Perinatal omega-3 sex-selectively mitigates neuropsychiatric impacts of prenatal THC in the cortico-striatal-hippocampal circuit

Mohammed H Sarikahya; Samantha L Cousineau; Marta De Felice; Hanna J Szkudlarek; Kendrick Lee; Aleksandra Doktor; Amanda Alcaide; Marieka V DeVuono; Anubha Dembla; Karen Wong; Mathanke Balarajah; Sebastian Vanin; Miray Youssef; Kuralay Zhaksylyk; Madeline Machado; Haseeb Mahmood; Susanne Schmid; Ken K-C Yeung; Daniel B Hardy; Walter Rushlow; Steven R Laviolette

doi:10.1038/s41380-025-03113-x

Perinatal omega-3 sex-selectively mitigates neuropsychiatric impacts of prenatal THC in the cortico-striatal-hippocampal circuit

Mol Psychiatry. 2025 Nov;30(11):5264-5282. doi: 10.1038/s41380-025-03113-x. Epub 2025 Jul 28.

Authors

Mohammed H Sarikahya^{1

2

3}, Samantha L Cousineau⁴, Marta De Felice^{1

2

3}, Hanna J Szkudlarek^{1

2

3}, Kendrick Lee^{2

3

5

6}, Aleksandra Doktor⁴, Amanda Alcaide¹, Marieka V DeVuono^{1

2

3}, Anubha Dembla¹, Karen Wong^{1

2}, Mathanke Balarajah^{1

4}, Sebastian Vanin^{2

3

5

6}, Miray Youssef^{1

2

3}, Kuralay Zhaksylyk^{1

2

3}, Madeline Machado^{1

2

3}, Haseeb Mahmood^{1

2

3}, Susanne Schmid^{2

7}, Ken K-C Yeung⁴, Daniel B Hardy^{2

3

5

6}, Walter Rushlow^{1

2

8}, Steven R Laviolette^{9

10

11

12

13}

Affiliations

¹ Addiction Research Group, Schulich School of Medicine & Dentistry, Western University, London, ON, N6A 5C1, Canada.
² Department of Anatomy and Cell Biology, Schulich School of Medicine & Dentistry, Western University, London, ON, N6A 5C1, Canada.
³ Lawson Health Research Institute, St. Josephs Health Care, London, ON, N6C 2R5, Canada.
⁴ Departments of Chemistry and Biochemistry, Western University, London, ON, N6A 3K7, Canada.
⁵ Departments of Physiology and Pharmacology, and Obstetrics and Gynecology, Western University, London, ON, N6A 5C1, Canada.
⁶ Children's Health Research Institute, St. Josephs Health Care, London, ON, N6C 2R5, Canada.
⁷ Department of Psychology, Western University, London, ON, N6A 3K7, Canada.
⁸ Department of Psychiatry, Western University, London, ON, N6A 3K7, Canada.
⁹ Addiction Research Group, Schulich School of Medicine & Dentistry, Western University, London, ON, N6A 5C1, Canada. steven.laviolette@schulich.uwo.ca.
¹⁰ Department of Anatomy and Cell Biology, Schulich School of Medicine & Dentistry, Western University, London, ON, N6A 5C1, Canada. steven.laviolette@schulich.uwo.ca.
¹¹ Lawson Health Research Institute, St. Josephs Health Care, London, ON, N6C 2R5, Canada. steven.laviolette@schulich.uwo.ca.
¹² Department of Psychiatry, Western University, London, ON, N6A 3K7, Canada. steven.laviolette@schulich.uwo.ca.
¹³ Division of Maternal, Fetal and Newborn Health, Children's Health Research Institute, St. Josephs Health Care, London, ON, N6C 2R5, Canada. steven.laviolette@schulich.uwo.ca.

Abstract

Prenatal Δ9-tetrahydrocannabinol exposure (PTE) poses long-lasting neuropsychiatric risks, as evidenced by clinical and preclinical studies, yet the neurobiological mechanisms remain poorly defined. Emerging evidence implicates the neurolipidome, a critical mediator of neurodevelopment and endocannabinoid signaling, as a potential contributor. Here, we demonstrate that dietary omega-3 fatty acid supplementation sex-selectively ameliorates neurodevelopmental deficits induced by PTE in a Wistar rat model. Omega-3 supplementation reduced cognitive and emotional disturbances in male offspring and normalized many neuronal and neurochemical abnormalities in the prefrontal cortex, nucleus accumbens, and ventral hippocampus. However, lipidomic analyses, regardless of omega-3 supplementation, uncovered pronounced, sex-specific PTE-induced disruptions in pathways critical for synaptic integrity and neurodevelopment, including those related to the endocannabinoid system. These findings provide new insights into the interplay between lipid metabolism and the endocannabinoid system in the context of PTE.

MeSH terms

Animals
Corpus Striatum / drug effects
Corpus Striatum / metabolism
Disease Models, Animal
Dronabinol* / adverse effects
Dronabinol* / pharmacology
Endocannabinoids / metabolism
Fatty Acids, Omega-3* / metabolism
Fatty Acids, Omega-3* / pharmacology
Female
Hippocampus / drug effects
Hippocampus / metabolism
Male
Nucleus Accumbens / drug effects
Nucleus Accumbens / metabolism
Prefrontal Cortex / drug effects
Prefrontal Cortex / metabolism
Pregnancy
Prenatal Exposure Delayed Effects* / metabolism
Rats
Rats, Wistar

Substances

Fatty Acids, Omega-3
Dronabinol
Endocannabinoids