Prenatal THC Exposure Induces Sex-Dependent Neuropsychiatric Endophenotypes in Offspring and Long-Term Disruptions in Fatty-Acid Signaling Pathways Directly in the Mesolimbic Circuitry.
Mohammed H Sarikahya, Samantha Cousineau, Marta De Felice, Kendrick Lee, Karen Kw Wong, Marieka V DeVuono, Tony Jung, Mar Rodríguez-ruiz, Tsun Hay Jason Ng, Dana Gummerson, Emma Proud, Daniel B Hardy, Ken K-C Yeung, Walter J Rushlow, Steven R Laviolette
eNeuro 2022 DOI: 10.1523/eneuro.0253-22.2022 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical experimental study in rats Peer reviewed |
|---|---|
| Population | Adult male and female offspring of pregnant Wistar rats |
| Dose | 3 mg/kg |
| Duration | Gestational day 7 to gestational day 22; assessments at prepubescence and adulthood |
| Topics | Cannabis |
| Keywords | Maldi ims Electrophysiology Lipidomics Mesolimbic system Prenatal cannabis exposure Sex differences |
| Key findings | Prenatal THC exposure in rats induced behavioral, neuronal, and molecular alterations in the mesolimbic system of offspring, resembling neuropsychiatric endophenotypes. Fatty-acid pathways in the developing brain lipidome were dysregulated, with female offspring showing prepubescent deficits that recovered by early adulthood while males had persistent deficits. Both sexes maintained enduring glutamatergic/GABAergic abnormalities in the nucleus accumbens. |
Abstract
Despite increased prevalence of maternal cannabis use, little is understood regarding potential long-term effects of prenatal cannabis exposure (PCE) on neurodevelopmental outcomes. While neurodevelopmental cannabis exposure increases the risk of developing affective/mood disorders in adulthood, the precise neuropathophysiological mechanisms in male and female offspring are largely unknown. Given the interconnectivity of the endocannabinoid (ECb) system and the brain's fatty acid pathways, we hypothesized that prenatal exposure to Δ9-tetrahydrocannabinol (THC) may dysregulate fetal neurodevelopment through alterations of fatty-acid dependent synaptic and neuronal function in the mesolimbic system. To investigate this, pregnant Wistar rats were exposed to vehicle or THC (3 mg/kg) from gestational day (GD)7 until GD22. Anxiety-like, depressive-like, and reward-seeking behavior, electrophysiology, and molecular assays were performed on adult male/female offspring. Imaging of fatty acids using matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI IMS) was performed at prepubescence and adulthood. We report that PCE induces behavioral, neuronal, and molecular alterations in the mesolimbic system in male and female offspring, resembling neuropsychiatric endophenotypes. Additionally, PCE resulted in profound dysregulation of critical fatty acid pathways in the developing brain lipidome. Female progeny exhibited significant alterations to fatty acid levels at prepubescence but recovered from these deficits by early adulthood. In contrast, males exhibited persistent fatty acid deficits into adulthood. Moreover, both sexes maintained enduring abnormalities in glutamatergic/GABAergic function in the nucleus accumbens (NAc). These findings identify several novel long-term risks of maternal cannabis use and demonstrate for the first time, sex-related effects of maternal cannabinoid exposure directly in the developing neural lipidome.
Comparable studies
Other preclinical and animal studies on cannabis, most cited first.
Citations in the library
Cited by 4
- Vaporized Δ9-tetrahydrocannabinol exposure in utero has negative effects on attention in a dose- and sex-dependent manner. Pharmacology, Biochemistry, and Behavior September 1, 2024
- Perinatal LC-ω-3-PUFA supplementation offsets prenatal THC-induced cognitive deficit via sex-specific modulation of hippocampal neuroplasticity. European Journal of Pharmacology June 1, 2026
- Prenatal THC exposure and binge-like alcohol drinking in early adolescence: From sex-specific drinking vulnerability to abnormal endocannabinoid-dopamine nexus in the nucleus accumbens. Journal of Psychopharmacology February 27, 2026
- Adolescent female rats are resistant to the affective and cognitive impacts of Δ9-tetrahydrocannabinol exposure despite long-lasting molecular and neuronal disturbances in the hippocampal-hypothalamic network. Psychopharmacology November 1, 2025
Cites 3
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