Effects of perinatal exposure to delta-9-tetrahydrocannabinol on the emotional reactivity of the offspring: A longitudinal behavioral study in Wistar rats

Rationale: The endocannabinoid system plays a crucial role in the control of emotionality and recent clinical findings have shown that heavy prenatal exposure to cannabis is significantly associated with self-reported anxiety symptoms in exposed children. However, the long-term neurobehavioral consequences of in utero exposure to low-moderate doses of cannabinoid compounds have never been investigated. Objective: The objective of this study was to investigate whether perinatal exposure to moderate doses of the active constituent of cannabis, the CB₁ cannabinoid receptor agonist delta-9-tetrahydrocannabinol (THC), influences the emotional reactivity of rat offspring. Methods: Primiparous Wistar rats were treated during pregnancy and lactation with doses of THC equivalent to the current estimates of moderate cannabis consumption in humans (2.5-5 mg kg^-1, per os, from gestational day 15 to postnatal day 9). The emotional reactivity of infant, adolescent, and adult offspring was investigated using the isolation-induced ultrasonic vocalization, social interaction, and elevated plus-maze tests, respectively. Results: Perinatal THC treatment did not affect parameters of reproduction; however, at the dose of 5 mg kg^-1, it increased the number of ultrasounds emitted by rat pups removed from the nest, inhibited social interaction and play behavior in the adolescent offspring, and induced an anxiogenic-like profile in the adult offspring tested in the elevated plus-maze test. Conclusion: These results suggest that the endocannabinoid system is involved in the control of emotionality since early developmental stages. Thus, even moderate doses of cannabinoid compounds, when administered during the perinatal period, can have profound consequences for brain maturation, leading to long-lasting neurodevelopmental alterations.