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

Abstract

Background and Purpose:Marijuana is the illicit drug most commonly used among pregnant and breastfeeding women. Different studies reported long-term adverse effects induced by in utero exposure to the main component of marijuana, Δ 9tetrahydrocannabinol (THC), both in rodents and in humans. However, little is known about any potential sex-dependent effects of marijuana consumption during pregnancy on newborns at early developmental ages. Experimental Approach:We studied the effects of prenatal exposure to the cannabinoid receptor agonist WIN55,212-2 (WIN; 0.5 mgÁkg −1 from GD5 to GD20) on the emotional reactivity and cognitive performance of male and female rat offspring from infancy through adolescence and tested the role of mGlu 5 receptor signalling in the observed effects.Key Results: Prenatally WIN-exposed male infant pups emitted less isolationinduced ultrasonic vocalizations compared with male control pups, when separated from the dam and siblings and showed increased locomotor activity while females were spared. These effects were normalized when male pups were treated with the positive allosteric modulator of mGlu 5 receptor CDPPB. When tested at the prepubertal and pubertal periods, WIN-prenatally exposed rats of both sexes did not show any difference in social play behaviour, anxiety and temporal order memory. Conclusions and Implications:We reveal a previously undisclosed sexual divergence in the consequences of fetal cannabinoids on newborns at early developmental ages, which is dependent on mGlu 5 receptor signalling. These results provide new impetus for the urgent need to investigate the functional and behavioural substrates of prenatal cannabinoid exposure in both the male offspring and the female offspring. Abbreviations: % OE, percentage of open arm entries; % TO, percentage of time spent in the open arms; CDPPB, the positive allosteric modulator of mGlu 5 receptors; CTRL, control; GD, gestational day; HDIPS, number of exploratory head dips; PND, postnatal day; SAP, number of stretched-attend postures; USVs, isolation-induced ultrasonic vocalizations; VEH, vehicle; WIN, the cannabinoid receptor agonist WIN 55,212-2.

Maternal cannabis vapor exposure causes long-term alterations in emotional reactivity, social behavior, and behavioral flexibility in offspring

“…Accordingly, our data further indicate that male (but not female) offspring exposed to CANTHC engaged in fewer social investigation behaviors than male AIR controls. However, this is somewhat inconsistent with previous rodent studies that have instead found no effects of prenatal cannabinoid exposure on social investigation (Manduca et al, 2020;Trezza et al, 2008). Importantly, the methodology and strategy for quantifying social investigation differed from ours, which may help to explain differences across studies.…”

“…While no other study to date has tested cannabinoid-exposed pups at P6, another study conducted by Trezza et al (2008) similarly documented an increase in the frequency of USVs emitted in THC-exposed offspring at P12. However, other studies have found decreased USVs in pups exposed to the synthetic cannabinoid WIN 55,212-2 (Antonelli et al, 2005;Manduca et al, 2020). It is important to note that, in addition to their use of a synthetic cannabinoid, these studies only recorded calls for the first 15 seconds of isolation in P10 pups, which may partially explain the differences between their findings and ours.…”

“…Specifically, CANTHC-exposed rats performed fewer play behaviors and pinned playmates later in the session than AIR controls. A decrease in social Maternal cannabis vapor exposure play behavior has been reported previously in THC-exposed offspring (Trezza et al, 2008), whereas others have reported no differences (Manduca et al, 2020). Accordingly, our data further indicate that male (but not female) offspring exposed to CANTHC engaged in fewer social investigation behaviors than male AIR controls.…”

“…Notably, an anxiogenic phenotype has been reported twice before in animal models of prenatal cannabinoid exposure; once using the EPM and another using the open field task (Newson and Kelly, 2008;Trezza et al, 2008). However, two other studies have indicated no differences in EPM behaviors (Bara et al, 2018;Manduca et al, 2020). Again, these incongruent findings may be due to differences in the drug employed, the route of administration, and the maternal exposure regimen.…”

Perinatal THC Exposure via Lactation Induces Lasting Alterations to Social Behavior and Prefrontal Cortex Function in Rats at Adulthood

“…The PFC is also a site of dense expression of CB1R 23 and is exquisitely sensitive to various ECS-related synaptopathies which manifest as a variety of cognitive disease states 24,25 . Previously, our lab has demonstrated that exogenous cannabinoid exposure during in utero development results in significant abnormalities in PFC synaptic function which underlie behavioral alterations lasting into adulthood in cannabinoid-exposed progeny 26,27 .…”