis, ). Other studies demonstrated that rats prenatally and/or postnatally exposed to cannabinoids displayed motor hyperactivity at infancy and adolescence but not at adulthood (Bara et al, ; Mereu et al, ; Navarro et al, ; Silva, Zhao, Popp, & Dow‐Edwards, ). These preclinical studies are in line with human data showing that children of both sexes prenatally exposed to cannabis are hyperactive and impulsive starting around age 6 (Fried & Smith, ; Goldschmidt, Richardson, Cornelius, & Day, ; Sharapova et al, ).…”

“…These deficits were paralleled by decreased levels of mGlu 5 R mRNA. Amplifying mGlu 5 R signalling with a positive allosteric modulator for mGlu 5 R normalized the social and synaptic deficits displayed by male WIN‐exposed rats (Bara et al, ).…”