Taking cannabis during pregnancy causes behavioral and neuronal deficits in male, but not female offspring, according to the results of a new study by researchers in France, Italy, and the U.S. The study, in rats, showed that male offspring exposed to cannabinoids taken by the mother during pregnancy were less sociable and spent less time interacting with their peers than control animals. Female offspring weren't affected. The study further suggested how the adverse effects in male rats could be reversed using a drug to increase signaling levels in a specific region of the brain.

“The deleterious effects of prenatal exposure to cannabinoids on social behavior were specific to male offspring only,” explains Anissa Bara, who undertook the research as a post-graduate student in the laboratory of study head Olivier Manzoni, Ph.D., Inserm research director at the Mediterranean Institute of Neurobiology, and director of the CannaLab. “But while social interaction was specifically impaired in males, locomotion, anxiety, and cognition remained unaffected in both sexes, suggesting discrete and sex-specific behavioral consequences of cannabinoid exposure during adulthood.” Bara is co-lead author of the team’s paper, titled, “Sex-dependent effects of in utero cannabinoid exposure on cortical function,” which is published in eLife.

Research over recent years suggests that about 7.5% of women between the ages of 18 and 25 years use cannabis during pregnancy, while the rate of use in all pregnant women is about 4%, the authors write. Δ9-tetrahydrocannabinol (THC) is the major psychoactive ingredient in cannabis-based preparations including marijuana. During pregnancy the drug readily crosses the placenta to reach the fetus. The main target of THC in the brain is the cannabinoid receptor type 1 (CB1R), which is involved in endocannabinoid signaling during neurodevelopment.

“As cannabinoids can cross the placenta, they may interfere with fetal endocannabinoid signaling during neurodevelopment, which is involved in regulating a variety of processes such as pregnancy, appetite, pain sensation, and mediating the pharmacological effects of cannabis,” notes Dr. Manzoni. “This could, in turn, lead to some serious long-term deficits. But despite increasing reports of cannabis consumption during pregnancy, the long-term consequences of prenatal cannabinoid exposure remain incompletely understood.”

Prior research indicates that cannabinoid use during pregnancy has numerous adverse effects on the behavior of offspring. To further investigate this link the researchers focused on social behavior, anxiety, locomotion, and cognition in adult offspring of mothers exposed to a single daily dose of either a synthetic cannabinoid or plant-derived THC, which was equivalent to moderate cannabis use in humans. They examined how prenatal cannabinoid exposure (PCE) affected synaptic and behavioral functions in the medial prefrontal cortex — a region of the brain that has been associated with neuropsychiatric disorders — in adult male and female offspring.

The results showed that adult male PCE offspring were less social, and didn't interact to the same degree with other rats as did control animals. The affected male PCE rats sniffed and played less, but there was no increase in attacks, nor was there evidence of altered anxiety or cognition. In contrast with the effects in male animals, there was also no difference in the social behavior of female PCE offspring when compared with female controls. “Thus, while social interaction was specifically impaired in PCE males, locomotion, anxiety, and cognition were spared in both sexes,” the authors write. “These data reveal discrete and sex-specific behavioral consequences of PCE at adulthood.”

The findings that PCE led to selective impairments in social interaction but didn't cause emotional or cognitive deficits indicated that the drug impacted on specific areas of the brain, rather than across the whole brain. Further studies suggested that PCE specifically to changes in synaptic plasticity in the prefrontal cortex (PFC) of adult males, and increased excitability of medial prefrontal cortex (mPFC) pyramidal cells, but again, only in male offspring.

Gene expression analyses indicated that PCE resulted in downregulation of levels of both mGlu5 and TRPVIR mRNA levels in the mPFC of PCE males. mGlu5 is an effector of endocannabinoid signaling. Treating the PCE males with a compound known as CDPPB, which is known to increase mGlu5 signaling, effectively normalized the synaptic and behavioral deficits in the animals, partly by activating CB1R. In subsequent tests the team showed that boosting levels of the endocannabinoid anandamide, an endogenous ligand of TRPV1, also corrected synaptic and behavioral deficits associated with PCE in male offspring. 

“In conclusion, these results provide compelling evidence for sexual divergence in the long-term functional and behavioral consequences of PCE and introduce strategies for reversing its detrimental effects,” the authors write. “The data provide new impetus for the urgent need to investigate the functional and behavioral substrates of neuropsychiatric diseases in both sexes.”

“Altogether, these results provide compelling evidence for sex-specific effects of prenatal cannabinoid exposure,” comments co-first author Antonia Manduca, Ph.D., Inserm postdoctoral researcher at the Mediterranean Institute of Neurobiology. “The fact that increasing mGlu5 signaling and enhancing anandamide levels helped to reverse the negative effects of early exposure in rats also hints at a new pharmacological strategy that could one day be trialed in humans.”

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