Vulnerability in the womb: Charting the effects of prenatal cannabinoid exposure to mitigate developmental actions on dopamine metabolic capacities and circuits.

Prenatal cannabis exposure (PCE) is increasingly recognized as a major public health concern as cannabis use during pregnancy continues to rise worldwide. While early studies focused on cannabinoid receptor-mediated alterations in neurotransmission, emerging evidence indicates that PCE induces long-lasting developmental reprogramming affecting neural circuits, metabolism, and endocrine regulation. In this roadmap, we propose a shift from viewing PCE as a discrete synaptic disturbance to considering it a disorder of developmental coordination. We discuss how prenatal cannabinoid exposure may alter mesolimbic dopamine circuit maturation through the interaction of neuronal excitability, mitochondrial bioenergetics, and stress-related hormonal signaling. Particular attention is given to mitochondrial-circuit coupling in dopaminergic neurons and the potential role of mitochondrial cannabinoid receptors (mtCB1) in shaping long-term neuronal function. We further highlight the contribution of astrocytes, microglia, and neuroimmune processes in determining vulnerability or resilience trajectories. We propose that PCE generates latent neurobiological vulnerabilities that may emerge during adolescence or later life when challenged by environmental or physiological stressors. This framework provides new opportunities for early intervention, and prevention, while also offering insights into how early-life metabolic and mitochondrial dysfunction may contribute to lifelong brain vulnerability, including increased susceptibility to age-related neurodegenerative disorders such as Alzheimer's disease.